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Infectious diseases,

tropical medicine and


sexually transmitted
diseases
Infection and infectious disease 19 Infections of the cardiovascular system 72
Infections of the nervous system 72 Bone
Principles and basic mechanisms 23
and joint infections 74 Urinary tract
Approach to the patient with a suspected infection 26 infections 74 Systemic/multisystem
infections 74
Antimicrobial chemotherapy 30
Bacterial infections seen in developing and tropical
Immunization against infectious diseases 41
countries 80
Viral infections: an introduction 43
Fungal infections 91
DNA viruses 43
Protozoal infections 95
RNA viruses 49
Helminthic infections 106
Transmissible spongiform encephalopathies (TSE or prion
Arthropod ectoparasites 117
disease) 60
Sexually transmitted infections 117
Bacterial infections 61
Skin and soft tissue infection 62 Human immune deficiency virus (HIV) and AIDS 129
Respiratory tract infections 64
Gastrointestinal infections 67
INFECTION AND INFECTIOUS our major conurbations have facilitated the resurgence of
tuberculosis and other infections. Prisons and refugee
DISEASE camps, where large numbers of people are forced to live
in close proximity, often under poor conditions, are
Infection remains the main cause of morbidity and
providing a breeding ground for devastating epidemics
mortality in man, particularly in underdeveloped areas
of infectious disease. There are new concerns about the
where it is associated with poverty and overcrowding. In
deliberate release of infectious agents such as smallpox or
the developed world increasing prosperity, universal
anthrax by terrorist groups or national governments.
immunization and antibiotics have reduced the preva-
In the developing world successes such as the
lence of infectious disease. However, antibiotic-resistant
eradication of smallpox have been balanced or outweighed
strains of microorganisms and diseases such as human
by the new plagues. Infectious diseases cause nearly 25% of
immunodeficiency virus (HIV) infection, variant
all human deaths (Table 2.1). Two billion people - one-third
Creutzfeldt-Jakob disease (vCJD), and severe acute
of the world's population - are infected with tuberculosis,
respiratory syndrome (SARS) have emerged. There is
500 million people catch malaria every year, and 200 million
increased global mobility, both enforced (as a result of
are infected with schistosomiasis. Infections are often
war, civil unrest, and natural disaster), and voluntary (for
multiple, and there is synergy both between different
tourism and economic benefit). This has aided the spread
infections, and between infection and other factors such as
of infectious disease and allowed previously localized
malnutrition. Many of the infectious diseases affecting
pathogens such as SARS and West Nile virus to establish
developing countries are preventable or treatable, but
themselves world-wide. An increase in the movement of
continue to thrive owing to lack of money and political will.
livestock and animals has enabled the spread of zoonotic
The climate also has consequences on diseases. The El
diseases like monkeypox, while changes in farming and
Nino Southern Oscillation (ENSO) is a climatic event
food-processing methods have contributed to an increase
originating in the Pacific Ocean that affects the weather
in the incidence of food and water-borne diseases.
world-wide, causing droughts and floods. ENSO affects,
Deteriorating social conditions in the inner city areas of
for example, the cholera risk and malaria epidemics.
19
Infectious diseases, tropical medicine and sexually transmitted diseases
Table 2.1 World-wide mortality from infectious Host-organisminteractions
diseases
____________________________________
Disease Estimated deaths Each of us is colonized with huge numbers of micro-
(in 2002/2003)
organisms (1014 bacteria, plus viruses, fungi, protozoa,
HIV/AIDS 5 million and worms) with which we coexist. The relationship with
Acute lower respiratory infection 3.8 million some of these organisms is symbiotic, in which both
Tuberculosis 2.5 million partners benefit, while others are commensals, living on
Diarrhoeal disease 1.8 million the host without causing harm. Infection and illness may
Malaria 1.2 million be due to these normally harmless commensals and
Measles 760 000
symbiotes evading the body's defences and penetrating
Tetanus 292 000
into abnormal sites. Alternatively, disease may be caused
Whooping cough 301 000
Meningitis 175 000
by exposure to exogenous pathogenic organisms which
Leishmaniasis 51 000 are not part of our normal flora.
Trypanosomiasis 48 000 The symptoms and signs of infection are a result of the
interaction between host and pathogen. In some cases,
such as the early stages of influenza, symptoms are
almost entirely due to killing of host cells by the invading
Infectious agents organism. Usually, however, the harmful effects of
infection are due to a combination of direct microbial
The causative agents of infectious diseases can be divided
pathogenicity, and the body's response to infection. In
into four groups.
meningococcal septicaemia, for example, much of the
tissue damage is caused by cytokines released in an
Prions are the most recently recognized and the simplest
attempt to fight the bacteria. In a few instances, such as
infectious agents, consisting of a single protein molecule.
chronic South American trypanosomiasis (Chagas'
They contain no nucleic acid and therefore no genetic
disease), morbidity is almost entirely immunological,
information: their ability to propagate within a host relies
with the parasite itself having little effect once the inflam-
on inducing the conversion of endogenous prion protein
matory process has been triggered. The molecular
PrPc into a protease resistant isoform PrPres.
mechanisms underlying host-pathogen interactions are
discussed in more detail on page 199.
Viruses contain both protein and nucleic acid, and so
carry the genetic information for their own reproduction.
However, they lack the apparatus to replicate auto- Sources of infection
nomously, relying instead on 'hijacking' the cellular
The endogenous skin and bowel commensals can cause
machinery of the host. They are small (usually less
disease in the host, either because they have been
than 200 nanometres in diameter) and each virus
transferred to an inappropriate site (e.g. bowel coliforms
possesses only one species of nucleic acid (either RNA or
causing urinary tract infection), or because host immunity
DNA).
has been attenuated (e.g. candidiasis in an immuno-
compromised host). Many infections are acquired from
Bacteria are usually, though not always, larger than other people, who may be symptomatic themselves or be
viruses. Unlike the latter they have both DNA and RNA, asymptomatic carriers. Some bacteria, like the meningo-
with the genome encoded by DNA. They are enclosed by coccus, are common transient commensals, but cause
a cell membrane, and even bacteria which have adopted invasive disease in a small minority of those colonized.
an intracellular existence remain enclosed within their Infection with other organisms, such as the hepatitis B
own cell wall. Bacteria are capable of fully autonomous virus, can be followed in some cases by an asymptomatic
reproduction, and the majority are not dependent on host but potentially infectious carrier state.
cells. Zoonoses are infections that can be transmitted from
wild or domestic animals to man. Infection can be
Eukaryotes are the most sophisticated infectious organ- acquired in a number of ways: direct contact with the
isms, displaying subcellular compartmentalization. animal, ingestion of meat or animal products, contact
Different cellular functions are restricted to specific with animal urine or faeces, aerosol inhalation, via an
organelles, e.g. photosynthesis takes place in the arthropod vector, or by inoculation of saliva in a bite
chloroplasts, DNA transcription in the nucleus and wound. Many zoonoses can also be transmitted from
respiration in the mitochondria. Eukaryotic pathogens person to person. Some zoonoses are listed in Table 2.2.
include unicellular protozoa, fungi (which can be uni- Most microorganisms do not have a vertebrate or
cellular or filamentous), and multicellular parasitic arthropod host but are free-living in the environment.
worms. The vast majority of these environmental organisms are
Other higher classes, notably the insects and the non-pathogenic, but a few can cause human disease
arachnids, also contain species which can parasitize man (Table 2.3). Person-to-person transmission of these infec-
and cause disease: these are discussed in more detail on tions is rare. Some parasites may have a stage of their life
page 117. cycle which is environmental (for example the free-living
20
Infection and infectious disease

Table 2.2 Zoonotic infections


Disease Pathogen Animal reservoir Mode of transmission
Prions
vCJD Priori protein Cattle Ingestion (CNS tissue)
Viral
Lassa fever Japanese Arenavirus Multimammate rat Direct contact
encephalitis Rabies Flavivirus Pigs Mosquito bite
Yellow fever Monkey Rhabdovirus Dog and other mammals Saliva, faeces (bats)
pox SARS Flavivirus Primates Mosquito bite
Orthopox virus Rodents, small mammals Uncertain Droplet
Coronavirus Civet cats and small mammals
Bacterial
Gastroenteritis Escherichia coli 0157 Cattle, chickens Ingestion (meat)
Salmonella enteritidis and others Chickens, cattle Ingestion (meat, eggs)
Campylobacter jejuni Various, e.g. chicken Ingestion (meat, milk, water)
Leptospirosis Leptospira interrogans Rodents Ingestion (urine)
Brucellosis Brucella abortus Cattle | Contact; ingestion of
Brucella melitensis Sheep, goats J milk/cheese
Anthrax Bacillus anthracis Cattle, sheep Contact; ingestion
Lyme disease Borrelia burgdorferi Deer Tick bite
Cat scratch fever Bartonella henselae Cats Flea bite
Plague Yersinia pestis Rodents Flea bite
Typhus Various Rickettsia spp. Various Arthropod bite
Psittacosis (ornithosis) Chlamydia psittaci Psittacine and other birds Aerosol
Others
Toxoplasmosis Toxoplasma gondii Cats and other mammals Ingestion (meat, faeces)
Cryptosporidiosis Cryptosporidium parvum Cattle Ingestion (faeces)
Hydatid disease Echinococcus granulosus Dogs Ingestion (faeces)
Trichinosis Thchinella spiralis Pigs, beans Ingestion (meat)
Toxocariasis Toxocara canis Dogs Ingestion
Cutaneous larva migrans Ancylostoma caninum Dogs Penetration of skin by larvae
Leishmaniasis Leishmania spp. Dogs Ingestion
vCJD, variant Creutzfeldt-Jakob disease; SARS, severe acute respiratory syndrome
larval stage of Secretions containing the
Strongyloides stercomlis infectious agent are
and the hookworms) even coughed, sneezed, or
though the adult worm breathed out, and are then
requires a vertebrate inhaled by a new victim.
host. Other pathogens can Some enteric viral
survive for periods in infections may also be
water or soil and may be spread by aerosols of
transmitted from host to faeces or vomit.
host via this route (see Environmental pathogens
below): these should not such as Legionella
be confused with true pneumophila, and zoonoses
environmental organisms. such as psittacosis, are
also acquired by aerosol
inhalation, while rabies
Routes of virus may be inhaled in
transmission the dust from bat
droppings.
Endogenous infection
The body's own
Faeco-oral spread
endogenous flora can
Transmission of
cause infection if the
organisms by the faeco-
organism gains access to
oral route can occur by
an inappropriate area of
direct transfer (usually in
the body. This can happen
small children), by
by simple mechanical
contamination of clothing
transfer, for example
or household items
colonic bacteria entering
(usually in institutions or
the female urinary tract.
conditions of poor
The non-specific host
hygiene), or most
defences may be breached,
commonly via
for example by cutting or
contaminated food or
scratching the skin and
water. Human and animal
allowing surface
faecal pathogens can get
commensals to gain
into the food supply at
access to deeper tissues;
any stage. Raw sewage is
this is frequently the
used as fertilizer in many
aetiology of cellulitis.
parts of the world,
There may be more
contaminating growing
serious defects in host
vegetables and fruit. Poor
immunity owing to
personal hygiene can
disease or chemotherapy,
result in contamination
allowing normally
during production,
harmless skin and bowel
packaging, preparation or
flora to produce invasive
serving of foodstuffs. In
disease.
the western world, the
centralization of food
Airborne spread
supply and increased
Many respiratory tract
processing of food has
pathogens are spread
allowed the potential for
from person to person
relatively minor episodes
by aerosol or droplet
of contamination to cause
transmission.
widely disseminated
outbreaks of food-borne
infection.
Infectious diseases, tropical medicine and se>
Table 2.3 Environmental organisms which can cause Table 2.4 Infections transmitted by arthropod
human infection vectors
Organism Disease (most common Disease
presentations) Infective organism
Vector
Bacteria
Burkholderia pseudomallei Melioidosis Dengue Yellow
Burkholderia cepacia Lung infection in cystic fibrosis fever West Nile
Flavivirus Mosquito
Pseudomonas spp. Various fever J Scrub
Legionella pneumophila Legionnaires' disease typhus Rickettsial
(pneumonia) spotted
Bacillus cereus Listeria Gastroenteritis fevers Tick-
monocytogenes Various Tetanus borne
Clostridium tetani Gangrene, septicaemia relapsing fever
Clostridium perfringens Pulmonary infections Louse-borne
Mycobacteria other than relapsing fever
Fungi Carrion's disease
tuberculosis
Candida sp. (MOTT) Local and disseminated Lyme disease
infection Plague Malaria
Cryptococcus Meningitis, pulmonary infection Lymphatic filariasis
neoformans Histoplasma Pulmonary infection Pulmonary
capsulatum Coccidioides infection Mucormycosis Onchocerciasis
immitis Mucor spp. (rhinocerebral, Leishmaniasis
cutaneous) African
Sporothrix schenkii Lymphocutaneous trypanosomiasis
sporotrichosis South American
Blastomyces dermatitidis Pulmonary infection trypanosomiasis
Aspergillus fumigatus Pulmonary infections

Orientiae tsutsugamushi Mite


Water-borne faeco-oral spread is usually the result of Rickettsia sp. Hard tick
inadequate access to clean water and safe sewage dis-
posal, and is common throughout the developing world. Borrelia duttoni Borrelia Soft tick
Global coverage for access to clean drinking water is 83%
recurrentis Body louse
of the world population but global sanitation coverage is
currently 58%. Sandfly
Bartonella bacilliformis
Borrelia burgdorferi Hard tick
Vector-borne disease Yersinia pestis Flea
Many tropical infections, including malaria, are spread Plasmodium sp. Mosquito
from person to person or from animal to person by an Wuchereria bancrofti Mosquito
arthropod vector. Vector-borne diseases are also found in Brugia malayi Mosquito
temperate climates, but are relatively uncommon. In most Onchocerca volvulus Blackfly
cases part of the parasite life cycle takes place within the Leishmania sp. Sandfly
body of the arthropod, and each parasite species requires Trypanosoma brucei Tsetse fly
a specific vector. Simple mechanical transfer of infective
Reduviid
organisms from one host to another can occur, but is rare.
bug
Some vector-borne diseases are shown in Table 2.4. Trypanosoma cruzi

Direct person-to-person spread


Organisms can be passed on directly in a number of ways. equipment, when infected medical equipment is reused, if
Sexually transmitted infections are dealt with on page 117. contaminated blood or blood products are transfused, or in
Skin infections such as ringworm, and ectoparasites such any sporting or accidental contact when blood is spilled.
as scabies and head lice, can be spread by simple skin-to-
skin contact. Other organisms are passed on by blood- (or Direct inoculation
occasionally other body fluid) to-blood transmission. In Infection can occur when pathogenic organisms breach
some cases such as HIV and hepatitis B virus this is the the normal mechanical defences by direct inoculation.
only route: in others such as malaria and Chagas' disease it Some of the circumstances in which this can occur are
is an unusual alternative to the normal arthropod vector. covered under endogenous infection and blood-to-blood
Blood-to-blood transmission can occur during sexual
transmission above. Some environmental organisms may
contact, from mother to infant peripartum, between
be inoculated by accident: this is a common mode of
intravenous drug users sharing any part of their injecting
transmission of tetanus and certain fungal infections.
Rabies virus may be inoculated by the bite of an infected
animal.

Consumption of infected material


Although many food-related zoonotic infections are due
to contamination of food with animal faeces (and are
thus, strictly speaking, faeco-oral), several diseases are
transmitted directly in animal products. These include
some strains of salmonella (eggs, chicken meat), brucellosis
(unpasteurized milk), and the prion diseases kuru and
vCJD (neural tissue).
Prevention and control is the only natural reservoir of infection, it may be
possible to eliminate disease by an intensive pro-
Methods of preventing infection depend upon the source gramme of case finding, treatment and immunization.
and route of transmission, as described above. This has been achieved in the case of smallpox. If there
■ Eradication of reservoir. In a few diseases, for which man is an animal or environmental reservoir complete
22
Principles and basic mechanisms
eradication is unlikely, but local control methods may Table 2.5 Notifiable diseases in England & Wales
decrease the risk of human infection (for example under the Public Health (Infectious Diseases)
killing of rodents to control plague, leptospirosis, and Regulations 1988
other diseases).
Acute encephalitis
■ For arthropod-vector-borne infections:
Acute poliomyelitis
- destroying vector species (which may be practical Anthrax
in certain circumstances) Cholera
- taking measures to avoid being bitten (e.g. insect Diphtheria
repellent sprays, bed nets). Dysentery (amoebic or bacillary)
■ For food-borne infections. Improvements in food Food poisoning
handling and preparation result in less contamination Leprosy
during processing, transport or preparation. Organisms Leptospirosis
intrinsically present in food can be killed by appro Malaria
Measles
priate preparation and cooking. Improved surveillance
Meningitis
and regulation of the food industry, as well as better
Meningococcal septicaemia (without meningitis)
health education for the public is necessary. Mumps
■ For faeco-oral infections. Thirty per cent of the world's Ophthalmia neonatorum
population do not have access to adequate safe Paratyphoid fever
drinking water, and over half do not have adequate Plague
sanitation. Improvements in water supply could Rabies
dramatically decrease the prevalence of faeco-oral Relapsing fever
infections. Rubella
■ For blood-borne infections. Prevention of blood transfer, Scarlet fever
Smallpox
e.g. in blood transfusions and contaminated medical
Tetanus
equipment. Donated blood is routinely tested for
Tuberculosis
infection in most developed countries. Typhoid fever
■ For infections spread by airborne and direct contact. Some Typhus
airborne-transmitted respiratory infections, and some Viral haemorrhagic fever
infections spread by direct contact, can be controlled Viral hepatitis
by isolating patients. This is often difficult, but Whooping cough
isolation is useful in patients with severe immuno Yellow fever
deficiency to protect them from infection.
■ Immunization (p. 42).
disease. This may result from inoculation of damaged
Cases of some infectious diseases should be notified to the
tissues, tissue invasion, a variety of virulence factors or
public health authorities so that they are aware of cases
toxin production.
and outbreaks. Diseases that are notifiable in England
and Wales are listed in Table 2.5.
Specificity
FURTHER READING Microorganisms are often highly specific with respect to
Kovats, RS et al. (2003) El Nino and health. Lancet 362: the organ or tissue they infect. For example, a number of
1481-1489. Health Protection viruses are hepatotropic, such as those responsible for
Agency website:
hepatitis A, B, C and E and yellow fever. This predilection
http://www.hpa.org.uk [Various authors] (2000)
Articles on all aspects of for specific sites in the body relates partly to the
zoonoses. Revue Scientifique et Technique 19(1): immediate environment in which the organism finds
33-317. World Health Report 2003. Online. itself; for example, anaerobic organisms colonize the
Available: anaerobic colon, whereas aerobic organisms are generally
http://www.who.int/whr/2003/en. found in the mouth, pharynx and proximal intestinal
tract. Other organisms that show selectivity include:
■ Streptococcus pneumoniae (respiratory tract)
■ Escherichia coli (urinary and alimentary tract).
PRINCIPLES AND BASIC Even within a species of bacterium such as E. coli, there
MECHANISMS are clear differences between strains with regard to their
ability to cause gastrointestinal disease (p. 69), which in
Man constantly interacts with the world of micro - turn differ from uropathogenic E. coli responsible for
organisms from birth to death. The majority cause no urinary tract infection.
harm and some play a role in the normal functioning of Within an organ a pathogen may show selectivity for a
the mouth, vagina and lower intestinal tract. However, particular cell type. In the intestine, for example, rota-
many microorganisms have the potential to produce virus predominantly invades and destroys intestinal
23
Infectious diseases, tropical medicine and sexually transmitted diseases
epithelial cells on the upper portion of the villus, whereas pneumoniae). Antigenic variation is an additional mechan-
reovirus selectively enters the body through the specialized ism for evading host defences that is recognized in
epithelial cells, known as M cells, that cover the Peyer's viruses (antigenic shift and drift in influenza), bacteria
patches (see p. 287). (flagella of salmonella and gonococcal pili), and protozoa
(surface glycoprotein changes in Trypanosoma).
Pathogenesis Epithelial attachment
Figure 2.1 summarizes some of the steps that occur Many bacteria attach to the epithelial substratum by
during the pathogenesis of infection. In addition, specific organelles called pili (or fimbriae) that contain a
pathogens have developed a variety of mechanisms to surface lectin(s) - a protein or glycoprotein that recognizes
evade host defences. For example, some pathogens specific sugar residues on the host cell. This family of
produce toxins directed at phagocytes - Staphylococcus molecules is known as adhesins (see p. 198). Following
aureus (a-toxin), Strep, pyogenes (streptolysin) and attachment, some bacteria, such as coagulase-negative
Clostridium perfringens (y-toxin), while others such as staphylococci (Staph. epidermidis), produce an extracellular
Salmonella spp. and Listeria monocytogenes can survive slime layer and recruit additional bacteria, which cluster
within macrophages. Several pathogens possess a capsule together to form a biofilm. These biofilms can be difficult
that protects against complement activation (Strep. to eradicate, and are a frequent cause of medical device-
associated infections which affect prosthetic joints and
heart valves as well as indwelling catheters. Some viruses
Pathogen entry (e.g. HIV) and protozoa (e.g. Plasmodium spp., Entamoeba
histolytica) attach to specific target-cell receptors. Other
Epithelial attachment parasites such as hookworm have specific attachment
or inoculation organs (buccal plates) that firmly grip the intestinal

I epithelium.

Multiplication
Colonization
Following epithelial attachment, pathogens may either
Colonization remain on the surface epithelium or within the lumen of

r
the organ they have colonized. Tissue invasion may

1
follow.
Invasion may result in:

Luminal/superficial ■ an intracellular location for the pathogen (e.g. viruses,


Tissue invasion
epithelial infection Toxoplasma gondii, Mycobacterium spp., Plasmodium
e.g. V. cholerae T. spp.)
vaginalis ■ an extracellular location for the pathogen (e.g.
Dermatophytoses
pneumococci, £. coli and Entamoeba histolytica)
X ■ invasion directly into the blood or lymph circulation
Extracellular
(e.g. schistosome schistosomula and trypanosomes).
Once the pathogen is firmly established in its target
e.g. Staphylococcus sp.
tissue, a series of events follows that usually culminates
E. histolytica
in damage to the host.
Intracellular Circulation
(blood/lymph) Tissue dysfunction or damage
e.g. Viruses e.g. Plasmodium sp. Microorganisms produce disease by a number of well-
Toxoplasma Filariasis
defined mechanisms:
Bacteraemias

^J Exotoxins and endotoxins


m Exotoxins have many diverse activities including
inhibition of protein synthesis (diphtheria toxin),
neurotoxicity (Clostridium tetani and C. botulinum) and
enterotoxicity, which results in intestinal secretion of
Cell/tissue injury
water and electrolytes (E. coli, Vibrio cholerae).
■ Endotoxin is a lipopolysaccharide (LPS) in the cell wall
of Gram-negative bacteria. It is responsible for many
of the features of septic shock (see p. 967), namely
e.g. Cytotoxin
hypotension, fever, intravascular coagulation and,
e.g. Enterotoxin
(V. cholerae, (Diphtheria, at high doses, death. The effects of endotoxin are
E coli) gas gangrene) mediated predominantly by release of tumour
necrosis factor.
Fig. 2.1 The pathogenesis of infection.
24
Principles and basic mechanisms
Staph. aureus presents an excellent example of the Immunological defences
repertoire of microbial virulence. The clinical expression Antibody and cell-mediated immune mechanisms play a
of disease varies according to site, invasion and toxin vital role in combating infection. All organisms can
production and is summarized in Table 2.6. Furthermore, initiate secondary immunological mechanisms, such as
host susceptibility to infection may be linked to genetic or complement activation, immune complex formation and
acquired defects in host immunity that may complicate antibody-mediated cytolysis of cells. The immunological
intercurrent infection, injury, ageing and metabolic response to infection is described in Chapter 4.
disturbances (Table 2.7).

Host response to infection


Natural defences
Metabolic and immunological
The natural host defences to infection are those of an
consequences of infection____________
intact surface epithelium with local production of Fever
secretions, antimicrobial enzymes (e.g. lysozyme in the Body temperature is controlled by the thermoregulatory
eye) and in the stomach, gastric acidity. The mucociliary centre in the anterior hypothalamus in the floor of the
escalator of the large airways is unique to the lung, third ventricle. Gram-negative bacteria contain lipo-
polysaccharide (LPS) and peptidoglycan, which is also a
component of Gram-positive bacterial cell walls. Toll-like
Table 2.6 Clinical conditions produced by receptors (TLR, p. 202) on monocytes and dendritic cells
Staphylococcus aureus recognize these lipopolysaccharides and generate signals
leading to formation of inflammatory cytokines, e.g. IL-1,
Due to Invasion Bones and joints -6, -12, TNF-oc and many others. These cytokines act on
Skin Osteomyelitis, arthritis
Furuncles
the thermoregulatory centre by increasing prostaglandin
Cellulitis Miscellaneous (PGE2) synthesis. The antipyretic effect of salicylates is
Impetigo Parotitis brought about, at least in part, through its inhibitory
Carbuncles Pyomyositis effects on prostaglandin synthase.
Septicaemia Fever production has a positive effect on the course of
Lungs Enterocolitis infection. However, for every 1°C rise in temperature,
Pneumonia there is a 13% increase in resting metabolic rate and
Lung abscesses Due to toxin oxygen consumption. Fever therefore leads to increased
Staphylococcal food
energy requirements at a time when anorexia leads to
Heart poisoning
decreased food intake. The normal compensatory mech-
Endocarditis Scalded skin syndrome
Pericarditis Bullous impetigo anisms in starvation (e.g. mobilization of fat stores) are
Staphylococcal scarlet fever inhibited in acute infections. This leads to an increase in
Central nervous system Toxic shock syndrome skeletal muscle breakdown, releasing amino acids, which,
Meningitis via gluconeogenesis, are used to provide energy.
Brain abscesses
Tumour necrosis factor (TNF)
Table 2.7 Examples of host factors that increase
TNF-a is released from a variety of phagocytic cells
susceptibility to staphylococcal infections
(macrophages/monocytes) and TNF-fS from non-
(predominantly S. aureus)
phagocytic cells (lymphocytes, natural killer cells) in
Injury to skin or mucous Abnormal leucocyte response to infections (bacterial endotoxin) and inflam-
membranes function matory stimuli. TNF itself then stimulates the release of a
Abrasions Job's syndrome Chediak- cascade of other mediators involved in inflammation and
Trauma (accidental or Higashi syndrome Steroid tissue remodelling, such as interleukins (IL-1 and IL-6),
surgical) therapy Drug-induced prostaglandins, leukotrienes and corticotropin. TNF is
Burns Insect leucopenia therefore responsible for many of the effects of an
bites infection.
Postvlral infections The biological behaviour of the pathogen and the
Metabolic abnormalities Influenza
consequent host response are responsible for the clinical
Diabetes mellitus
Uraemia Miscellaneous conditions expression of disease that often allows clinical recog-
Excess alcohol consumption nition. The incubation period following exposure can be
Foreign bodies* Malnutrition Malignancies helpful (e.g. chickenpox 14-21 days). The site and
Intravenous and other Old age distribution of a rash may be diagnostic (e.g. shingles)
indwelling catheters while symptoms of cough, sputum and pleuritic pain
Cardiac and orthopaedic point to lobar pneumonia. Fever and meningismus
prosthesis characterize classical meningitis. Infection may remain
Tracheostomies localized or become disseminated and give rise to the
* Often Staphylococcus epidermidis sepsis syndrome and disturbances of protein metabolism
25
Infectious diseases, tropical medicine and sexually transmitted diseases
FURTHER READING Clinical examination
Bassler BL (2002) Small talk: cell-to-cell communication
in bacteria. Cell 109: 421^24. Ghannoum M, O'Toole A thorough examination covering all systems is required.
GA (2004) Microbial Biofilm. Skin rashes and lymphadenopathy are common features of
Washington DC: ASM Press. Opal SM, infectious diseases, and the ears, eyes, mouth and throat
DePalo V (2000) Anti-inflammatory should also be inspected. Infections commonly associated
cytokines. Chest 117:1162-1172. Opal SM, Huber CE with a rash are listed in Box 2.1. Rectal, vaginal and penile
(2002) The toll-like receptors and examination is required in sexually transmitted infections.
their role in septic shock. Critical Care 6: 125-136. The fever pattern may occasionally be helpful, e.g. the
Vallance BA, Finlay BB (2000) Exploitation of host cells
tertian fever of falciparum malaria, but too much weight
by enteropathogenic Escherichia coli. Proceedings of
the National Academy of Sciences of the United States of should not be placed on the pattern or degree.
America 97(16): 8799-8806.
Investigations
In some infections such as chickenpox the clinical
and acid-base balance (Ch. 15). Many infections are self- presentation is so distinctive that no investigations are
limiting, and immune and non-immune host defence normally necessary to confirm the diagnosis. Other cases
mechanisms will eventually clear the pathogens. This is require investigation.
generally followed by tissue repair, which may result in
complete resolution or leave residual damage.
APPROACH TO THE PATIENT Sox 2.1 Infections commonly associated with a
rash
WITH A SUSPECTED INFECTION
Macular/maculopapular
Infectious diseases can affect any organ or system, and Measles
can cause a wide variety of symptoms and signs. Fever is Rubella
Enteroviruses
often regarded as the cardinal feature of infection, but not
Human herpesvirus 6
all febrile illnesses are infections, and not all infectious
Epstein-Barr virus
diseases present with a fever. History-taking and Cytomegalovirus
examination should aim to identify the site(s) of infection, Parvovirus
and also the likely causative organism(s). Human immunodeficiency virus (HIV)
Dengue
Typhoid
History Secondary syphilis
A detailed history is taken with specific questions about Rickettsia - spotted fevers
epidemiological risk factors for infection. These are based Vesicular
on the sources of infection and routes of transmission Chickenpox (herpes zoster virus)
discussed above. Shingles (herpes zoster virus)
Herpes simplex virus
■ Travel history: some diseases are more prevalent in Hand, foot and mouth disease (Coxsackie virus)
certain geographical locations, and many infections Herpangina (Coxsackie virus)
common in the tropics are seen rarely if at all in the UK.
Petechial/haemorrhagic
■ Food and water history: systemic as well as gastro- Meningococcal septicaemia
enteric infections can be caught via this route. Any septicaemia with disseminated intravascular
■ Occupational history. coagulation (DIC)
■ Animal contact: domestic, farm and wild animals can Tick typhus Viruses
all be responsible for zoonotic infection. (Table 2.23)
■ Sexual activity: as well as the traditional sexually trans Erythematous
mitted diseases, HIV, hepatitis B and very occasionally Scarlet fever
hepatitis C can all be transmitted sexually. Some enteric Lyme disease (erythema chronicum migrans)
infections are more common among male homosexuals. Toxic shock syndrome
■ Intravenous drug use: as well as blood-borne viruses,
Urticarial
drug injectors are susceptible to a variety of bacterial Toxocariasis Strongyloidiasis
and fungal infections due to inoculation. Tattooing, Schistosomiasis Cutaneous
body piercing and receipt of blood products (especially larva migrans
outside the UK) are also risk factors for blood-borne
viruses. Others
Tick typhus (eschar) Primary
■ Leisure activities: certain pastimes may predispose to
syphilis (chancre) Anthrax
water-borne infections or zoonoses. (ulcerating papule)
261
Approach to the patient with a suspected infection
2
General investigations (to assess health and Box 2.2 General investigations for a patient with
identify organ(s) involved) suspected infection
These will vary depending on circumstances: Investigation Possible cause
■ Blood tests. Routine blood count, ESR and C-reactive Full blood count
protein, biochemical profile, urea and electrolytes are Neutrophilia Bacterial infection
performed in the majority of cases (Box 2.2). Neutropenia Viral infection H,
Brucellosis
■ Imaging. X-ray, ultrasound, echocardiography, CT
Typhoid
and MR scanning are used to identify and localize
Typhus
infections. Biopsy or aspiration of tissue for micro Overwhelming sepsis
biological examination may also be facilitated by Lymphocytosis Viral infection
ultrasound or CT guidance. Lymphopenia Atypical HIV infection (not specific)
■ Radionuclide scanning after injection of indium- or lymphocytes Infectious mononucleosis
technetium-labelled white cells (previously harvested Eosinophilia Invasive parasitic infection
from the patient) may occasionally help to localize Thrombocytopenia Overwhelming sepsis
infection. It is most effective when the peripheral Malaria
white cell count is raised, and is of particular value in ESR or C-reactive All
localizing occult abscesses. protein Urea and Potentially deranged in
severe illness from any
electrolytes
cause
Microbiological investigations (to identify
causative organism) Non-specific feature of
Diagnostic services range from simple microscopy to Liver enzymes
many infections Mild
molecular probes. It is often helpful to discuss the clinical Minor elevation of
viral hepatitis Viral
transferases
problem with a microbiologist to ensure that appropriate hepatitis (usually A,
tests are performed, and that specimens are collected and Grossly deranged
Bor E)
transported correctly. transferases, elevated
bilirubin May be deranged in
Microscopy and culture hepatitis, and in
Coagulation overwhelming infection
Specimens to be sent for microscopy and culture
(Box 2.3). of any type
Box 2.3 Specimens and indications for microscopy and culture

Specimen Investigation
Blood Giemsa stain for malaria
Stains for other parasites
Culture
Urine Microscopy and culture
Tuberculosis (TB) culture

Faeces

Throat swabs

Sputum

Cerebrospinal fluid
Indication
Any symptomatic traveller returning from a malarious area
Specific tropical infections
Rash aspirate: All suspected bacterial infections
Petechial All suspected bacterial infections
Suspected TB

«-
Vesicular
Unexplained leucocytes in urine
Microscopy ± iodine stain Suspected protozoal diarrhoea
Culture
Electron microscopy/viral culture
(not usually necessary to do both)
J
Clostridium difficile toxin Culture
Viral culture

All unexplained diarrhoea


Suspected viral diarrhoea in children
Microscopy and culture Viral meningitis
Auramine stain/TB culture Diarrhoea following hospital stay or antibiotic treatment
Other special stains/cultures Suspected bacterial tonsillitis and pharyngitis
Viral meningitis
Microscopy and culture Viral respiratory infections where urgent diagnosis is
Auramine stain/TB culture considered necessary Unusual
Other special stains/cultures chest infections; pneumonia
Suspected TB
Polymerase chain reaction

Microscopy and culture Viral


culture
Immunocompromised patients Suspected fungal
infections Suspected meningitis Suspected TB, meningitis
Immunocompromised patients Suspected fungal
infections Suspected encephalitis or viral or bacterial
meningitis

Meningococcal disease
Herpes simplex/zoster
Infectious diseases, tropical medicine and sexually transmitted diseases
■ Blood and urine should routinely be sent for bacterial Serious infections may require supportive therapy in
culture regardless of whether fever is present at the addition to antibiotics. It is always preferable to have a
time. definite microbial diagnosis before starting treatment, so
■ Cerebrospinal fluid, sputum and biopsy specimens are that an antibiotic with the most appropriate spectrum of
sent if clinically indicated. activity and site of action can be used. However, some
■ Special culture techniques are required for fungi, myco- patients are too unwell to wait for results (which in the
bacteria, and some other bacteria such as Brucella spp., case of culture may take days). In diseases such as
and the laboratory must be informed if these are meningitis or septicaemia delay in treatment may be fatal
suspected. and therapy must be started on an empirical basis.
■ Faeces should not routinely be sent for viral investi Appropriate samples for culture should be taken before
gations: viral gastroenteritis is rare except in infants the first dose of antibiotic, and an antibiotic regimen
and the institutionalized elderly, and is self-limiting. chosen on the basis of the most likely causative
Protozoa should be considered as a cause of diarrhoea organisms. Usually patients are less unwell, and specific
in returning travellers, immunocompromised patients, therapy can be deferred pending results. Antibiotic
toddlers, homosexual men, farm workers, and in any therapy is discussed in more detail on page 30.
cases of prolonged unexplained diarrhoea. Detection
of a specific clostridial toxin is a more reliable test for
diarrhoea caused by Clostridium difficile than culture of Special circumstances
the organism itself. Stool culture is a costly routine test Overseas travellers. A detailed travel itinerary,
and is often requested indiscriminately. including any flight stopovers should be taken from
anyone who is unwell after arriving in this country from
Immunodiagnostic tests abroad. Previous travel should also be covered as some
These can be divided into two types: infections may be chronic or recurrent. It is necessary to
find out not just which countries were visited but also the
■ tests that detect viral or bacterial antigen, using a
type of environment: a stay in a remote jungle village
polyvalent antiserum or a monoclonal antibody carries different health risks from a holiday in an air-
■ tests that detect serological response to infection. conditioned coastal holiday resort. Food and water
These investigations are valuable in the identification of consumption, bathing and swimming habits, animal and
organisms that are difficult to culture, especially viruses insect contact, and contact with human illness all need to
and fungi, and can also be helpful when antibiotics have be recorded. Enquiry should be made about sexual
been administered before samples were obtained. How- contacts, drug use and medical treatment (especially
ever, care is needed in the interpretation of serological parenteral) while abroad. In some parts of the world over
tests. Elevated antibody titres on a single occasion 90% of professional sex workers are HIV positive, and
(especially of IgG) are rarely diagnostic, and in some hepatitis B and C are very common in parts of Africa and
infections it may be difficult to distinguish between old Asia. In addition to the investigations described in the
and acute infection. Paired serological tests a few weeks previous section, special tests may be needed depending
apart, or specific assays for IgM (indicating an acute on the epidemiological risks and clinical signs, and
infection) are more helpful. malaria films are mandatory in anyone who is unwell
after being in a malarious area. Some of the more com-
Nucleic acid detection mon causes of a febrile illness in returning travellers to
Specific genes from many pathogenic microorganisms the UK are listed in Table 2.8.
have been cloned and sequenced. Nucleic acid probes can
be designed to detect these sequences, identifying
pathogen-specific nucleic acid in body fluids or tissue.
The utility of this approach has been greatly enhanced by Table 2.8 Causes of febrile illness in travellers
the development of amplification techniques such as the
Tropical countries
polymerase chain reaction (PCR), which increases the
Malaria
amount of target DNA/RNA in the sample to be tested. Schistosomiasis
However PCR assays for many organisms are still in the Dengue Tick
process of development. typhus

Treatment Economically less-


developed countries
Many infections, particularly those caused by viruses, are Typhoid
self-limiting and require no treatment. The mainstay of Tuberculosis
treatment for most infectious diseases is antimicrobial Dysentery
chemotherapy. The choice of antibiotic should be Hepatitis A
governed by: Amoebiasis
■ the clinical state of the patient returning to the UK
the likely cause of the infection.
Specific geographical areas
(see text)
Histoplasmosis
Brucellosis

World-wide
Pneumonia
URTI
UTI
Traveller's diarrhoea
Viral infection URTI, upper respiratory tract infection; UTI, urinary tract infection
28 1
Approach to the patient with a suspected infection

Immunocompromised patients. Advances in medical like Lassa fever, and concerns about the bioterrorist use of
treatment over the past three decades have led to a huge agents such as smallpox mean that there is still the
increase in the number of patients living with immuno- potential for unexpected outbreaks of life-threatening
deficiency states. Cancer chemotherapy, the use of disease. During the world-wide SARS outbreak in 2003,
immunosuppressive drugs and the world-wide AIDS scrupulous infection control procedures reduced spread
epidemic have all contributed to this. The presentation of infection. However, in the 'inter-epidemic' period it is
may be very atypical in the immunocompromised patient difficult to maintain the same level of 'alert'. HCWs
with few, if any, localizing signs or symptoms. Infection should remain vigilant because the early symptoms of
can be due to organisms which are not usually pathogenic, many of these diseases are non-specific.
including environmental bacteria and fungi. The normal
physiological responses to infection (e.g. fever, neutro-
philia) may be diminished or absent. The onset of
Pyrexia of unknown origin______________
symptoms may be sudden, and the course of the illness History, clinical examination and simple investigation
fulminant. A high index of suspicion for infections in will reveal the cause of a fever in most patients. In a small
people who are known to be immunosuppressed is number, however, no diagnosis is apparent despite
required. These patients should usually be given early continuing symptoms. The term pyrexia (or fever) of
and aggressive antibiotic therapy without waiting for the unknown origin (PUO) is sometimes used to describe this
results of investigations. Samples for culture should be problem. Various definitions have been suggested for
sent before starting treatment, but therapy should not be PUO: a useful one is 'a fever persisting for > 2 weeks,
delayed if this proves difficult. The choice of antibiotics with no clear diagnosis despite intelligent and intensive
should be guided by the likely causative organisms: these investigation'. Patients who are known to have HIV or
are shown in Box 2.4. other immunosuppressing conditions are normally
excluded from the definition of PUO, as the investigation
Highly transmissible infections. Relatively few and management of these patients is different.
patients with infectious disease present a serious risk to Successful diagnosis of the cause of PUO depends on
healthcare workers (HCW) and other contacts. However, a knowledge of the likely and possible aetiologies. These
the appearance of diseases like severe acute respiratory have been documented in a number of studies, and are
syndrome (SARS), the occasional importation of zoonoses summarized in Box 2.5.

Sox 2.4 Common causes of infection in immunocompromised patients


Defic Sple Causes Orga d are) s
ienc nect nism e Cryptococc i
y omy Chemother s N
r us n
apy e
Neutr E m neoforman f
Myeloablati i
openi s i s l
ve therapy s
a c d Candida u
Immunosu s
i spp. e
ppressant h e
s Cryptospori n
drugs e r
dium z
r i
A parvum a
i a
s Pneumocys e
c
p tis carinii
Cellul h m
HIV e Toxoplasm M
ar i e
infecti r a gondii a
immu a n
on g l
ne H i
Lymp a
defec c i a
homa n r
ts o l e
Myelo g i
l l m
ablati i a
l u o
ve t
s p
thera i
K h d
py s
l i i
Cong p
e l s
enital p
b u
syndr
s . s
omes N
i .
e C i
l a n
Hum g
oral l n f o
imm a d l n
une i u o
defici p d e r
encie n a n r
s Congenital e z h
syndromes u s a o
Chronic m p e e
lymphocyti o p
Te a
c n . S
r e
leukaemia i t
m Resp
Corticoster r S
i a irator
oids e t
n e y
a p r
Congenital sync
l syndromes S t e
ytial
o p
t virus
c c ,
a Cyto
S
o p meg o
u p
m h alovir c
r n
p y us c
g e
l l Epst u
e u
e o ein- s
m r m
c Barr
e y o
o virus p
n n
c Herp n
t T i
c es e
r a
u simpl u
d a e
s ex m
e u and o
f m N
a zost n
i a .
u er i
c Salm a
r m
i onell e
e e
e a
u n
n spp.
s E i
c Myc n n
i obac
S t g
e teriu
t e i
s m
a r t
spp. o
( p i
(esp.
h v d
C M.
. i i
5 aviu
- r s
m-
C e u
intra
9 p s H
cellul
) i e .
Infectious diseases, tropical medicine and sexually transmitted diseases
o Box 2.5 Causes of pyrexia of unknown origin
Infection (20-40%)
and temporal artery biopsy should be considered in the
elderly (p. 583). Bronchoscopy can be used to obtain
samples for microbiological and histological examination
Pyogenic abscess if sputum specimens are not adequate. Serological tests
Tuberculosis
have greatly improved the diagnosis of infectious causes
Infective endocarditis
Toxoplasmosis of PUO, but should be used with caution. The more tests
Epstein-Barr virus (EBV) infection that are done, the greater is the danger of a false positive
Cytomegalovirus (CMV) infection or misleading result, and serological tests should only be
Primary HIV infection ordered and interpreted in the context of the clinical
Brucellosis findings and epidemiology.
Lyme disease
Malignant disease (10-30%) Treatment of a patient with a persistent fever is aimed at
Lymphoma the underlying cause, and if possible only symptomatic
Leukaemia treatment should be used until a diagnosis is made. Blind
Renal cell carcinoma antibiotic therapy may make diagnosis of an occult infec-
Hepatocellular carcinoma tion more difficult, and empirical steroid therapy may
Collagen vascular disease (15-20%) mask an inflammatory response without treating the
Adult Still's disease underlying cause. In a few patients no cause for the fever
Rheumatoid arthritis Systemic is found despite many months of investigation and
lupus erythematosus Wegener's follow-up. In most of these the symptoms do eventually
granulomatosis Giant cell settle spontaneously, and if no definite cause has been
arteritis
identified after 2 years the long-term prognosis is good.
Miscellaneous (10-25%)
Drug fevers FURTHER READING
Thyrotoxicosis Ellis C (2004) The returned traveller. Clinical Medicine 4:
Inflammatory bowel disease 506-509.
Sarcoidosis Mourad O, Palda A, Detsky A (2003) A comprehensive
Granulomatous hepatitis evidence-based approach to fever of unknown origin.
Factitious fever Archives of Internal Medicine 163: 545-551.
Familial Mediterranean fever Vanderschuerren S, Knochaert D, Adrianssens T et al.
Undiagnosed (5-25%) (2003) Prolonged febrile illness to fever of unknown
origin. Archives of Internal Medicine 163: 1033-1041.
A detailed history and examination is essential, taking ANTIMICROBIAL
into account the possible causes, and the examination
should be repeated on a regular basis in case new signs
CHEMOTHERAPY
appear. Investigation findings to date should be reviewed,
obvious omissions amended and abnormalities followed Principles of use
up. Confirm that the patient does have objective evidence of Antibiotics are among the safest of drugs, especially those
a raised temperature: this may require admission to hospital used to treat community infections. They have had a
if the patient is not already under observation. Some people major impact on the life-threatening infections and
have an exaggerated circadian temperature variation reduce the morbidity associated with surgery and many
(usually peaking in the evening), which is not pathological. common infectious diseases. This in turn is, in part,
The range of tests available is discussed above. responsible for the overprescribing of these agents which
Obviously investigation is guided by particular abnor- has led to concerns with regard to the increasing inci -
malities on examination or initial test results, but in some dence of antibiotic resistance.
cases 'blind' investigation is necessary. Some investigations, Most antibiotic prescribing, especially in the community,
especially cultures, should be repeated regularly, and is empirical. Even in hospital practice, microbiological
serial monitoring of inflammatory markers such as C- documentation of the nature of an infection and the
reactive protein allows assessment of progress. susceptibility of the pathogen is generally not available
Improvements in imaging techniques have diminished for a day or two. Initial choice of therapy relies on a
the need for invasive investigations in PUO, and scanning clinical diagnosis and, in turn, a presumptive micro-
has now superseded the blind diagnostic laparotomy. biological diagnosis. Such 'blind therapy' is directed at
Ultrasound, echocardiography, CT, MRI, and labelled the most likely pathogen(s) responsible for a particular
white cell scanning can all help in establishing a syndrome such as meningitis, urinary tract infection or
diagnosis if used appropriately: the temptation to scan all pneumonia. Initial therapy in the severely ill patient is
patients with PUO from head to toe as a first measure often broad spectrum in order to cover the range of
should be avoided. Biopsy of liver and bone marrow may possible pathogens but should be narrowed down once
be useful even in the absence of obvious abnormalities, microbiological information becomes available.
30
Antimicrobial chemotherapy
2
Bactericidal versus bacteriostatic has settled, oral administration should be considered for
In the majority of infections there is no firm evidence that those commenced on parenteral therapy. Treatment for
bactericidal drugs (penicillins, cephalosporins, amino- 5-7 days is adequate for most infections. Shorter-course
glycosides) are more effective than bacteriostatic drugs, therapy (3 days or less) is appropriate for those with
but it is generally considered necessary to use the former symptomatic uncomplicated bacteriuria (cystitis).
in the treatment of bacterial endocarditis and in patients Minimizing the duration of therapy lowers the risks of
in whom host defence mechanisms are compromised, adverse reactions and superinfection with Candida spp. or
particularly in those with neutropenia. Clostridium difficile, as well as the cost of therapy.
Combinations of drugs are occasionally required for Drugs which are concentrated intracellularly, such as
reasons other than providing broad-spectrum cover. erythromycin, quinolones and tetracyclines are used in
Tuberculosis is initially treated with three or four agents treating mycoplasma, brucella and legionella infections.
to avoid resistance emerging. Synergistic inhibition is
achieved by using penicillin and gentamicin in entero- Renal and hepatic insufficiency
coccal endocarditis or gentamicin and ceftazidime in life- Many drugs require dose reduction in renal failure to avoid
threatening pseudomonas infection. toxic accumulation. This applies to the (Madams and
especially the aminoglycosides and vancomycin. Tetra-
Pharmacokinetic factors cyclines, other than doxycycline and minocycline, should
To be successful, sufficient antibiotic must penetrate to be avoided. In those with hepatic insufficiency, caution or
the site of the infection. Knowledge of the standard dose reduction is required for agents such as isoniazid,
pharmacokinetic considerations of absorption, distri- ketoconazole, clindamycin, interferon and rifampicin.
bution, metabolism and excretion for the various drugs is
required. Difficult sites include the brain, eye and Therapeutic drug monitoring
prostate, while loculated abscesses are inaccessible to To ensure therapeutic yet non-toxic drug concentrations,
most agents. serum concentrations of drugs such as the aminoglycosides
Many mild-to-moderate infections can be treated and vancomycin are monitored, especially in those with
effectively with oral antibiotics provided that the patient impaired or changing renal function. Peak (1 hour post-
is compliant. Parenteral administration is indicated in the dose) and trough (pre-dose) serum samples are assayed.
severely ill patient to ensure rapid high blood and tissue However, with the increasing use of once-daily amino-
concentrations of drug. Some antibiotics can only be glycoside dosage regimens, random but timed serum
administered parenterally, such as the aminoglycosides assays are being adopted.
and extended-spectrum cephalosporins. Parenteral
therapy is also required in those unable to swallow or Antibiotic chemoprophylaxis
where gastrointestinal absorption is unreliable. The value of antibiotic chemoprophylaxis has been
questioned as there are few controlled trials to prove
Dose and duration of therapy efficacy (p. 832). However, there are still a number of
This will vary according to the nature, severity and indications for which the prophylactic use of antibiotics is
response to therapy. still advised (Table 2.9). These include surgical pro-
Prolonged treatment (up to 6 weeks) is necessary for cedures where the risk of infection is high (colon surgery)
some varieties of infective endocarditis, while pulmonary or the consequences of infection are serious (endocarditis,
tuberculosis is treated for at least 6 months. In treating post-splenectomy sepsis). The choice of agent(s) is deter-
many common infections, improvement occurs within mined by the likely infectious risk and the established
2-3 days; once the patient is afebrile or the leucocytosis efficacy and safety of the regimen.
Table 2.9 Antibiotic chemoprophylaxis
Clinical problem Aim Drug regimen*
Infective endocarditis (IE) To prevent infection in: Dental, oral, respiratory tract or oesophageal
procedures
High risk, e.g:
Amoxicillin, 3 g oral 1 hour pre-procedure or
Previous IE
2 g IV < 30 min pre-procedure
Prosthetic heart valves
Note: with previous IE add gentamicin
Mitral valve prolapse with MR or thickened
1.5 mg/kg IV < 30 min pre-procedure If
valve leaflets Complex congenital heart
allergic to penicillin use clindamicin
disease
Moderate risks, e.g. Acquired valvular Genitourinary or gastrointestinal procedures
heart disease Non-cyanotic congenital Amoxicillin and gentamicin If allergic to
heart defects Structural cardiac penicillin use vancomicin and gentamicin
abnormalities
Phenoxymethylpenicillin 500 mg 12-hourly
To prevent serious pneumococcal sepsis Cont'd
Splenectomy/spleen
malfunction
31
Infectious diseases, tropical medicine and sexually transmitted diseases
Table 2.9 (Cont'd) Antibiotic chemoprophylaxis
Clinical problem Aim Drug regimen*
Rheumatic fever To prevent recurrence and further cardiac Phenoxymethylpenicillin 250 g x 2 daily or
damage sulfadiazine 1g if allergic to penicillin
Meningitis: Due to
meningococci To prevent infection in close contacts Adults: rifampicin 600 mg twice-daily for 2 days
(Children < 1 year: 5 mg/kg; > 1 year: 10
mg/kg)
Alternatives (single dose) ciprofloxacin 500 mg
(p.o.) or ceftriaxone 250 mg (i.m)
Due to H. influenzae To reduce nasopharyngeal carriage and prevent Adults: rifampicin 600 mg daily for 4 days
type b infection in close contacts (Children: < 3 months 10 mg/kg; > 3
months 20 mg/kg)
Tuberculosis To prevent infection in exposed (close contacts) Oral isoniazid 300 mg daily for 6 months
tuberculin-negative individuals, infants of infected (Children: 5-10 mg/kg daily)
mothers and immunosuppressed patients
* Unless stated, doses are those recommended in adults
Note: new guidelines for IE laid down by AGREE (Appraisal of Guidelines for Research and Evaluation), http://www.agreecollabration.org/
Mechanisms of action and resistance to Table 2.10 Site of action of antibiotics
antimicrobial agents Site of action Antibiotic
Antibiotics act at different sites of the bacterium Cell wall Penicillin, cephalosporins,
(Table 2.10). vancomycin, monobactams
Resistance to an antibiotic can be the result of: Inhibits protein synthesis Macrolides, aminoglycosides,
tetracyline, oxazolidinones
■ impaired or altered permeability of the bacterial cell
Inhibits RNA synthesis Rifampicin
envelope, e.g. penicillins in Gram-negative bacteria Inhibits DNA synthesis Quinolones and metronidazole
■ active expulsion from the cell by membrane efflux Folic acid antagonists Sulphonamides and
systems trimethoprim
■ alteration of the target site (e.g. single point mutations
in E. coli or a penicillin-binding protein in Strep,
pneumoniae leading to acquired resistance - see below) The development or acquisition of resistance to an
■ specific enzymes which inactivate the drug before or antibiotic by bacteria invariably involves either a muta -
after cell entry tion at a single point in a gene or transfer of genetic
■ development of a novel metabolic bypass pathway. material from another organism (Fig. 2.2).
32
.«*■

Mutation
- Single point gene mutation

/
Naked DNA /- Incorporated into recipient's
chromosomal DNA
Transformation
----------^" Donor

( Phage (virus) DNA - Incorporated into recipient's

Transduction ------>r*ri --------- chromosomal DNA

~~— Donor

-Plasmid (extrachromosomal DNA)


containing resistance (R) factor

Donor
M M *'
Fig. 2.2 Some mechanisms for the development of resistance to antimicrobial drugs. These involve either a single
point mutation or transfer of genetic material from another organism (transformation, transduction or R factor transfer).
Antimicrobial chemotherapy
Larger fragments of DNA may be introduced into a Table 2.11 Some bacteria that have developed
bacterium either by transfer of 'naked' DNA or via a resistance to common antibiotics
bacteriophage (a virus) DNA vector. Both the former Pathogen Previously fully sensitive to
(transformation) and the latter (transduction) are depen-
Streptococcus pneumoniae Penicillin, erythromycin,
dent on integration of this new DNA into the recipient cefotaxime
chromosomal DNA. This requires a high degree of Strep, pyogenes Erythromycin, tetracycline
homology between the donor and recipient chromosomal Staphylococcus aureus Penicillin, methicillin,
DNA. ciprofloxacin Penicillin,
Finally, antibiotic resistance can be transferred from Neisseria gonorrhoeae ciprofloxacin Amoxicillin,
one bacterium to another by conjugation, when extra- Haemophilus influenzae chloramphenicol Amoxicillin,
chromosomal DNA (a plasmid) containing the resistance Enterobacteria trimethoprim,
ciprofloxacin, gentamicin
factor (R factor) is passed from one cell into another
Salmonella spp. Shigella Amoxicillin, sulphonamides,
during direct contact. Transfer of such R factor plasmids ciprofloxacin Amoxicillin,
can occur between unrelated bacterial strains and involve trimethoprim,
spp. Pseudomonas
large amounts of DNA and often codes for multiple tetracycline
antibiotic resistance. aeruginosa Gentamicin
Transformation is probably the least clinically relevant
Extended-spectrum
mechanism, whereas transduction and R factor transfer Benzylpenicillin and its
long-acting parenteral penicillins
are usually responsible for the sudden emergence of
multiple antibiotic resistance in a single bacterium. Table 2.12 Classification of penicillins
Increasing resistance to many antibiotics has developed relatives Ampicillin, pivampicillin,*
(Table 2.11). Benzylpenicillin talampicillin*
Benethamine penicillin* Amoxicillin
Benzathine penicillin* Co-amoxiclav, pivmecillinam
FURTHER READING Clemizole penicillin* Co-fluampicil
Finch RG, Williams RJ (eds) (1999) Antibiotic Procaine benzylpenicillin
resistance. Bailliere's Clinical Infectious Diseases. (procaine penicillin) Penicillins active against
London: Bailliere Tindall. Hughes WT, Armstrong Pseudomonas
D, Bodey GP et al. (2002) Oral alternatives to Azlocillin,* mezlocillin,*
Guidelines for the use of antimicrobial agents in benzylpenicillin piperacillin, ticarcillin
neutropenic patients with cancer. Clinical Infectious Azidocillin*
Diseases 34: 730-751. Murray BE (2000) Vancomycin- Phenoxymethylpenicillin
resistant enterococcal (penicillin V)
infections. New England Journal of Medicine 342:
710-721. Ramsdale DR, Turner-Stokes L (2004) (i-Lactamase-stable
Prophylaxis and penicillins
treatment of infective endocarditis in adults. Clinical Flucloxacillin
Medicine 4: 545-55. Stalam M, Kaye D (2000) Antibiotic Oxacillin*
agents in the elderly. Methicillin*
Infectious Disease Clinics of North America 14: 357-369. Nafcillin*
Steinke D, Davey P (2001) Association between
antibiotic resistance and community prescribing: a * Not available in the UK
critical review of bias and confounding in published
studies. Clinical Infectious Diseases 33 (Suppl 3):
S193-S205.
Side chains
ANTIBACTERIAL DRUGS Cyclic dipeptide I (L-
cysteine + D-valine)

p-Lactams (penicillins, cephalosporins


Ampicillin // \)—CH—CO-"'"'-'
and monobactams) A—N—k 3
,CI
Penicillins (Table 2.12) / " ^
Cloxacillin
0
Structure. The (3-lactams share a common ring
structure (Fig. 2.3). Changes to the side-chain of
COOH
benzylpenicillin (penicillin G) render the phenoxymethyl
Ticarcillin
derivative (penicillin V) acid resistant and allow it to be
orally absorbed. The presence of an amino group in the
phenyl radical of benzylpenicillin increases its anti-
microbial spectrum to include many Gram-negative and
Gram-positive organisms. More extensive modification of
IS-Lactam Thiazolidine
ring ring
-CH- ■ I
COOH

Fig. 2.3 The structure of penicillins.


33
Infectious diseases, tropical medicine and sexually transmitted diseases
the side-chain (e.g. as in flucloxacillin) renders the drug Cephalosporin
insensitive to bacterial penicillinase. This is useful in
treating infections caused by penicillinase ((3-lactamase)-
producing staphylococci.

Mechanisms of action. P-lactams block bacterial cell


COOH
wall mucopeptide formation by binding to and
inactivating specific penicillin-binding proteins (PBPs), B-Lactam Dihydrothiazine
which are peptidases involved in the final stages of cell ring ring
wall assembly and division. Methicillin-resistant Staph.
Fig. 2.4 The structure of a cephalosporin.
aureus (MRSA) (see p. 63) produce a low-affinity PBP
which retains its peptidase activity even in the presence
of high concentrations of methicillin.
approximately 90% of patients with infectious mono-
Indications for use. Benzylpenicillin can only be given nucleosis who receive this drug. Co-amoxiclav causes a
parenterally and is often the drug of choice for serious cholestatic jaundice six times more frequently than
infections, notably infective endocarditis, meningococcal, amoxicillin.
streptococcal, clostridial infections (tetanus, gas gangrene),
actinomycosis, anthrax, and spirochaetal infections Cephalosporins and cephamycins (Fig. 2.4) The
(syphilis, yaws). cephalosporins have an advantage over the
Phenoxymethylpenicillin (penicillin V) is an oral penicillins in that they are resistant to staphylococcal
preparation that is used chiefly to treat streptococcal penicillinases (but are still inactive against methicillin-
pharyngitis and as prophylaxis against rheumatic resistant staphylococci) and have a broader range of
fever. activity that includes both Gram-negative and Gram-
Flucloxacillin is used in infections caused by positive organisms, but excludes enterococci and anaerobic
penicillinase-producing staphylococci. bacteria. Ceftazidime and cefpirome are active against
Ampicillin is susceptible to penicillinase, but its Pseudomonas aeruginosa. Cefoxitin is a cephamycin.
antimicrobial activity includes streptococci, pneumococci
and enterococci as well as Gram-negative organisms such Indications for use (Table 2.13). These potent broad-
as Salmonella spp., Shigella spp., E. colt, H. influenzae and spectrum antibiotics are useful for the treatment of
Proteus spp. Drug resistance has, however, eroded its serious systemic infections, particularly when the precise
efficacy against these Gram-negatives. It is widely used in nature of the infection is unknown. They are commonly
the treatment of respiratory tract infections. Amoxicillin used for serious sepsis in postoperative and immuno-
has similar activity to ampicillin, but is better absorbed compromised patients, particularly during cytotoxic
when given by mouth. chemotherapy of leukaemia and other malignancies.
The extended-spectrum penicillin, ticarcillin is active They are used in pneumonia, meningitis, peritonitis and
against pseudomonas infections, as is the acylureido- urinary tract infections.
penicillin piperacillin in combination with sulbactam.
Clavulanic acid is a powerful inhibitor of many Interactions. There are relatively few interactions.
bacterial fS-lactamases and when given in combination
with an otherwise effective agent such as amoxicillin Toxicity. The toxicity is similar to that of the penicillins
(co-amoxiclav) or ticarcillin can broaden the spectrum but is less common. Some 10% of patients are allergic to
of activity of the drug. Sulbactam acts similarly and is both groups of drugs. The early cephalosporins caused
available combined with ampicillin, while tazobactam proximal tubule damage, although the newer derivatives
in combination with piperacillin is effective in appen- have fewer nephrotoxic effects.
dicitis, peritonitis, pelvic inflammatory disease, and
complicated skin infections. The penicillin pi-lactamase
Monobactams
combinations are also active against (3-lactamase-
Aztreonam is currently the only member of this class
producing staphylococci.
available. It is a synthetic (i-lactam and, unlike the
Pivmecillinam has significant activity against Gram- penicillins and cephalosporins, has no ring other than the
negative bacteria including E. coli, Klebsiella, Enterobacter
(i-lactam, hence its description as a monobactam.
and salmonellae but no activity against pseudomonas. Its mechanism of action is by inhibition of bacterial cell
wall synthesis. It is resistant to most fi-lactamases and
Interactions. Penicillins inactivate aminoglycosides
does not induce P-lactamase production.
when mixed in the same solution.
Indications for use. Aztreonam's spectrum of activity
Toxicity. Generally, the penicillins are very safe. Hyper- is limited to aerobic Gram-negative bacilli. With the
sensitivity (skin rash (common), urticaria, anaphylaxis), exception of urinary tract infections, aztreonam should be
encephalopathy and tubulointerstitial nephritis can used in combination with metronidazole (for anaerobes)
occur. Ampicillin also produces a hypersensitivity rash in and an agent active against Gram-positive cocci (a
34
Antimicrobial chemotherapy

Table 2.13 Some examples of cephalosporins


Activity Use
First generation Gram-positive cocci and Urinary tract infections
Cefalexin (oral) Gram-negative organisms
Cefradine (oral) Penicillin allergy
Cefadroxil (oral)
Second generation Extended spectrum Prophylaxis and treatment of Gram-negative
Cefuroxime More effective than first generation against infections and mixed aerobic-anaerobic infections
Cefamandole £ coli, Klebsiella spp. and Proteus mirabilis,
but less effective against Gram-positive
organisms
Cefoxitin Cefaclor Includes Bacteroides fragilis Peritonitis
(oral) Cefuroxime
(oral) Cefprozil (oral)
Third generation Broad-spectrum Especially severe infection with Enterobacteriaceae,
Cefotaxime More potent against aerobic Gram-negative Pseudomonas aeruginosa (ceftazidime, cefpirome)
Ceftazidime bacteria than first or second generation and Neisseria gonorrhoeae, N. meningitidis, Lyme
disease (ceftriaxone)
Cefpirome Urinary tract infections and infections with neutropenia
Ceftriaxone Once daily. Septicaemia, pneumonia, meningitis
Cefpodoxime (oral)
Cefixime (oral)
Fourth generation Aerobic Gram-negative bacteria Febrile, neutropenic patients
Cefepime* including P. aeruginosa
* Unavailable in the UK
penicillin or erythromycin). It is a useful alternative to Aminoglycosides
aminoglycosides in combination therapy, largely for the
treatment of intra-abdominal sepsis. Structure. These antibiotics are polycationic compounds
of amino sugars (Fig. 2.5).
Toxicity. As for the fS-lactam antibiotics.
Mechanism of action. Aminoglycosides interrupt
bacterial protein synthesis by inhibiting ribosomal
Carbapenems function (messenger and transfer RNA).
The carbapenems are semisynthetic P-lactams and
include imipenem, meropenem and ertapenem. They are Indications for use. Streptomycin is bactericidal and is
currently the most broad spectrum of antibiotics, being rarely used except for the treatment of tuberculosis.
active against the majority of Gram-positive and Gram- Occasional indications include endocarditis (with
negative as well as anaerobic bacterial pathogens. penicillin/ampicillin). Neomycin is used only for the
Ertapenem, unlike the others, is not active against topical treatment of eye and skin infections. Even though
Pseudomonas or Acinetobacter spp. They differ in their
it is poorly absorbed, prolonged oral administration can
dosage and frequency of administration. Imipenem is produce ototoxicity.
partially inactivated in the kidney by enzymatic Gentamicin and tobramycin are given parenterally.
inactivation and is therefore administered in combination They are highly effective against many Gram-negative
with cilastatin. organisms including Pseudomonas spp. They are
Indications for use. They are used for serious
nosocomial infections when multiple-resistant Gram- Aminoglycoside

negative bacilli or mixed aerobe and anaerobe infections


Glycosidic linkage
are suspected.
Amino
sugar _ Amino
Toxicity. This is similar to that of P-lactam antibiotics. ~sugar
Nausea, vomiting and diarrhoea occur in less than 5% of
Amino _
cases. Imipenem may cause seizures and should not be sugar
used to treat meningitis; meropenem is safe for this
indication. :
Fig. 2.5 The structure of an aminoglycoside.
35
Infectious diseases, tropical medicine and sexually transmitted
£ diseases
synergistic with a penicillin against Enterococcus spp. They cause brown discoloration of growing teeth, and
Netilmicin and amikacin have a similar spectrum but are thus these drugs are not given to children or pregnant
more resistant to the aminoglycoside-inactivating women. Photosensitivity can occur.
enzymes (phosphorylating, adenylating or acetylating)
produced by some bacteria. Their use should be restricted
to gentamicin-resistant organisms.
Macrolides
Interactions Enhanced nephrotoxicity occurs with Erythromycin
other nephrotoxic drugs, ototoxicity with some diuretics,
and neuromuscular blockade with curariform drugs. Structure. Erythromycin consists of a lactone ring with
unusual sugar side-chains.
Toxicity. This is dose-related. Aminoglycosides are
nephrotoxic and ototoxic (vestibular and auditory), Mechanism of action. Erythromycin inhibits protein
particularly in the elderly. Therapeutic drug monitoring synthesis by interrupting ribosomal function.
is necessary in ensuring therapeutic and non-toxic drug
concentrations. Indications for use. Erythromycin has a similar (but
not identical) antibacterial spectrum to penicillin and is
useful in individuals with penicillin allergy. It can be
Tetracyclines given orally or parenterally. It is the preferred agent in the
treatment of pneumonias caused by Legionella spp. and
Structure. These are bacteriostatic drugs possessing a Mycoplasma spp. It is also effective in the treatment of
four-ring hydronaphthacene nucleus (Fig. 2.6). Included infections due to Bordetdla pertussis (whooping cough),
among the tetracyclines are tetracycline, oxytetracycline, Campylobacter spp., Chlamydia spp. and Coxiella spp.
demeclocycline, lymecycline, doxycycline and minocycline.
Other macrolides
Mechanism of action. Tetracyclines inhibit bacterial These include clarithromycin, azithromycin and
protein synthesis by interrupting ribosomal function telithromycin. They have a broad spectrum of activity
(transfer RNA). that includes selective Gram-negative organisms,
mycobacteria and Toxoplasma gondii. Compared with
Indications for use. Tetracyclines are active against erythromycin, they have superior pharmacokinetic
Gram-positive and Gram-negative bacteria but their use properties with enhanced tissue and intracellular
is now limited, partly owing to increasing bacterial penetration and longer half-life that allows once or twice
resistance. A tetracycline is used for the treatment of acne daily dosage. Clarithromycin is widely recommended as
and rosacea. Tetracyclines are also active against V. a component of triple therapy regimens (usually with a
cholerae, Rickettsia spp., Mycoplasma spp., Coxiella burnetii, proton pump inhibitor and amoxicillin) for the
Chlamydia spp. and Brucella spp. Resistance is now eradication of Helicobacter pylori. Azithromycin is used for
common with Strep, pneumoniae. trachoma (see p. 84).

Interactions. The efficacy of tetracyclines is reduced by Interactions. Erythromycin and other macrolides
antacids and oral iron-replacement therapy. interact with theophyllines, carbamazepine, digoxin and
ciclosporin, occasionally necessitating dose adjustment of
Toxicity. Tetracyclines are generally safe drugs, but these agents.
they may enhance established or incipient renal failure,
although doxycycline is safer than others in this group. Toxicity. Diarrhoea, vomiting and abdominal pain
are the main side-effects of erythromycin (less with
clarithromycin and azithromycin) and are, in part, a
consequence of the intestinal prokinetic properties of the
Tetracycline macrolides. Macrolides may also rarely produce
cholestatic jaundice after prolonged treatment. QTC
prolongation is a recognized cardiac effect of the
macrolides. This may have serious consequences if the
syndrome of 'torsades de pointes' is induced.

CONH2
Chloramphenicol_____________________
OH
Structure. Chloramphenicol is the only naturally
Fig. 2.6 The structure of a tetracycline. Substitution of occurring antibiotic containing nitrobenzene (Fig. 2.7).
CH3, OH or H at positions A to D produces variants of This structure probably accounts for its toxicity in
tetracycline. humans and for its activity against bacteria.
36
Antimicrobial chemotherapy
Chloramphenicol Resistance. Resistance may occur rapidly and is the
reason why fusidic acid is given in combination with
another antibiotic.

Toxicity. Fusidic acid may occasionally be hepatotoxic


but is generally a safe drug and if necessary can be given
during pregnancy.

Sulphonamides and trimethoprim_______


Structure. The sulphonamides are all derivatives of the
prototype sulphanilamide. Trimethoprim is a 2,4-
Fig. 2.7 The structure of chloramphenicol. diaminopyrimidine.

Mechanism of action. Sulphonamides block thymidine


Mechanism of action. Chloramphenicol competes and purine synthesis by inhibiting microbial folic acid
with messenger RNA for ribosomal binding. It also synthesis. Trimethoprim prevents the reduction of
inhibits peptidyl transferase. dihydrofolate to tetrahydrofolate (see Fig. 8.12).

Indications for use. Chloramphenicol is rarely used in Indications for use. Sulfamethoxazole is mainly used
developed countries. In developing countries it has been in combination with trimethoprim (as co-trimoxazole). Its
invaluable in the treatment of severe infections caused by use is now largely restricted to the treatment and
Salmonella typhi and S. paratyphi (enteric fevers) and H. prevention of Pneumocystis carinii infection and listeriosis
influenzae (meningitis and acute epiglottitis) which are in developed countries, although it is still in widespread
still prevalent in countries where Hib vaccination has not use in developing countries. It may also be used for
been introduced. It is also active against Yersinia pestis toxoplasmosis and nocardiosis and as a second-line agent
(plague) and is used topically for the treatment of in acute exacerbations of chronic bronchitis and in
purulent conjunctivitis. Drug resistance is currently urinary tract infections. Trimethoprim alone is often used
eroding the efficacy of chloramphenicol. for urinary tract infections and acute-on-chronic
bronchitis, as the side-effects of co-trimoxazole are most
Interactions. Chloramphenicol enhances the activity of commonly due to the sulphonamide component.
anticoagulants, phenytoin and oral hypoglycaemic Sulfapyridine in combination with 5-aminosalicylic
agents. acid (i.e. sulfasalazine) is used in inflammatory bowel
disease.
Toxicity. Severe irreversible bone marrow suppression
is rare but nevertheless now restricts the usage of this Resistance. Resistance to sulphonamides is often
drug to only the severely ill patient. Chloramphenicol plasmid-mediated and results from the production of
should not be given to premature infants or neonates sulphonamide-resistant dihydropteroate synthetase from
because of their inability to conjugate and excrete this altered bacterial cell permeability to these agents.
drug; high blood levels lead to circulatory collapse and
the often fatal 'grey baby syndrome'. Interactions. Sulphonamides potentiate oral anti-
coagulants and hypoglycaemic agents.
Fusidic acid Toxicity. Sulphonamides cause a variety of skin
Structure. Fusidic acid has a structure resembling that eruptions, including toxic epidermal necrolysis, the
of bile salts (see p. 350). Stevens—Johnson syndrome, thrombocytopenia, folate
deficiency and megaloblastic anaemia with prolonged
Mechanism of action. It is a potent inhibitor of usage. It can provoke haemolysis in individuals with
bacterial protein synthesis. Its entry into cells is facilitated glucose-6-phosphate dehydrogenase deficiency and
by the detergent properties inherent in its structure. therefore should not be used in such people. Co-
trimoxazole should also be avoided in the elderly if
Indications for use. Fusidic add is mainly used for possible, as deaths have been recorded, probably owing
penicillinase-producing Staph. aureus infections such as to the sulphonamide component.
osteomyelitis (it is well concentrated in bone) or endo
carditis, and for other staphylococcal infections
Quinolones__________________________
accompanied by septicaemia. The drug is well absorbed
orally but is relatively expensive and should be used in The quinolone antibiotics, such as ciprofloxacin,
combination with another staphylococcal agent to norfloxacin, ofloxacin and levofloxacin, are useful oral
prevent resistance emerging. •. . ., .-..■ broad-spectrum antibiotics, related structurally to
■>:.■ nalidixic acid. The latter achieves only low serum
37
Infectious diseases, tropical medicine and sexually transmitted diseases
Quinolone Linezolid
COO

Fig. 2.9 The structure of linezolid, an oxazolidinone.

Fig. 2.8 The structure of a quinolone (ciprofloxacin). the formation of a functional 70S complex essential to
bacterial translation.

concentrations after oral administration and its use is Indications for use. Linezolid is active against a variety
limited to the urinary tract where it is concentrated. of Gram-positive pathogens including vancomycin-
Newer quinolones, including moxifloxacin, gemifloxacin resistant Enterococcus faecium (unfortunately resistant
and gatifloxacin, have greater activity against Gram- organisms have already been reported), methicillin-
positive pathogens. The structure is shown in Figure 2.8. resistant Staph. aureus and penicillin-resistant Strep,
pneumonias. It is also active against group A and group B
Mechanism of action. The quinolone group of streptococci. Clinical experience has demonstrated efficacy
bactericidal drugs inhibit bacterial DNA synthesis by in a variety of hospitalized patients with severe to life-
inhibiting topoisomerase IV and DNA gyrase, the threatening infections, such as bacteraemia, hospital-
enzyme responsible for maintaining the superhelical acquired pneumonia and skin and soft tissue infections. It
twists in DNA. can be given both intravenously and by mouth.

Indications for use. The extended-spectrum quinolones Interactions. Linezolid interacts reversibly as a non-
such as ciprofloxacin have activity against Gram-negative, selective inhibitor of monoamine oxidase, and has the
including Pseudomonas aeruginosa, and some Gram- potential for interacting with serotoninergic and adrenergic
positive bacteria (e.g. anthrax, p. 82). They are useful in agents.
Gram-negative septicaemia, skin and bone infections,
urinary and respiratory tract infections, meningococcal Toxicity. Side-effects include gastrointestinal disturb-
carriage, in some sexually transmitted diseases such as ances, headache, rash, hypertension and reversible
gonorrhoea and non-specific urethritis due to Chlamydia thrombocytopenia. Safety has not yet been shown in
trachomatis, and in severe cases of travellers' diarrhoea pregnancy.
(see p. 70). The newer oral quinolones provide an alter-
native to (3-lactams in the treatment of community- Nitroimidazoles
acquired lower respiratory tract infections.
Structure. These agents are active against anaerobic
Resistance bacteria and some pathogenic protozoa. The most widely
. resistant. In many countries 10-20% of E. coli are
used drug is metronidazole (Fig. 2.10). Others include
tinidazole and nimorazole.
Interactions. Ciprofloxacin can induce toxic concen-
trations of theophylline. Mechanism of action. After reduction of their nitro
group to a nitrosohydroxyl amino group by microbial
Toxicity. Gastrointestinal disturbances, photosensitive enzymes, nitroimidazoles cause strand breaks in
rashes and occasional neurotoxicity can occur. Avoid in microbial DNA.
childhood and pregnancy. Tendon damage including
rupture has been reported.

Metronidazole
Oxazolidinones
Structure. The oxazolidinones are a novel class of NO,
antibacterial agents of which linezolid (Fig. 2.9) is the first
to become available. ... . ...............
-CH2CH2OH
Mechanism of action. The oxazolidinones inhibit CH,
protein synthesis by binding to the bacterial 23S
ribosomal RNA of the 59S sub-unit, thereby preventing Fig. 2.10 The structure of metronidazole, a
nitroimidazole.
38
Antimicrobial chemotherapy
Indications for use. Metronidazole plays a major role Table 2.14 Antifungal agents
in the treatment of anaerobic bacterial infections, Allylamines
particularly those due to Bacteroides spp. It is also used Polyenes
Terbinafine
prophylactically in colonic surgery. It may be given orally,
by suppository (well absorbed and cheap) or intra - Other antifungals
venously (very expensive). It is also the treatment Amorolfine (topical only)
of choice for amoebiasis, giardiasis and infection with 5-Flucytosine
Trichomonas vaginalis. Griseofulvin
Amphotericin, nystatin
Interactions. Nitroimidazoles can produce a disulfiram-
Echinocandins
like reaction with ethanol and enhance the anticoagulant
Caspofungin
effect of warfarin.
Azoles
Toxicity. Nitroimidazoles are tumorigenic in animals Miconazole, ketoconazole,
and mutagenic for bacteria, although carcinogenicity has fluconazole, itraconazole,
not been described in humans. They cause a metallic voriconazole
taste, and polyneuropathy with prolonged use. They Topical clotrimazole,
should be avoided in pregnancy. sulconazole, tolnaftate,
econazole, tioconazole

Glycopeptides
The glycopeptides are antibiotics active against Gram- ANTITUBERCULOSIS DRUGS
positive bacteria and act by inhibiting cell wall synthesis. These are described on page 932. Kifampicin is also used
in other infections apart from tuberculosis.
Vancomycin
Vancomycin is given intravenously for methicillin-
resistant Staph. aureus and other multiresistant Gram- ANTIFUNGAL DRUGS (Table 214)
positive organisms. It is also used for treatment and
prophylaxis against Gram-positive infections in
Polyenes
penicillin-allergic patients. It is used for Strep, pneumoniae Polyenes react with the sterols in fungal membranes,
meningitis when caused by penicillin-resistant strains. By increasing permeability and thus damaging the
mouth it is an alternative to metronidazole for Clostridium organism. The most potent is amphotericin, which is used
difficile-associated colitis. Vancomycin-resistant enterococci intravenously in severe systemic fungal infections.
(VRE) are now seen, as well as vancomycin-resistant Nephrotoxicity is a major problem and dosage levels
Staphylococcus (p. 63). must take background renal function into account.
Liposomal amphotericin is less toxic but very expensive.
Toxicity. Vancomycin can cause ototoxicity and nephro- Nystatin is not absorbed through mucous membranes
toxicity and thus serum levels should be monitored. Care and is therefore useful for the treatment of oral and
must be taken to avoid extravasation at the injection site enteric candidiasis and for vaginal infection. It can only
as this causes necrosis and thrombophlebitis. Too rapid be given orally or as pessaries.
infusion can produce symptomatic release of histamine
(red man syndrome).
Azoles
Teicoplanin Imidazoles such as ketoconazole, miconazole and
This glycopeptide antibiotic is less nephrotoxic than clotrimazole are broad-spectrum antifungal drugs. They
vancomycin. It has more favourable pharmacokinetic are predominantly fungistatic and act by inhibiting
properties, allowing once-daily dosage. fungal sterol synthesis, resulting in damage to the cell
wall. Ketoconazole is active orally but can produce liver
Other antibiotics damage. It is effective in candidiasis and deep mycoses
including histoplasmosis and blastomycosis but not in
Clindamycin is not widely used because of its toxic side- aspergillosis and cryptococcosis.
effect, antibiotic-associated colitis (pseudomembranous Clotrimazole and miconazole are used topically for the
colitis). It is active against Gram-positive cocci including treatment of ringworm and cutaneous and genital
some penicillin-resistant staphylococci. It is also active candidiasis. Econazole and tioconazole are used for the
against anaerobes, especially bacteroides. It is well con- topical treatment of cutaneous and vaginal candidiasis
centrated in bone and used for osteomyelitis. and dermatophyte infections.

Quinupristin and dalfopristin. A combination of these Triazoles. These include fluconazole, voriconazole and
streptogramin antibiotics is used for Gram-positive itraconazole. Fluconazole is noted for its ability to enter
bacteria which have failed to respond to other antibacterials. CSF and is used for candidiasis and for the treatment of
central nervous system (CNS) infection with Cryptococcus
neoformans. Itraconazole fails to penetrate CSF. It is the
agent of choice for non-life-threatening blastomycosis and
histoplasmosis. It is also moderately effective in invasive
aspergillosis. Toxicity is mild. The problem associated with
3d
poor absorption of the capsules in the absence of food has Aciclovir
been overcome with the liquid formulation. Voriconazole
has broad-spectrum activity that includes Candida,
Ctyptococcus and Aspergillus spp. and other filamentous
fungi. It is available for oral and intravenous use. Adverse
effects include rash, visual disturbance and abnormalities
of liver enzymes. It is indicated for invasive aspergillosis
and severe Candida infections unresponsive to ampho-
teracin and fluconazole respectively.
Allylamines Fig. 2.11 The structure of aciclovir.
Terbinafine has antifungal and anti-inflammatory activity Table 2.15 Antiviral agents (for drugs against HIV
orally and is useful for the treatment of superficial see Table 2.53)
mycoses such as dermatophyte infections, onychomycosis
and cutaneous candidiasis. A topical formulation is also
available to treat fungal skin infections.

Echinocandins _________
This is a new class of antifungals which act by inhibiting
the cell wall polysaccharide, glucan. Caspofungin is active
against Candida spp. and Aspergillus spp. and is indicated
for serious aspergillosis unresponsive to other drugs. It is
administered intravenously.

Other antifungals
____________________________________
Flucytosine. The fluorinated pyridine derivative,
flucytosine, is used in combination with amphotericin B
for systemic fungal infection. Side-effects are uncommon,
although it may cause bone marrow suppression. It is
active when given orally or parenterally.

Griseofulvin. Griseofulvin, a naturally occurring anti-


fungal, is widely used for the treatment of more extensive
superficial mycoses and onychomycosis.

Amorolfine. Amorolfine is available for the topical


treatment of fungal skin and nail infections.
Drug
Use
Nucleoside analogues
Aciclovir Topical - HSV infection
Oral and intravenous - VZV
and HSV
Famciclovir Oral - VZV and HSV
Valaciclovir Oral - VZV and HSV
Ganciclovir Intravenous and oral - CMV
Valganciclovir Oral - CMV
Adefovir Oral - HBV infection
Cidofovir Intravenous - CMV
Pyrophosphate analogues
Foscarnet Intravenous - CMV
Adamantanes
Amantadine Oral - influenza A
Neuraminidase inhibitors
Zanamivir Topical (inhalation) - influenza
A and B
Oseltamivir Oral - influenza A and B
Ribavirin Topical (inhalation) - RSV
Oral - Lassa fever, hepatitis C
Palivizumab Prevention of RSV
Alpha-interferon (INF-a) HBV, HCV, some malignancies
(e.g. renal cell carcinoma)
(Pegylated INF-a) (Given once weekly)
ANTIVIRAL DRUGS oral and topical preparations are available for the
treatment of herpes simplex and varicella zoster virus
Drugs for HIV infection are discussed on page 144. infections (Table 2.15).
A pro-drug of aciclovir, valaciclovir, has been
Nucleoside analogues developed. Coupling of the amino acid valine to the
acyclic side-chain of aciclovir allows better intestinal
Aciclovir. Aciclovir (Fig. 2.11) is an acyclic nucleoside
absorption. The valine is removed by enzymic action and
analogue which acts as a chain terminator of herpesvirus aciclovir is released into the circulation. A similar pro-
DNA synthesis. This drug is converted to aciclovir drug of a related nucleoside analogue (penciclovir) is the
monophosphate by a virus-encoded thymidine kinase antiherpes drug, famciclovir. The mode of action and
produced by alpha herpesviruses, herpes simplex types 1 efficacy of famciclovir are similar to those of aciclovir.
and 2 and varicella zoster virus (Table 2.15). Conversion
to the triphosphate is then achieved by cellular enzymes. Ganciclovir. This guanine analogue is structurally
Aciclovir triphosphate competes with deoxyguanine similar to aciclovir, with extension of the acyclic side-
triphosphate and the drug is incorporated into the chain by a carboxymethyl group. It is active against
growing chains of herpesvirus DNA. This highly specific herpes simplex viruses and varicella zoster virus by the
mode of activity, targeted only to virus-infected cells, same mechanism as aciclovir. In addition, phosphorylation
means that aciclovir has very low toxicity. Intravenous, by a protein kinase encoded by the UL97 region of
40
Immunization against infecti
2
cytomegalovirus renders it potently active against this ribavirin combinations, have lower relapse rates than
virus. Thus ganciclovir is currently the first-line treatment those receiving interferon alone.
for cytomegalovirus disease. Intravenous and oral
preparations are available as is an oral pro-drug, Palivizumab
valganciclovir. Unlike aciclovir, ganciclovir has a This monoclonal antibody is specifically indicated to
significant toxicity profile including neutropenia, prevent seasonal respiratory syncytial virus (RSV) infec-
thrombocytopenia and the likelihood of sterilization by tion in infants at high risk of this infection. It is
inhibiting spermatogenesis. For this reason, it is reserved administered by intramuscular injection.
for the treatment or prevention of life- or sight-threatening
cytomegalovirus infection. Interferons (see also p. 202)
These are naturally occurring proteins produced by virus-
Cidofovir. This is a phosphonate derivative of an infected cells, macrophages and lymphocytes. Interferons
acyclic nucleoside which is a DNA polymerase chain are stimulated by a number of factors, including viral
inhibitor. It is administered intravenously for the nucleic acid, and render uninfected cells resistant to infec-
treatment of severe cytomegalovirus (CMV) infections in tion with the same - or in some circumstances different
patients with AIDS. It is given with probenecid, and as it -viruses. They have been synthesized commercially by
is nephrotoxic, particular attention should be given to either culture of lymphoblastoid cells or by recombinant
hydration and to monitoring renal function. DNA technology and are licensed for therapeutic use.
The potency of INF-cx has been enhanced by coupling
Adefovir dipivoxil is used in the treatment of chronic the protein with polyethylene glycol. The resulting PEG
hepatitis B (see p. 372). interferon given once weekly has been shown to improve
the response to treatment of hepatitis B and C.
Pyrophosphate analogues
Foscarnet (sodium phosphonoformate) is a simple
pyrophosphate analogue which inhibits viral DNA FURTHER READING
polymerases. It is active against herpesviruses and its [Anon] (2004) Caspofungin and voriconazole for fungal
main roles are as a second-line treatment for severe infections. Drugs and Therapeutics Bulletin 1: 5-8.
cytomegalovirus disease and for the treatment of Finch RG, Greenwood D, Norrby R, Whitley R (2003)
aciclovir-resistant herpes simplex infection. It is given Antibiotic and Chemotherapy, 8th edn. Edinburgh:
Churchill Livingstone.
intravenously and the potential for severe side-effects, Herbrecht R, Denning DW, Patterson TF et al. (2002) for
particularly renal damage, limits its use. the Invasive Fungal Infections Group of the European
Organisation for Research and Treatment of Cancer
Amantadine. Amantadine is a synthetic symmetrical and the Global Aspergillus Study Group. Voriconazole
amine which is active prophylactically and versus amphotericin B for primary therapy of invasive
therapeutically against influenza A virus (it is inactive aspergillosis. New England Journal of Medicine 347(6):
against influenza B virus). Its prophylactic efficacy is 408-115.
similar to that of influenza vaccine and it is occasionally Jacoby GA, Munoz-Price LS (2004) The new
fi-Lactamases. New England Journal of Medicine 352:
used to prevent the spread of influenza A in institutions
380-391.
such as nursing homes. Although CNS side-effects such Stevens DL, Herr D, Lampiris H et al. (2002) Linezolid
as insomnia, dizziness and headache may occur (it is versus vancomycin for the treatment of methicillin-
also used as a treatment for Parkinson's disease), these resistant Staphylococcus aureus infections. Clinical
are not usually produced by the lower doses currently Infectious Diseases 341:1481-1490.
recommended. Walsh TJ (2002) Echinocandins - an advance in the
primary treatment of invasive candidiasis. New
Neuraminidase inhibitors England Journal of Medicine 347(25): 2070-2072.
Two drugs that inhibit the action of the neuraminidase of
influenza A and B have been introduced. Zanamavir is
administered by inhalation and oseltamivir is an oral
preparation. Both have been shown to be effective in IMMUNIZATION AGAINST
reducing the duration of illness in influenza.
INFECTIOUS DISEASES
Ribavirin
Although effective antimicrobial chemotherapy is avail-
This synthetic purine nucleoside derivative which
able for many diseases, the ultimate aim of any infectious
interferes with 5'-capping of messenger RNA, is active
disease control programme is to prevent infection
against several RNA viruses. It is administered by a
occurring. This is achieved either by:
small-particle aerosol generator (SPAG) to infants with
acute respiratory syncytial virus (RSV) infection. In a ■ eliminating the source or mode of transmission of an
clinical trial in Sierra Leone it was shown to reduce the infection (p. 22)
mortality of Lassa fever virus infection. Individuals with ■ reducing host susceptibility to environmental
hepatitis C virus infection, treated with alpha-interferon- pathogens.
Infectious diseases, tropical medicine and sexually transmitted diseases
Immunization, influenzae infection, Box 2.6 e
Recommended n
immunoprophylaxi notably meningitis (see
C
p.! immunization
s and schedules: (i) in the MMR
immunotherapy_______________________ UK; (ii) WHO model D
Immunization has FURTHER READING schedule for T
changed the course and Ada G (2001) Vaccines developing countries a
and vaccination. New R
natural history of many Time of immunization
infectious diseases. England Vaccine
Journal of O
Passive immunization by (i) UK* P
administering preformed Medicine 345:1042- 2 months
1053. Beverley P (ed.) V
antibody, either in the 3 months ,
(2002) Vaccination. 4 months
form of immune serum or British Medical M
purified normal 12-15 months M
Bulletin 62. 3-5 years
immunoglobulin, High KP (2001) R
10-14 years 15- BCG*
provides short-term Nutritional 18 years
immunity and has been strategies to T
boost (ii) Developing countries5 d
effective in both the
immunity and prevent Birth (or first contact) ,
prevention
infection in elderly 6 weeks 10 weeks 14 O
(immunoprophylaxis) and P
individuals. Clinical weeks 9 months
treatment V
(immunotherapy) of a Infectious Diseases
33:1892-1900. Jackson r
number of bacterial and
LA, Neuzil KM, Yu O et O
viral diseases (Table al. for the Vaccine D P
2.16). The active Safety Datalink (2003) P V
immunization schedule Effectiveness of T ,
currently recommended is pneumococcal , B
summarized in Box 2.6. polysaccharide H C
Long-lasting immunity is vaccine in older adults. i G
achieved only by active New England b
immunization with a live Journal of Medicine , D
attenuated or an 348(18): 1747-1755. John O P
TJ (2000) The final stages P T
inactivated organism
of the global eradication V ,
(Table 2.17). Active of polio. New England , O
immunization may also be Journal of Medicine 343: M P
performed with microbial 806-807. Public Health e V
toxin (either native or Laboratory Service n ,
modified) - that is, a (2002) C H
toxoid. Immunization Immunoglobulin , B
should be kept up to date handbook. London: B V
with booster doses PHLS. Online. O
throughout life. Travellers Available: G D
to developing countries, http://www.hpa.org. * P
uk/infections/topics D T
especially if visiting rural _az/ P ,
areas, should in addition immunoglobulin/ T O
enquire about further immunoglobulinHandbo , P
specific immunizations. ok.pdf. Salisbury DM, H V
In 1974 the World Begg NT (eds) (1996) i ,
Health Organization Immunization b H
introduced the Expanded Against Infectious , B
Programme on Diseases. London: O V
Immunization (EPI). HMSO. P
V D
Twenty years later more
, P
than 80% of the world's Protection for M T
children had been travellers to e ,
immunized against
developing/tropica n O
tuberculosis, diphtheria,
l countries___________________________C P
tetanus, pertussis, polio D V
and measles. It is hoped There has been a huge a ,
that poliomyelitis will increase in the number of P H
shortly be eradicated people travelling to T B
world-wide, which will developing countries, , V
match the past success of mainly for recreation and H
leisure. The risk of i M
global smallpox
infection depends on the b e
eradication. Introduction of ,
area to be visited, the a
conjugate vaccines against O
type of activity and the s
Haemophilus influenzae P l
type b (Hib) has proved underlying health V e
highly effective in , s
controlling invasive H. M
, FURTHER READING
Y CDC travel health site:
F http://www.cdc.gov/trav
1
el Dupont H, Steffen R
1
(2000) Textbook of Travel
Medicine
DPT, adsorbed diphtheria,
and Health. Hamilton,
whole cell pertussis,
Ontario: Decker. WHO
tetanus triple vaccine; Hib,
Travel Health Site:
Haemophilus influenzae b
http://www.who.int/ith
vaccine; OPV, oral polio
vaccine; MenC,
meningococcus group C
conjugate vaccine; aR
acellular pertussis; MMR,
measles, mumps, rubella
triple vaccine; BCG, bacille
Calmette-Guerin
(tuberculosis vaccine); d,
adsorbed low-dose
diphtheria; HBV, hepatitis B
vaccine; YF, yellow fever
vaccine
* Changing from OPV to
inactivated polio vaccine; ? HBV
vaccine
to be added to schedule
f
Children at high risk of
contact with tuberculosis
* Tuberculin-
negative children at
low risk of contact
with
tuberculosis
§
Model scheme,
adapted locally
depending on need
and availability of
vaccines 1 In
endemic areas

of the traveller. Advice


should therefore always be
based on an individual
assessment.
Protection for
travellers can be divided
into three categories:
■ Personal protection,
e.g.
- insect repellent
- bed netting
- avoidance of
animals
- care with food and
drink
■ Chemoprophylaxis, e.g.
antimalarials
■ Immunization, e.g.
- yellow fever
- hepatitis A and B
- typhoid.
Because situations and
risks can change rapidly,
websites (which can be
regularly updated) are
often the best source of
advice on travel health.
■■■- : ■ ,. i;; -,r : :
DNA viruses

Table 2.16 Examples of passive immunization available


Infection Antibody Indication Efficacy
Bacterial
Tetanus Human tetanus immune globulin Prevention and treatment
Diphtheria Horse serum Prevention and treatment
Botulism Horse serum Treatment
Viral
Hepatitis A Human normal immune globulin Prevention (rarely requirec
Measles j Human hepatitis B immune globulin Prevention
Hepatitis B
Varicella zoster Human varicella zoster immune Prevention
globulin
Rabies Human rabies immune globulin Prevention
Table 2.17 Preparations available for active a helical or icosahedral structure to the virus. Some
immunization viruses also possess an envelope consisting of lipid and
Live attenuated vaccines protein.
Oral polio (Sabin) Hepatitis viruses are discussed on page 362.
Measles
Mumps
Rubella
Yellow fever DNA VIRUSES
BCG
Typhoid
Details of the structure, size and classification of human
Inactivated conjugate vaccines
DNA viruses are shown in Table 2.18.
Hepatitis A
Pertussis ADENOVIRUSES
Typhoid - whole cell and Vi antigen
Polio Adenovirus infection commonly presents as an acute
Influenza pharyngitis, and extension of infection to the larynx and
Cholera trachea in infants may lead to croup. By school age the
Meningococci (groups A and C) majority of children show serological evidence of
Meningococcus group C previous infection. Certain subtypes produce an acute
Rabies
conjunctivitis associated with pharyngitis. In adults,
Pneumococcal
Haemophilus influenzae type b
adenovirus causes acute follicular conjunctivitis and
rarely pneumonia that is clinically similar to that
Toxoids produced by Mycoplasma pneumoniae (see p. 924).
Diphtheria Adenoviruses have also been implicated as a cause of
Tetanus gastroenteritis (see p. 52) without respiratory disease and
may be responsible for acute mesenteric lymphadenitis in
Recombinant vaccines children and young adults. Mesenteric adenitis due to
Hepatitis B adenoviruses may lead to intussusception in infants.
BCG, bacille Calmette-Guerin

HERPESVIRUSES
Members of the herpesviruses are important causes
of a wide range of human diseases. Details are sum-
VIRAL INFECTIONS: marized in Table 2.19. The hallmark of all herpesvirus
AN INTRODUCTION infections is the ability of the viruses to establish latent (or
silent) infections that then persist for the life of the
Viruses are much smaller than other infectious agents individual.
(see Tables 2.18 and 2.20) and contain either DNA or
RNA, not both as in bacteria and other microorganisms.
Since they are metabolically inert, they must live intra- Herpes simplex virus (HSV) infection
cellularly, using the host cell for synthesis of viral proteins (Kg. 2.12) __________________________
and nucleic acid. Viruses have a central nucleic acid core Two types of HSV have been identified: HSV-1 is the
surrounded by a protein coat that is antigenically unique major cause of herpetic stomatitis, herpes labialis ('cold
for a particular virus. The protein coat (capsid) imparts sore'), keratoconjunctivitis and encephalitis, whereas
i43
Infectious diseases, tropical medicine and sexually transmitted diseases mi »nmww«in HIWIII
iimiiniNnuwmi

I Table 2.18 Human DNA viruses


Structure Approximate size Family Viruses
Symmetry Envelope
Icosahedral 80 nm Adenovirus Adenoviruses
Icosahedral + 100 nm (160 nm with envelope) Herpesvirus Herpes simplex virus (HSV)
types 1 and 2
Varicella zoster virus
Cytomegalovirus
Epstein-Barr virus (EBV)
Human herpesvirus type 6 (HHV-6)
Human herpesvirus type 7 (HHV-7)
Human herpesvirus type 8 (HHV-8)
Icosahedral + 42 nm Hepadnavirus Hepatitis B virus (HBV)
Icosahedral 50 nm Papovavirus Human papillomavirus
Polyomavirus
Icosahedral 23 nm Parvovirus Parvovirus B19
Complex + 300 nm x 200 nm Poxvirus Variola virus
Vaccinia virus
Monkeypox
Cowpox
Orf
Molluscum contagiosum

Table 2.19 Major diseases caused by human herpesviruses


Subfamily Virus Children Adults Immunocompromised
a-Herpesvirus Stomatitis* Cold sores Dissemination
Herpes simplex type 1 Keratitis
Erythema multiforme
Primary genital herpes* Dissemination
Herpes simplex type 2 Recurrent genital herpes
Shingles Dissemination
Varicella zoster virus Chickenpox*
(3-Herpesvirus Pneumonitis
Cytomegalovirus Congenital*
Retinitis
Gastrointestinal
Pneumonitis
Human herpesvirus type 6 Roseola infantum*
y-Herpesvirus Human herpesvirus type 7 Roseola infantum* Infectious Lymphoma
Epstein-Barr virus mononucleosis* Burkitt's
lymphoma
Nasopharyngeal carcinoma
Kaposi's sarcoma Kaposi's sarcoma
Human herpesvirus type 8
' Signifies primary infection
HSV-2 causes genital herpes and may also be responsible
for systemic infection in the immunocompromised host.
These divisions, however, are not rigid, for HSV-1 can
give rise to genital herpes and HSV-2 can cause
pharyngitis.
The portal of entry of HSV-1 infection is usually via the
mouth or occasionally the skin. The primary infection
may go unnoticed or may produce a severe inflammatory
reaction with vesicle formation leading to painful ulcers
(gingivostomatitis; see Fig. 2.13). The virus then remains
latent, most commonly in the trigeminal ganglia, but may
be reactivated by stress, trauma, febrile illnesses and
ultraviolet radiation, producing the recurrent form of the
disease known as herpes labialis ('cold sore'). Approxi -
mately 70% of the population are infected with HSV-1
Fig. 2.12 Electronmicrograph of herpes simplex virus. and recurrent infections occur in one-third of individuals.
44 I
DNA viruses
Infectious virus is spread from fresh skin lesions by direct
contact or airborne transmission and the period of
infectivity in chickenpox extends from 2 days before the
appearance of the rash until the skin lesions are all at
the crusting stage. Following recovery from chickenpox
the virus then remains latent in dorsal root and cranial
nerve ganglia.

Clinical features of chickenpox


Fourteen to twenty-one days after exposure to VZV, a
brief prodromal illness of fever, headache and malaise
heralds the eruption of chickenpox, characterized by the
rapid progression of macules to papules to vesicles to
pustules in a matter of hours (Fig. 2.14). In young children
the prodromal illness may be very mild or absent. The
Fig. 2.13 Primary herpes simplex type 1 illness tends to be more severe in older children and can
(gingivostomatitis). be debilitating in adults. The lesions occur on the face,
scalp and trunk, and to a lesser extent on the extremities.
It is characteristic to see skin lesions at all stages of
Reactivation often produces localized paraesthesiae in the development on the same area of skin. Fever subsides as
lip before the appearance of a cold sore. soon as new lesions cease to appear. Eventually the
Complications of HSV-1 infection include transfer to pustules crust and heal without scarring.
the eye (dendritic ulceration, keratitis), acute encephalitis Important complications of chickenpox include
(p. 1167), skin infections such as herpetic whitlow, and pneumonia, which generally begins 1-6 days after the
erythema multiforme (see p. 1342). skin eruption, and bacterial superinfection of skin lesions.
In genital herpes the primary infection is usually more Pneumonia is more common in adults than in children
severe and recurrences are common. The virus remains and cigarette smokers are at particular risk. Pulmonary
latent in the sacral ganglia and during recurrence can symptoms are usually more striking than the physical
produce a radiculomyelopathy, with pain in the groin, findings, although a chest radiograph usually shows
buttocks and upper thighs. Primary anorectal herpes diffuse changes throughout both lung fields. CNS
infection is common in male homosexuals (see p. 125). involvement occurs in about 1 per 1000 cases and most
Immunocompromised patients such as those receiving commonly presents as an acute truncal cerebellar ataxia.
intensive cancer chemotherapy or those with the acquired The immunocompromised are susceptible to disseminated
immunodeficiency syndrome (AIDS) may develop infection with multiorgan involvement.
disseminated HSV infection involving many of the
viscera. In severe cases death may result from hepatitis Clinical features of shingles
and encephalitis. Shingles (see p. 1321) occurs at all ages but is most
Neonates may develop primary HSV infection follow- common in the elderly, producing skin lesions similar to
ing vaginal delivery in the presence of active genital HSV chickenpox, although classically they are unilateral and
infection in the mother. The disease in the baby varies restricted to a sensory nerve (dermatomal) distribution
from localized skin lesions to widespread visceral disease (Fig. 2.15). Shingles never occurs as a primary infection
often with encephalitis. Caesarean section should but results from reactivation of latent VZV from dorsal
therefore be considered if active genital HSV infection is
present during labour.
Humoral antibody develops following primary
infection, but mononuclear cell responses are probably
more important in preventing dissemination of disease.
The clinical picture, diagnosis and treatment are
described on page 132.

Varicella zoster virus (VZV) infection


VZV produces two distinct diseases, varicella (chickenpox)
and herpes zoster (shingles). The primary infection is
chickenpox. It usually occurs in childhood, the virus
entering through the mucosa of the upper respiratory
tract. It should be noted that in some countries (e.g. the
Indian subcontinent) a different epidemiological pattern
exists with most infections occurring in adulthood.
Chickenpox rarely occurs twice in the same individual. Fig. 2.14 Chickenpox in an adult. Generalized VZV.
45
Infectio s, tropical medicine and sexually transmitted diseg
46
1 .

Diagnosis
. : ■ ■ • ■ . . ■ . . . trigeminal nerve has an associated incidence
of acute and chronic ophthalmic
complications of 50%. Early treatment with
The diseases are usually recognized clinically but can be aciclovir reduces this to 20% or less. As for
confirmed by electronmicroscopy, immunofluorescence chickenpox, all immunocompromised
or culture of vesicular fluid and by serology. individuals should be given aciclovir at the
onset of shingles.
Prophylaxis and treatment
Chickenpox usually requires no treatment in healthy
children and infection results in lifelong immunity. Cytomegalovirus (CMV)
However, the disease may be fatal in the immuno- infection_____________________________
compromised, who can be offered protection, after expo- Infection with CMV is found world-wide
sure to the virus, with zoster immune immunoglobulin and has its most
(ZIG). profound effects as an opportunistic
Anyone with chickenpox who is over the age of infection in the immunocompromised,
Fig. 2.15 16 years should be considered for antiviral therapy with particularly in recipients of bone-marrow
Shingles aciclovir, or a similar drug, if they present within 72 hours and solid organ transplants and in patients
- VZV of onset. Women in pregnancy are prone to severe with AIDS. Over 50% of the adult
affecting chickenpox and, in addition, there is a risk of intrauterine
population have serological evidence of
a
infection with structural damage to the fetus (mainly in latent infection with the virus, although
dermato
me. the mid trimester - risk rate 2%). For these reasons infection is generally symptomless. As with
Reproduc prophylactic ZIG is recommended for women in preg- all herpes-viruses, the virus persists for
ed with nancy exposed to varicella zoster virus and, if chickenpox life, usually as a latent infection in which
kind develops, aciclovir treatment should be given. (NB: the naked DNA is situated extra-
permissio aciclovir has not been licensed for use in pregnant chromosomally in the nuclei of the cells
n of women.) If a woman has chickenpox at term, her baby in the endothelium of the arterial wall and
Imperial should be protected by ZIG if delivery occurs within in T lymphocytes.
College 5 days of the onset of the mother's illness. An effective
School of varicella vaccine is used in many parts of the USA; it is Clinical features
Medicine.
available on a named-patient basis in the UK. In healthy adults CMV infection is usually
Shingles is also treated with aciclovir and the duration asymptomatic but may cause an illness
root and/ of lesion formation and time to healing can be reduced by similar to infectious mono-nucleosis, with
or cranial early treatment. Aciclovir, valaciclovir and famciclovir fever, occasionally lymphocytosis with
nerve have all been shown to reduce the burden of zoster- atypical lymphocytes, and hepatitis with
ganglia. associated pain when treatment is given in the acute or without jaundice. The Paul-Bunnell test
The phase. Shingles involving the ophthalmic division of the for heterophile antibody is negative.
onset of Infection may be spread by kissing, sexual
the rash intercourse or blood transfusion, and
of transplacentally to the fetus. Disseminated
shingles fatal infection with widespread visceral
is involvement occurs in the
usually immunocompromised (see p. 138) and may
preceded cause encephalitis, retinitis, pneumonitis
by and diffuse involvement of the gastro-
severe intestinal tract.
dermato Intrauterine infection usually occurs in
mal pain, primary
indicatin infection acquired during pregnancy and
g the may have
involve serious consequences in the fetus; CNS
ment of involvement may
sensory cause microcephaly and motor disorders.
nerves in Jaundice and
its hepatosplenomegaly are common, and
pathogen thrombo-
esis. cytopenia and haemolytic anaemia also
Virus is occur. Evidence
dissemin of CNS involvement may be provided by
ated demonstration
from of periventricular calcification on X-ray.
freshly ..... : , .-■.,-.-:
formed
vesicles Diagnosis
and may Serological tests can identify latent (IgG)
cause or primary (IgM) infection. The virus can
chickenp also be identified in tissues by the presence
ox in of characteristic intranuclear 'owl's eye'
suscepti inclusions (Fig. 2.16) on histological staining
ble and by direct immunofluorescence. Culture
contacts. in human embryo fibro-blasts is usually
slow but blood,
diagnosi urine and
s can be respirato
accelerat ry
ed by
immunof
luoresce
nt
detectio
n of
antigen
in the
cultures.
The
polymer
ase
chain
reaction,
which
can be
quanti-
tative,
provides
a
sensitive
way of
detectin
g CMV
in blood
and
other
body
fluids.

Treat
ment
In the
immuno
compete
nt,
infectio
n is
usually
self-
limiting
and no
specific
treatmen
t is
required.
In the
immuno
suppres
sed,
ganciclo
vir
(5mg/kg
daily
for 14-
21 days)
reduces
retinitis
and
gastroint
estinal
damage
and can
eliminate
CMV
from
DNA viruses
increased risk of hypogammaglobulinaemia and/or
lymphoma.
EBV is the cause of oral hairy leucoplakia in AIDS
patients and is the major aetiological agent responsible
for Burkitt's lymphoma, nasopharyngeal carcinoma,
post-transplant lymphoma, and the immunoblastic
lymphoma of AIDS patients and Hodgkin's lymphoma.
Different levels of expression of EBV latency genes occur
in the various clinical conditions caused by the virus.

Diagnosis
EBV infection should be strongly suspected if atypical
mononuclear cells (glandular fever cells) are found in the
peripheral blood. It can be confirmed during the second
week of infection by a positive Paul-Bunnell reaction,
Fig. 2.16 Typical 'owl-eye' inclusion-bearing cell which detects heterophile antibodies (IgM) that agglutinate
infected with cytomegalovirus. sheep erythrocytes. False-positives can occur in other
conditions such as viral hepatitis, Hodgkin's lymphoma
and acute leukaemia. The Monospot test is a sensitive and
secretions. It is less effective against pneumonitis. In easily performed screening test for heterophile anti-
patients who are continually immunocompromised, bodies. Specific EBV IgM antibodies indicate recent
particularly those with AIDS, maintenance therapy may infection by the virus. Clinically similar illnesses are
be necessary. Drug resistance has been reported in AIDS produced by CMV and toxoplasmosis but these can be
patients and transplant recipients. Bone marrow toxicity distinguished serologically.
is common. No antiviral drugs are currently available for
routine treatment of CMV in neonates and the toxicity of Treatment
ganciclovir prohibits its use in most cases. Two other The majority of cases require no specific treatment and
drugs, foscarnet and cidofovir, are available for the recovery is rapid. Corticosteroid therapy is advised when
treatment of CMV infection but both are nephrotoxic and there is neurological involvement (e.g. encephalitis,
their use should be restricted to those with severe disease. meningitis, Guillain-Barre syndrome) or when there is
marked thrombocytopenia or haemolysis.
Epstein-Barr virus (EBV) infection
Human herpesvirus type 6 (HHV-6)
This virus causes an acute febrile illness known as ____________________________________
infectious mononucleosis (glandular fever), which occurs
world-wide in adolescents and young adults. EBV is This human herpesvirus infects CD4+ T lymphocytes,
probably transmitted in saliva and by aerosol. occurs world-wide, and exists as a latent infection in
over 85% of the adult population. It is spread by contact
Clinical features with oral secretions. The virus causes roseola infantum
The predominant symptoms are fever, headache, malaise (exanthem subitum) which presents as a high fever
and sore throat. Palatal petechiae and a transient macular followed by generalized macular rash in infants. HHV-6
rash are common, the latter occurring in 90% of patients is a common cause of febrile convulsions, and aseptic
who have received ampicillin (inappropriately) for the meningitis or encephalitis may occur as rare compli-
sore throat. Cervical lymphadenopathy, particularly of cations. Reactivation in the immunocompromised may
the posterior cervical nodes, and splenomegaly are lead to severe pneumonia.
characteristic. Mild hepatitis is common, but other com-
plications such as myocarditis, meningitis, encephalitis, Treatment
mesenteric adenitis and splenic rupture are rare. Supportive management only is recommended for the
Although some young adults remain debilitated and common infantile disease. Ganciclovir can be used in the
depressed for some months after infection, the evidence immunocompromised.
for reactivation of latent virus in healthy individuals is
controversial, although this is thought to occur in Human herpesvirus type 7 (HHV-7)
immunocompromised patients. Following primary
infection, EBV remains latent in resting memory B This virus is similar to HHV-6 in being a T lymphotropic
lymphocytes. It has been shown in vitro that of nearly 100 herpesvirus. It is also present as a latent infection in over
viral genes expressed during replication, approximately 85% of the adult population and it is known to infect
only 10 are expressed in the latently infected B cells. CD4+ helper T cells by using the CD4 antigen (the main
Severe, often fatal infectious mononucleosis may result receptor employed by HIV). The full spectrum of disease
from a rare X-linked immunoproliferative syndrome due to HHV-7 has not yet been fully characterized, but,
affecting young boys. Those who survive have an like HHV-6, it is known to cause roseola infantum in
infants. , , . : ,
47
Infectious diseases, tropical medicine and sexually transmitted diseases
Human herpesvirus type 8 (Kaposi's POXVIRUSES ?
sarcoma-associated herpesvirus) Smallpox (variola)
This human herpesvirus is strongly associated with the This disease was eradicated in 1977 following an
aetiology of classical and AIDS-related Kaposi's sarcoma. aggressive vaccination policy and careful detection of
Antibody prevalence is high in those with tumours but new cases coordinated by the World Health Organization.
relatively low in the general population of most Its possible use in bioterrorism has resulted in the
industrialized countries. High rates of infection (> 50% reintroduction of smallpox vaccination in some countries
population) have been described in central and southern (p. 1031).
Africa and this matches the geographic distribution of
Kaposi's sarcoma before the era of AIDS. HHV-8 can be Monkeypox
sexually transmitted among homosexual men, through This is a rare zoonosis that occurs in small villages in the
heterosexual sex and through exposure to blood from tropical rainforests in several countries of western and
needle sharing. It is thought that salivary transmission central Africa. Its clinical effects, including a generalized
may be the predominant route in Africa. HHV-8 RNA vesicular rash, are indistinguishable from smallpox, but
transcripts have been detected in Kaposi's sarcoma cells person-to-person transmission is unusual. Serological
and in circulating mononuclear cells from patients with surveys indicate that several species of squirrel are likely
the tumour. This virus may also have a pathogenetic role to represent the animal reservoir.
in primary pulmonary hypertension.
Cowpox
Cowpox produces large vesicles which are classically on
PAPOVAVIRUSES __________ the hands in those in contact with infected cows. The
lesions are associated with regional lymphadenitis and
These viruses tend to produce chronic infections, often
fever. Cowpox virus has been found in a range of species
with evidence of latency. They are capable of inducing
including domestic and wild cats, and the reservoir is
neoplasia in some animal species and were among the
first viruses to be implicated in tumorigenesis. Human thought to exist in a range of rodents.
papillomaviruses, of which there are at least 70 types, are
responsible for the common wart and have been Vaccinia virus
implicated in the aetiology of carcinoma of the cervix This is a laboratory virus and does not occur in nature in
(mainly types 16 and 18) and oral cancer (type 16). The either humans or animals. Its origins are uncertain but it
human BK virus, a polyomavirus, is generally found in has been invaluable in its use as the vaccine to prevent
immunocompromised individuals and may be detected smallpox. Vaccination is now not recommended except
in the urine of 15-40% of renal transplant patients, in for laboratory personnel handling certain poxviruses for
patients receiving cytotoxic chemotherapy, and in those experimental purposes or in contingency planning to
with immunodeficiency states. A related virus, JC, is the manage a deliberate release of smallpox virus. It is being
cause of progressive multifocal leucoencephalopathy assessed experimentally as a possible carrier for new
(PML) which presents as dementia in the immuno- vaccines. - ■ • ■ • ; • ■ ;
compromised and is due to progressive cerebral
destruction resulting from accumulation of the virus in Orf
brain tissue. This poxvirus causes contagious pustular dermatitis in
For genital warts see page 126. sheep and hand lesions in humans (see p. 1322).

Molluscum contagiosum
This is discussed on page 1322.
HUMAN PARVOVIRUS B19
FURTHER READING
Human parvovirus B19 produces erythema infectiosum Cohen JI (2000) Epstein-Barr infection. New England
(fifth disease), a common infection in schoolchildren. The Journal of Medicine 343: 1778-1787. Frey SE,
rash is typically on the face (the 'slapped-cheek' Belshe RB (2004) Poxvirus zoonoses. New
appearance). The patient is well and the rash can recur England Journal of Medicine 350: 324-327. Gnann
over weeks or months. Asymptomatic infection occurs in JW, Whitley RJ (2002) Herpes zoster. New
20% of children. Moderately severe self-limiting arthro- England Journal of Medicine 347: 340-346. Prober
pathy (see p. 573) is common if infection occurs in C (2005) Sixth disease and the ubiquity of
human herpes viruses. New England journal of
adulthood. Aplastic crisis may occur in patients with Medicine 352: 753-755. Whitley R, Roizman B
chronic haemolysis (e.g. sickle cell disease). Chronic (2001) Herpes simplex
infection with anaemia occurs in immunocompromised infections. Lancet 357: 1513-1518. Young NS,
subjects. Hydrops fetalis (3% risk) and spontaneous Brown KE (2004) Parvovirus B19. New
abortion (9% risk) may result from infection during the England Journal of Medicine 350: 586-598.
first and second trimesters of pregnancy.
48
RNA viruses
RNA VIRUSES Abortive poliomyelitis
Abortive poliomyelitis occurs in approximately 4—5% of
PICORNAVIRUSES cases and is characterized by the presence of fever, sore
throat and myalgia. The illness is self-limiting and of
Poliovirus infection (poliomyelitis) short duration.
____________________________________
Non-paralytic poliomyelitis
Poliomyelitis occurs when a susceptible individual is Non-paralytic poliomyelitis has features of abortive
infected with poliovirus type 1, 2 or 3. These viruses have poliomyelitis as well as signs of meningeal irritation, but
a propensity for the nervous system, especially the recovery is complete.
anterior horn cells of the spinal cord and cranial nerve
motor neurones. Poliomyelitis is found world-wide but Paralytic poliomyelitis
its incidence has decreased dramatically following Paralytic poliomyelitis occurs in approximately 0.1% of
improvements in sanitation, hygiene and the widespread infected children (1.3% of adults). Several factors
use of polio vaccines. Spread is usually via the faeco-oral predispose to the development of paralysis:
route, as the virus is excreted in the faeces.
■ male sex
Clinical features ■ exercise early in the illness
The incubation period is 7-14 days. Although polio is ■ trauma, surgery or intramuscular injection, which
essentially a disease of childhood, no age is exempt. The localize the paralysis
clinical manifestations vary considerably. ■ recent tonsillectomy (bulbar poliomyelitis).
This form of the disease is characterized initially by
Inapparent infection features simulating abortive poliomyelitis. Symptoms
Inapparent infection is common and occurs in 95% of subside for 4-5 days, only to recur in greater severity with
infected individuals.
Table 2.20 Human RNA viruses
Structure Approximate size Family Viruses
Symmetry Envelope
Icosahedral _ 30 nm Picornavirus Poliovirus
Coxsackievirus
Echovirus
Enterovirus 68-72
Rhinovirus
Icosahedral - 80 nm Reovirus Reovirus
Rotavirus
Icosahedral + 50-80 nm Togavirus Rubella virus
Alphaviruses
Flaviviruses
Spherical + 80-100 nm Bunyavirus Congo-Crimean haemorrhagic fever
Hantavirus
Spherical - 35-40 nm Calicivirus Noravirus
Hepatitis E
Spherical - 28-30 nm Astrovirus Astrovirus
Helical + 80-120 nm Orthomyxovirus Influenza viruses A, B and C
Helical + 100-300 nm Paramyxovirus Measles virus
Mumps virus
Respiratory syncytial virus
Human metapneumovirus
Nipah virus
Hendra virus
Helical + 80-220 nm Coronavirus URTI (229E, OC43)
SARS
Helical + 60-175 nm Rhabdovirus Lyssavirus - rabies
Helical + 100 nm Retrovirus Human immunodeficiency viruses
(HIV 1 and 2)
Human T cell lymphotropic virus
(HTLV 1 and 2)
Helical + 100-300 nm Arenavirus Lassa virus
Lymphocytic choriomeningitis virus
Pleomorphic + Filaments or circular forms; Filovirus Marburg virus
100x130-2600 nm Ebola virus

49
Infectious diseases, tropical medicine and sexually transmitted diseases
signs of meningeal irritation and muscle pain, which is expected within the next 1-2 years. However, there have
most prominent in the neck and lumbar region. These been recent outbreaks in West Africa where cultural
symptoms persist for a few days and are followed by the taboos have disrupted the polio vaccination campaign
onset of asymmetric paralysis without sensory involve- and recently in the Sudan. Trivalent oral poliovaccine
ment. The paralysis is usually confined to the lower limbs (OPV) (active virus) is currently used (see Box 2.6);
in children under 5 years of age and the upper limbs in occasionally, inactivated poliovirus vaccine (IPV) is used
older children, whereas in adults it manifests as intramuscularly for the immunocompromised and their
paraplegia or quadriplegia. family contacts and for women in pregnancy. Recent
studies using inactivated poliovirus vaccine have
Bulbar poliomyelitis revealed greater potency than the original Salk IPV. The
Bulbar poliomyelitis is characterized by the presence of greater reliability of IPV in hot climates and the scientific
cranial nerve involvement and respiratory muscle and ethical problems of continuing to use OPV in
paralysis. Soft palate, pharyngeal and laryngeal muscle countries free from poliomyelitis, mean that IPV is to be
palsies are common. introduced for immunization schedules in the UK in the
Aspiration pneumonia, myocarditis, paralytic ileus future.
and urinary calculi are late complications of poliomyelitis.
Coxsackievirus, echovirus and other
Diagnosis enterovirus infections
The diagnosis is a clinical one. Distinction from Guillain-
Barre syndrome is easily made by the absence of sensory These viruses are spread by the faeco-oral route. They
involvement and the asymmetrical nature of the paralysis each have a number of different types and are responsible
in poliomyelitis. Laboratory confirmation and distinction for a broad spectrum of disease involving the skin and
between the wild virus and vaccine strains is achieved by mucous membranes, muscles, nerves, the heart (Table 2.21)
virus culture, neutralization and temperature marker and, rarely, other organs, such as the liver and pancreas.
tests. They are frequently associated with pyrexial illnesses and
are the most common cause of aseptic meningitis.
Treatment
Treatment is supportive. Bed rest is essential during the Herpangina
early course of the illness. Respiratory support with inter- This disease is mainly caused by Coxsackie A viruses and
mittent positive-pressure respiration is required if the presents with a vesicular eruption on the fauces, palate
muscles of respiration are involved. Once the acute phase and uvula. The lesions evolve into ulcers. The illness is
of the illness has subsided, occupational therapy, physio- usually associated with fever and headache but is short-
therapy and occasionally surgery have important roles in lived, recovery occurring within a few days.
patient rehabilitation.
Hand, foot and mouth disease
Prevention and control This disease is mainly caused by Coxsackievirus A16 or
Immunization has dramatically decreased the prevalence A10. Oral lesions are similar to those seen in herpangina
of this disease world-wide and global eradication of the but may be more extensive in the oropharynx. Vesicles
virus, coordinated by the World Health Organization, is and a maculopapular eruption also appear, typically on
Table 2.21 Picornavirus infections (excluding poliovirus and rhinovirus)
Disease Coxsackievirus Echovirus Enterovirus
B (types 1-9, 11-7, 29-33) (types 68-71)
(types 8,-Be)
(types A^Aa, A24)
50 Cutaneous and oropharyngeal
Herpangina +++
Hand, foot and mouth +++
Erythematous rashes +
Neurological
Paralytic +
Meningitis ++
Encephalitis ++
Cardiac
Myocarditis and pericarditis +
Muscle
Myositis (Bornholm disease) +
+++, often causes; ++, sometimes causes; +/arely causes; ±, possibly
causes
the palms of the hands and the soles of the feet, but also
on other parts of the body. This infection commonly
affects children. Recovery occurs within a week.

Neurological disease
Other enteroviruses in addition to poliovirus can cause a
broad range of neurological disease, including meningitis,
encephalitis, and a paralytic disease characteristic of
poliomyelitis.

Heart and muscle disease


Enteroviruses are cause of acute myocarditis and peri-
carditis, from which, in general, there is complete recovery.
However, these viruses can also cause chronic congestive
cardiomyopathy and, rarely, constrictive pericarditis.
Skeletal muscle involvement, particularly of the
intercostal muscles, is a feature of Bornholm disease, a
febrile illness usually due to Coxsackievirus B. The pain
may be of such an intensity as to mimic pleurisy or an
acute abdomen. The infection affects both children and Fig. 2.17 Electronmicrograph of human rotavirus.
adults and may be complicated by meningitis or cardiac
involvement.
infections are common, and bottle-fed babies are more
likely to be symptomatic than those that are breast-fed.
Rhinovirus infection __________________
Adults may become infected with rotavirus but
Rhinoviruses are responsible for the common cold (see symptoms are usually mild or absent. The virus may,
p. 895). Chimpanzees and humans are the only species to however, cause outbreaks of diarrhoea in patients on care
develop the common cold. ICAM-1 is the cellular receptor of the elderly wards.
(p. 199) for rhinovirus and it is only in these two species
that the specific binding domain is present. Peak Clinical features
incidence rates occur in the colder months, especially The illness is characterized by vomiting, fever, diarrhoea,
spring and autumn. There are multiple rhinovirus and the metabolic consequences of water and electrolyte
immunotypes (>100), which makes vaccine control loss.
impracticable. In contrast to enteroviruses, which
replicate at 37°C, rhinoviruses grow at 33°C (the Diagnosis and treatment
temperature of the upper respiratory tract), which The diagnosis can be established by ELISA for the detec-
explains the localized disease characteristic of common tion of rotavirus antigen in faeces and by electron-
colds. microscopy of faeces. Histology of the jejunal mucosa in
children shows shortening of the villi, with crypt hyper-
REOVIRUSES plasia and mononuclear cell infiltration of the lamina
propria.
Reovirus infection Treatment is directed at overcoming the effects of
water and electrolyte imbalance with adequate oral
Reovirus infection occurs mainly in children, causing rehydration therapy and, when indicated, intravenous
mild respiratory symptoms and diarrhoea. A few deaths fluids (see Box 2.9). Antibiotics should not be prescribed.
have been reported following disseminated infection of Rhesus-human reassortant vaccines have been
brain, liver, heart and lungs. developed whereby a human rotavirus VP7 is expressed
on the surface of a rhesus rotavirus. The tetravalent
Rotavirus infection vaccine contains three reassortants for human rotavirus
G-types 1, 2 and 4 plus the rhesus rotavirus (G-type 3).
Rotavirus (Latin rota = wheel) is so named because of its This vaccine (IRRV-TV; rhesus (human) rotavirus -
electronmicroscopic appearance with a characteristic tetravalent vaccine) has been shown to give high levels of
circular outline with radiating spokes (Fig. 2.17). It is protection in children in resource-deprived countries.
responsible world-wide for both sporadic cases and Although initially licensed by the FDA in the USA, it has
epidemics of diarrhoea, and is currently one of the most been withdrawn owing to an increased incidence of
important causes of childhood diarrhoea. More than intussusception in the vaccinees. :■ .
870 000 children under the age of 5 years are estimated to
die annually in resource-deprived countries, compared
with 75-150 in the USA. The prevalence is higher during Other viruses
the winter months in non-tropical areas. Asymptomatic Other viruses associated with gastroenteritis are shown in
Table 2.22. These include members of two major families
which can be recognized by their electronmicroscopic
appearance. Caliciviruses, which include the noraviruses
51
Infectious diseases, tropical medicine and sexually transmitted diseases
Table 2.22 Viruses associated with gastroenteritis
Rotavirus (groups A, B, C, D and E)
Enteric adenovirus (types 40 and 41)
Noravirus (Norwalk-like viruses of calicivirus family)
Astrovirus

(previously known as Norwalk agent, a small round


structured virus) and astroviruses, are responsible for
winter vomiting. Although gastroenteritis viruses are
normally spread by the faeco-oral route, aerosol spread
also occurs.

TOGAVI RUSES
This family comprises three genera: the rubiviruses, Fig. 2.18 Rubella rash.
which include rubella virus; and the alphaviruses and
flaviviruses, which each include some of the arthropod-
borne viruses. Congenital rubella syndrome is characterized by the
presence of fetal cardiac malformations, especially patent
Rubella ductus arteriosus and ventricular septal defect, eye
lesions (especially cataracts), microcephaly, mental
Rubella ('German measles') is caused by a spherical, retardation and deafness.
enveloped RNA virus which is easily killed by heat and The expanded rubella syndrome consists of the
ultraviolet light. While the disease can occur sporadically, manifestations of the congenital rubella syndrome plus
epidemics are not uncommon. It has a world-wide distri- other effects including hepatosplenomegaly, myocarditis,
bution. Spread of the virus is via droplets; maximum interstitial pneumonia and metaphyseal bone lesions.
infectivity occurs before and during the time the rash is
present. Diagnosis and treatment
The diagnosis may be suspected clinically, but laboratory
Clinical features diagnosis is essential to distinguish the illness from other
The incubation period is 14-21 days, averaging 18 days. virus infections (e.g. echovirus) and drug rashes. This is
The clinical features are largely determined by age, with achieved by demonstrating a rising antibody titre
symptoms being mild or absent in children under 5 years. (measured using the sensitive haemagglutination-
During the prodrome the patient may develop malaise inhibiting antibody (HAI) test or ELISA) in two successive
and fever. Mild conjunctivitis and lymphadenopathy may blood samples taken 14 days apart or by the detection of
be present. The distribution of the lymphadenopathy is rubella-specific IgM. The virus can be cultured from throat
characteristic and involves particularly the suboccipital, swabs (or oral fluid samples), urine and, in the case of
postauricular and posterior cervical groups of lymph intrauterine infection, the products of conception.
nodes. Small petechial lesions on the soft palate Treatment is supportive. .
(Forchheimer spots) are suggestive but not diagnostic.
Splenomegaly may be present. Prevention
The eruptive or exanthematous phase usually occurs Human immunoglobulin can decrease the symptoms of
within the first 7 days of the initial symptoms. The rash this already mild illness, but does not prevent the
first appears on the forehead and then spreads to involve teratogenic effects. Several live attenuated rubella
the trunk and the limbs. It is pinkish red, macular and vaccines have been used with great success in preventing
discrete, although some of these lesions may coalesce this illness and these have been successfully combined
(Fig. 2.18). It usually fades by the second day and rarely with the measles and mumps (MMR) vaccine. The side-
persists beyond the third day after its appearance. effects of vaccination have been dramatically decreased
by using vaccines prepared in human embryonic
Complications fibroblast cultures (RA 27/3 vaccine). Use of the vaccine
Complications are rare. They include superadded is contraindicated during pregnancy or if there is a likeli-
pulmonary bacterial infection, arthralgia, haemorrhagic hood of pregnancy within 3 months of immunization.
manifestations due to thrombocytopenia, encephalitis Inadvertent use of the vaccine during pregnancy has not,
and the congenital rubella syndrome. Rubella affects the however, revealed a risk of teratogenicity.
fetuses of up to 80% of all women who contract the infec-
tion during the first trimester of pregnancy. The incidence
of congenital abnormalities diminishes in the second Arbovirus (arthropod-borne) infection
trimester and no ill-effects result from infection in the Arboviruses are zoonotic viruses, with the possible
third trimester. exception of the O'nyong-nyong fever virus of which
52
RNA viruses

humans are the only known vertebrate hosts. They are Flaviviruses
transmitted through the bites of insects, especially There are 60 viruses in this group, some of which are
mosquitoes, and ticks. Over 385 viruses are classified as transmitted by ticks and others by mosquitoes.
arboviruses. Culex, Aedes and Anopheles mosquitoes
account for the transmission of the majority of these
viruses.
Yellow fever
Although most arbovirus diseases are generally mild, Yellow fever, caused by a flavivirus, results in an illness of
epidemics are frequent and when these occur the widely varying severity so that the disease is under-
mortality is high. In general, the incubation period is less reported. It is a disease confined to Africa (90% of cases)
than 10 days. The illness tends to be biphasic and, as in and South America between latitudes 15° N and 15° S. For
other viral fevers, pyrexia, conjunctival suffusion, a rash, poorly understood reasons, yellow fever has not been
retro-orbital pain, myalgia and arthralgia are common. reported from Asia, despite the fact that climatic
Lymphadenopathy is seen in dengue. Lifelong immunity conditions are suitable and the vector, Aedes aegypti, is
to a particular virus is usual. In some of these viral fevers, common. The infection is transmitted in the wild by A.
haemorrhage is a feature (Table 2.23). Increased vascular africanus in Africa and the Haemagogus species in South
permeability, capillary fragility and consumptive and Central America. Extension of infection to humans
coagulopathy have been implicated as causes of the (via the mosquito or from monkeys) leads to the
haemorrhage. Encephalitis resulting from cerebral occurrence of 'jungle' yellow fever. A. aegypti, a domestic
invasion may be prominent in some fevers. mosquito which lives in close relationship to humans, is
responsible for human-to-human transmission in urban
Alphaviruses areas (urban yellow fever). Once infected, a mosquito
The 24 viruses of this group are all transmitted by remains so for its whole life.
mosquitoes; eight result in human disease. These viruses
are globally distributed and tend to acquire their Clinical features
names from the location where they were first isolated The incubation period is 3-6 days. When the infection is
(such as Ross River, Eastern Venezuelan, and Western mild, the disease is indistinguishable from other viral
encephalitis viruses) or by the local expression for a major fevers such as influenza or dengue.
symptom caused by the virus (such as chikungunya, Three phases in the severe (classical) illness are
meaning 'doubled up'). Infection is characterized by recognized. Initially the patient presents with a high fever
fever, skin rash, arthralgia, myalgia and sometimes of acute onset, usually 39^0°C, which then returns to
encephalitis. normal in 4-5 days. During this time, headache is
prominent. Retrobulbar pain, myalgia, arthralgia, a
flushed face and suffused conjunctivae are common.
Epigastric discomfort and vomiting are present when the
Table 2.23 Viral infections associated with illness is severe. Relative bradycardia (Faget's sign) is
haemorrhagic manifestations*
present from the second day of illness. The patient then
Togavirus makes an apparent recovery and feels well for several
Flavivirus days. Following this 'phase of calm' the patient again
Yellow fever (urban and sylvan) develops increasing fever, deepening jaundice and
Dengue haemorrhagic fever hepatomegaly. Ecchymosis, bleeding from the gums,
Kysanur Forest disease Omsk haematemesis and melaena may occur. Coma, which is
haemorrhagic fever Rift Valley
usually a result of uraemia or haemorrhagic shock, occurs
fever Alphavims Chikungunya
for a few hours preceding death. The mortality rate is up
Bunyavirus to 40% in severe cases. The pathology of the liver shows
Congo-Crimean haemorrhagic fever mid-zone necrosis, and eosinophilic degeneration of
Hantavirus infections hepatocytes (Councilman bodies) (see p. 362).

Arena virus Diagnosis and treatment


Argentinian haemorrhagic fever The diagnosis is established by a careful history of travel
Bolivian haemorrhagic fever Lassa and vaccination status, and by isolation of the virus
fever Epidemic haemorrhagic fever (when possible) from blood during the first 3 days of
illness. Serodiagnosis is possible, but in endemic areas
Filovirus
Marburg
cross-reactivity with other flaviviruses is a problem.
Ebola
Treatment is supportive. Bed rest (under mosquito
nets), analgesics, and maintenance of fluid and electrolyte
* Most of these are arboviruses. Some (e.g. hantavirus, Lassa fever) balance are important.
have a rodent vector. The source and transmission route of filoviruses
is not known.
Prevention and control
Yellow fever is an internationally notifiable disease. It is
easily prevented using the attenuated 17D chick embryo
Infectious diseases, tropical medicine and sexually transmitted diseases
vaccine. Vaccination is not recommended for children and there is laboratory evidence of a consumptive
under 9 months and immunosuppressed patients unless coagulopathy.
there are compelling reasons. For the purposes of
international certification, immunization is valid for Diagnosis and treatment
10 years, but protection lasts much longer than this and Isolation of dengue virus by tissue culture in sera
probably for life. The WHO Expanded Programme of obtained during the first few days of illness is diagnostic.
Immunization includes yellow fever vaccination in Demonstration of rising antibody titres by neutralization
endemic areas. (most specific), haemagglutination inhibition 'ELISA'
or complement-fixing antibodies in sequential serum
samples is evidence of dengue virus infection. Blood tests
Dengue show leucopenia and thrombocytopenia.
This is the commonest arthropod-borne viral infection in Treatment is supportive with analgesics and adequate
humans: over 100 million cases occur every year in the fluid replacement; in DHF, blood transfusion may be
tropics, with over 10 000 deaths from dengue haemor- necessary.
rhagic fever. Dengue is caused by a flavivirus and is
found mainly in Asia, South America and Africa, Prevention
although it has been reported from the USA. Four dif- Travellers should be advised to sleep under impregnated
ferent antigenic varieties of dengue virus are recognized nets but this is not very effective as the mosquito bites
and all are transmitted by the daytime-biting A. aegypti in daytime. Topical insect repellents should be used. Adult
which breed in standing water in refuse dumps in inner mosquitoes should be destroyed by sprays, and breeding
cities. A. albopictus is a less common transmitter. Humans sites should be eradicated.
are infective during the first 3 days of the illness (the
viraemic stage). Mosquitoes become infective about
2 weeks after feeding on an infected individual, and
Rift Valley fever
remain so for the rest of their lives. The disease is usually Rift Valley fever, caused by a flavivirus, is primarily an
endemic. Immunity after the illness is partial. acute febrile illness of livestock - sheep, goats and camels.
It is found in southern and eastern Africa. The vector in
Clinical features East Africa is Culex pipiens and in southern Africa, Aedes
The incubation period is 5-6 days following the mosquito cabdlus. Following an incubation period of 3-6 days, the
bite. Asymptomatic or mild infections are common. Two patient has an acute febrile illness that is difficult to
clinical forms are recognized. distinguish clinically from other viral fevers. The
temperature pattern is usually biphasic. The initial febrile
Classic dengue fever illness lasts 2-A days and is followed by a remission and
Classic dengue fever is characterized by the abrupt onset a second febrile episode. Complications are indicative of
of fever, malaise, headache, facial flushing, retrobulbar severe infection and include retinopathy, meningo-
pain which worsens on eye movements, conjunctival encephalitis, haemorrhagic manifestations and hepatic
suffusion and severe backache, which is a prominent necrosis. Mortality approaches 50% in severe forms of the
symptom. Lymphadenopathy, petechiae on the soft illness. Treatment is supportive.
palate and skin rashes may also occur. The rash is
transient and morbilliform. It appears on the limbs and Japanese encephalitis
then spreads to involve the trunk. Desquamation occurs
subsequently. Cough is uncommon. The fever subsides Japanese encephalitis is a mosquito-borne encephalitis
after 3—4 days, the temperature returns to normal for a caused by a flavivirus. It has been reported most
couple of days, and then the fever returns, together with frequently from the rice-growing countries of South East
the features already mentioned, but milder. This biphasic Asia and the Far East. Culex tritaeniorhynchus is the most
or 'saddleback' pattern is considered characteristic. Severe important vector and this feeds mainly on pigs as well as
fatigue, a feeling of being unwell and depression are birds such as herons and sparrows. Humans are
common for several weeks after the fever has subsided. accidental hosts.
As with other viral infections, the clinical manifes-
Dengue haemorrhagic fever (DHF) tations are variable. The onset is heralded by severe
Dengue haemorrhagic fever is a severe form of dengue rigors. Fever, headache and malaise last 1-6 days. Weight
fever and is believed to be the result of two or more loss is prominent. In the acute encephalitic stage the fever
sequential infections with different dengue serotypes. It is is high (38^1 °C), neck rigidity occurs and neurological
a disease of children and has been described almost signs such as altered consciousness, hemiparesis and
exclusively in South East Asia. The disease has a mild convulsions develop. Mental deterioration occurs over a
start, often with symptoms of an upper respiratory tract period of 3^ days and culminates in coma. Mortality
infection. This is then followed by the abrupt onset of varies from 7-40% and is higher in children. Residual
shock and haemorrhage into the skin and ear, epistaxis, neurological defects such as deafness, emotional lability
and hemiparesis occur in about 70% of patients who have
haematemesis and melaena known as the dengue shock
had CNS involvement. Convalescence is prolonged.
syndrome. Serum complement levels are depressed
54
RNA viruses
Antibody detection in serum and CSF by IgM capture cells at specific receptor sites. Cell penetration, probably
ELISA is a useful rapid diagnostic test. An inactivated by pinocytosis, and release of replicated viruses from the
mouse brain vaccine is effective and available. Treatment cell surface is effected by budding through the cell
is supportive. membrane facilitated by the action of the enzyme
neuraminidase (N) which is also present on the viral
envelope. ISH subtypes (H1-H15) and nine N subtypes
West Nile virus (N1-N9) have been identified for influenza A viruses but
In 1999, the West Nile virus was first recognized in the only HI, H2, H3 and Nl and N2 have established stable
western hemisphere (New York, USA) and it had lineages in the human population since 1918.
previously been reported in Africa, Asia and parts of ■ Influenza A is generally responsible for pandemics
Europe. The outbreak in the USA produced thousands of and epidemics.
symptomatic and symptomless infections with 1% result- ■ Influenza B often causes smaller or localized and
ing in encephalitis. It is spread by mosquitoes and infects milder outbreaks, such as in camps or schools.
birds, humans and horses. It can also be transmitted with ■ Influenza C rarely produces disease in humans.
blood transfusions, breast-feeding and organ donation.
Antigenic shift describes the capacity of influenza A to
develop new antigenic variants at irregular intervals. This
BUNYAVIRUSES results from genetic recombination of the RNA of the
Bunyaviruses belong to a large family of more than virus (which is arranged in eight segments) with that of
200 viruses, most of which are arthropod-borne. an animal orthomyxovirus.
Antigenic drift (minor changes in influenza A and
B viruses) results from point mutations leading to amino
Congo-Crimean haemorrhagic fever acid changes in the two surface glycoproteins, haemag-
This is found mainly in Asia and Africa. The primary hosts glutinin (H) and neuraminidase (N), which induce
are cattle and hares and the vectors are the Hyalomma humoral immunity.
ticks. Following an incubation period of 3-6 days there is Thus, changes due to antigenic shift or drift render the
an influenza-like illness with fever and haemorrhagic individual's immune response less able to combat the
manifestations. The mortality is 10-50%. new variant.
Major shifts in the antigenic make-up of influenza A
viruses provide the necessary conditions for major
Hantaviruses pandemics, whereas minor antigenic drifts give rise to
Hantaviruses are enzootic viruses of wild rodents which less severe epidemics because immunity in the popu-
are spread by aerosolized excreta and not by insect lation is less blunted.
vectors. The most severe form of this infection is Korean The most serious pandemic of influenza occurred in
haemorrhagic fever (or haemorrhagic fever with renal 1918, and was associated with more than 20 million
syndrome - HFRS). This condition has a mortality of 5- deaths world-wide. In 1957, a major shift in the antigenic
10% and is characterized by fever, shock and haemor- make-up of the virus led to the appearance of influenza
rhage followed by an oliguric phase. Milder forms of the A2 type H2-N2, which caused a world-wide pandemic. A
disease are associated with related viruses (e.g. Puumala further pandemic occurred in 1968 owing to the
virus) and may present as nephropathia epidemica, an emergence of Hong Kong influenza type H3-N2, and
acute fever with renal involvement. It is seen in minor antigenic drifts have caused outbreaks around the
Scandinavia and in other European countries in people world ever since. In 1997, avian H5-N1 strain of influenza
who have been in contact with bank voles. In the USA, a A was found in humans and represented a major change
new hantavirus (transmitted by the deer mouse) termed in viral surface antigens. Avian flu re-emerged in 2004-5.
Sin Nombre was identified as the cause of outbreaks Purified haemagglutinin and neuraminidase from
of acute respiratory disease in adults, referred to as recently circulating strains of influenza A and B viruses
hantavirus pulmonary syndrome (HPS). Other hantavirus are incorporated in current vaccines.
types and rodent vector systems have been associated Sporadic cases of influenza and outbreaks among
with this syndrome. groups of people living in a confined environment are
Diagnosis of hantavirus infection is made by an ELISA frequent. The incidence increases during the winter
technique for specific antibodies. months. Spread is mainly by droplet infection but fomites
and direct contact have also been implicated.
The clinical features, diagnosis, treatment and
ORTHOMYXOVIRUSES ZZZ prophylaxis of influenza are discussed on page 898.
Influenza
PARAMYXOVIRUSES
Three types of influenza virus are recognized: A, B and C.
The influenza virus is a spherical or filamentous enveloped These are a heterogeneous group of enveloped viruses of
virus. Haemagglutinin (H), a surface glycopeptide, aids varying size that are responsible for parainfluenza, mumps,
attachment of the virus to the wall of susceptible host measles and other respiratory infections (Fig. 2.19).
55
Infectious diseases, tropical medicine and sexually transmitted diseases

Fig. 2.20 Measles. Courtesy of Dr MW McKendrick, Royal


Hallamshire Hospital, Sheffield.
Fig. 2.19 Typical measles
(mumps). m The pre-emptive and catarrhal stage. This is the stage of
viraemia and viral dissemination. Malaise, fever,
rhinorrhoea, cough, conjunctival suffusion and the
Electronmicrograph of a paramyxovirus pathognomonic Koplik's spots are present during this
Parainfluenza stage. Koplik's spots are small, greyish, irregular
lesions surrounded by an erythematous base and are
Parainfluenza is caused by the parainfluenza viruses found in greatest numbers on the buccal mucous
types I-IV; these have a world-wide distribution and membrane opposite the second molar tooth. They
cause acute respiratory disease. Type IV appears to be less occur a day or two before the onset of the rash.
virulent than the other types and has been linked only to ■ The eruptive or exanthematous stage. This is characterized
mild upper respiratory diseases in children and adults. by the presence of a maculopapular rash that initially
Parainfluenza is essentially a disease of children and occurs on the face, chiefly the forehead, and then
presents with features similar to the common cold. When spreads rapidly to involve the rest of the body (Fig.
severe, a brassy cough with inspiratory stridor and features 2.20). At first the rash is discrete but later it may
of laryngotracheobronchitis (croup) are present. Fever is become confluent and patchy, especially on the face
usually present for 2-3 days and may be more prolonged if and neck. It fades in about 1 week and leaves behind a
pneumonia develops. The development of croup is due to brownish discoloration.
submucosal oedema and consequent airway obstruction in
the subglottic region. This may lead to cyanosis, subcostal Although measles is a relatively mild disease in the
and intercostal recession and progressive airway obstruc- healthy child, it carries a high mortality in the mal -
tion. Infection in the immunocompromised is usually nourished and in those who have other diseases. Compli -
prolonged and may be severe. Treatment is supportive with cations are common in such individuals and include
oxygen, humidification and sedation when required. The bacterial pneumonia, bronchitis, otitis media and gastro-
role of steroids is controversial. enteritis. Less commonly, myocarditis, hepatitis and
encephalomyelitis may occur. In those who are mal-
nourished or those with defective cell-mediated immunity,
Measles (rubeola) the classical maculopapular rash may not develop and
Measles is a highly communicable disease that occurs widespread desquamation may occur. The virus also
world-wide. With the introduction of aggressive immu causes the rare condition, subacute sclerosing panen-
nization policies, the incidence of measles has fallen cephalitis, which may follow measles infection occurring
dramatically in the West, but it still remains one of the early in life (<18 months of age). Persistence of the virus
most common childhood infections in resource-deprived with reactivation pre-puberty results in accumulation of
countries, where it is associated with a high morbidity virus in the brain, progressive mental deterioration and a
and mortality. It is spread by droplet infection and the fatal outcome (see p. 1240).
period of infectivity is from 4 days before until 2 days Maternal measles, unlike rubella, does not cause fetal
after the onset of the rash. , , abnormalities. It is, however, associated with sponta-
neous abortions and premature delivery.
Clinical features
The incubation period is 8-14 days. Two distinct phases Atypical measles
of the disease can be recognized. In the past, a severe illness called atypical measles occurred
in individuals given an inactivated vaccine (now with -
drawn). This vaccine conferred incomplete protection
and on exposure to the wild measles virus they developed
56
RNA viruses
high fever, myalgia, abdominal pain and a variety of skin Diagnosis and treatment
rashes which could be mistaken for scarlet fever, The diagnosis of mumps is on the basis of the clinical
meningococcal disease or varicella. Pneumonia was features. In doubtful cases, serological demonstration of a
invariably present and pulmonary infiltrates persisted for fourfold rise in antibodies detected by complement
years in some cases. fixation or indirect haemagglutination or neutralization
tests on acute and convalescent sera is diagnostic. Virus
Diagnosis and treatment can be isolated in cell culture from saliva, throat swab,
Most cases of measles are diagnosed clinically but, if necess- urine and CSF and identified by immunofluorescence or
ary, immunofluorescence, virus culture and serological haemadsorption.
tests (complement fixation test (CFT), haemagglutination Treatment is supportive. Attention should be given to
inhibition tests) are used to confirm the diagnosis. adequate nutrition and mouth care. Analgesics should be
Treatment is supportive. Antibiotics are indicated only used to relieve pain. .. ■
if secondary bacterial infection occurs.
Prevention
Prevention Active immunization. Children are immunized with
A previous attack of measles confers a high degree of the MMR vaccine (Box 2.6). Vaccination is contraindicated
immunity and second attacks are uncommon. Normal in immunosuppressed individuals, during pregnancy, or
human immunoglobulin given within 5 days of exposure in those with severe febrile illnesses.
effectively aborts an attack of measles. It is indicated for
previously unimmunized children below 3 years of age,
during pregnancy, and in those with debilitating disease. Respiratory syncytial virus infection
Respiratory syncytial virus (RSV) is a paramyxovirus that
Active immunization. Children are immunized with causes many respiratory infections in epidemics each
the combined mumps-measles-rubella (MMR) vaccine winter. It is a common cause of bronchiolitis in infants,
(Box 2.6). which is complicated by pneumonia in approximately
10% of cases. The infection normally starts with upper
Mumps __________ respiratory symptoms. After an interval of 1-3 days a
cough and low-grade fever may develop. The onset of
Mumps is the result of infection with a paramyxovirus. It
bronchiolitis is characterized by dyspnoea and hyper-
is spread by droplet infection, by direct contact or
expansion of the chest with subcostal and intercostal
through fomites. Humans are the only known natural
recession. The disease may be severe and potentially
hosts. The peak period of infectivity is 2-3 days before the
fatal in babies with underlying cardiac or respiratory
onset of the parotitis and for 3 days afterwards.
disease. RSV infection has been associated with the
occurrence of sudden infant death syndrome (SIDS).
Clinical features
Immunity is short-lived and, consequently, reinfection
The incubation period averages 18 days. Although no age can occur throughout life. RSV is occasionally the cause of
is exempt, it is primarily a disease of school-aged children outbreaks of pneumonia in the elderly and in the
and young adults; it is uncommon before the age of immunocompromised.
2 years. The prodromal symptoms are non-specific and
Transfer of infection between children in hospital
include fever, malaise, headache and anorexia. This is
commonly occurs unless infected patients are isolated or
usually followed by severe pain over the parotid glands,
cohorted. Meticulous attention to handwashing and other
with either unilateral or bilateral parotid swelling. The
infection control measures reduces the risk of trans -
enlarged parotid glands obscure the angle of the mandible
mission by staff members.
and may elevate the ear lobe, which does not occur in
cervical lymph node enlargement. Trismus due to pain is Diagnosis and treatment
common at this stage. Submandibular gland involvement
Immunofluorescence on nasopharyngeal aspirates, virus
occurs less frequently.
culture and serology are the usual ways of confirming the
Complications diagnosis.
Treatment is generally supportive, but aerosolized
CNS involvement is the most common extrasalivary-
ribavirin can be given to severe cases, particularly those
gland manifestation of mumps. Clinical meningitis
with underlying cardiac or respiratory disease see p. 41).
occurs in 5% of all infected patients, and 30% of patients
with CNS involvement have no evidence of parotid gland Prevention
involvement.
No vaccine is available for RSV but high-risk children
Epididymo-orchitis develops in about one-third of
(including those with bronchopulmonary dysplasia and
patients who develop mumps after puberty. Bilateral
congenital heart disease) can be protected against severe
testicular involvement results in sterility in only a small
disease by monthly administration of either a hyper-
percentage of these patients. Pancreatitis, oophoritis,
immune globulin against RSV, or a humanized mono-
myocarditis, mastitis, hepatitis and polyarthritis may also
clonal antibody Palivizumab, during the winter months
occur.
(see p. 41).
57
Infectious diseases, tropical medicine and sexually transmitted diseases
Metapneumovirus With the exception of Australia, New Zealand and the
Antarctic, human rabies has been reported from all
This recently discovered virus causes approximately 20% continents. Transmission is usually through the bite of an
of lower respiratory tract infections in infants and young infected animal. However, the percentage of rabid bites
children. leading to clinical disease ranges from 10% (on the legs)
to 80% (on the head). Other forms of transmission, if they
Hendra and Nipah viruses occur, are rare.
Hendra virus (formerly called equine morbillivirus) and Having entered the human body, the virus replicates
Nipah virus are newly recognized zoonotic viruses that in the muscle cells near the entry wound. It penetrates the
have caused disease in humans who have been in contact nerve endings and travels in the axoplasm to the spinal
with infected animals (horses and pigs respectively). The cord and brain. In the CNS the virus again proliferates
viruses are named after the locations where they were before spreading to the salivary glands, lungs, kidneys
first isolated, Hendra in Australia and Nipah in Malaysia, and other organs via the autonomic nerves.
and both are classified as paramyxoviruses. Hendra virus There have been only two recorded cases of survival
has caused severe respiratory distress in horses and from clinical rabies.
humans and Nipah virus caused a major outbreak of viral
encephalitis (265 cases and 105 deaths) in Malaysia Clinical features
between September 1998 and April 1999. Treatment of The incubation period is variable and may range from a
these conditions is largely supportive, although there is few weeks to several years; on average it is 1-3 months.
some evidence that early treatment with ribavirin may In general, bites on the head, face and neck have a shorter
reduce the severity of the diseases. incubation period than those elsewhere. In humans, two
distinct clinical varieties of rabies are recognized:
CORONAVIRUSES ■ furious rabies - the classic variety
■ dumb rabies - the paralytic variety.
Human coronaviruses were first isolated in the mid 1960s
and the majority of isolates (related to the reference
Furious rabies
strains 229E and OC43) have been associated with
The only characteristic feature in the prodromal period is
common colds. In November 2002, an apparently new
the presence of pain and tingling at the site of the initial
viral disease occurred in China (Guangdong province)
wound. Fever, malaise and headache are also present.
and this spread rapidly in other parts of the Far East and
About 10 days later, marked anxiety and agitation or
also in Canada (Toronto and Vancouver).
depressive features develop. Hallucinations, bizarre
This disease, known as 'severe acute respiratory
behaviour and paralysis may also occur. Hyper-
syndrome' (SARS-COV) of which bronchopneumonia has
excitability, the hallmark of this form of rabies, is
been a major feature, is caused by a previously unknown
precipitated by auditory or visual stimuli. Hydrophobia
coronavirus. Similarity of this virus to coronaviruses
(fear of water) is present in 50% of patients and is due to
isolated from civet cats, raccoons and ferret badgers
severe pharyngeal spasms on attempting to eat or drink.
indicates the likelihood that SARS is a zoonotic disease.
Aerophobia (fear of air) is considered pathognomonic of
The epidemic was finally brought under control in the
rabies. Examination reveals hyperreflexia, spasticity, and
summer of 2003 and by then there had been > 8000 cases
evidence of sympathetic overactivity indicated by
with approximately 800 deaths.
pupillary dilatation and diaphoresis.
The patient goes on to develop convulsions, respiratory
RHABDOVIRUSES paralysis and cardiac arrhythmias. Death usually occurs
in 10-14 days.
Rabies
Dumb rabies
Rabies is a major problem in some countries, and Dumb rabies, or paralytic rabies, presents with a sym-
established infection is invariably fatal. It is a genotype 1, metrical ascending paralysis resembling the Guillain-
single-stranded RNA virus of the Lyssavirus genus. The Barre syndrome. This variety of rabies commonly occurs
rabies virus is bullet-shaped and has spike-like structures after bites from rabid bats.
arising from its surface containing glycoproteins that
cause the host to produce neutralizing, haemagglutination-
inhibiting antibodies. The virus has a marked affinity for Diagnosis
nervous tissue and the salivary glands. It exists in two The diagnosis of rabies is generally made clinically. Skin-
major epidemiological settings: punch biopsies are used to detect antigen with an
■ Urban rabies is most frequently transmitted to humans
immunofluorescent antibody test on frozen section. Viral
through rabid dogs and, less frequently, cats. RNA can be isolated using the reverse transcription
■ Sylvan (wild) rabies is maintained in the wild by a host
polymerase chain reaction (RT-PCR). Isolation of viruses
of animal reservoirs such as foxes, skunks, jackals, from saliva or the presence of antibodies in blood or CSF
mongooses and bats. may establish the diagnosis. The corneal smear test is not
recommended as it is unreliable. The classic Negri bodies
58
RNA viruses
are detected at post-mortem in 90% of all patients with Table 2.24 Human lymphotropic retroviruses
rabies; these are eosinophilic, cytoplasmic, ovoid bodies,
Subfamily Virus Disease
2-10 run in diameter, seen in greatest numbers in the
neurones of the hippocampus and the cerebellum. The Lentivirus HIV-1 AIDS
diagnosis should be made pathologically on the biting HIV-2 AIDS
animal using RT-PCR, immunofluorescence assay (IFA) Oncovirus HTLV-1* Adult T cell leukaemia/
or tissue culture of the brain. lymphoma
Tropical spastic paraparesis
Treatment HTLV-2 Myelopathy
Once the CNS disease is established, therapy is symp- * HTLV, human T cell lymphotropic virus

tomatic as death is virtually inevitable. The patient


should be nursed in a quiet, darkened room. Nutritional,
respiratory and cardiovascular support may be necessary. HIV-1 and the related virus, HIV-2, are further
Drugs such as morphine, diazepam and chlorpromazine classified as lentiviruses ('slow' viruses) because of their
should be used liberally in patients who are excitable. slowly progressive clinical effects.
HIV-1 and HIV-2 are discussed on page 130.
Prevention HTLV-1 causes adult T cell leukaemia/lymphoma and
Pre-exposure prophylaxis. This is given to individuals tropical spastic paraparesis (see p. 1193).
with a high risk of contracting rabies, such as laboratory
workers, animal handlers and veterinarians. Two doses of
human diploid cell vaccine (HDCV) 1.0 mL deep ARENAVIRUSES
subcutaneously or intramuscularly given 4 weeks apart Arenaviruses are pleomorphic, round or oval viruses
provides effective immunity. A reinforcing dose is given with diameters ranging from 50—300 nm. The virion
after 12 months and additional reinforcing doses are surface has club-shaped projections, and the virus itself
given every 1-3 years depending on the risk of exposure. contains a variable number of characteristic electron-
Vaccines of nervous-tissue origin are still used in some dense granules that represent residual, non-functional
parts of the world. These, however, are associated with host ribosomes. The prototype virus of this group is
significant side-effects and are best avoided if HDCV is lymphocytic choriomeningitis virus, which is a natural
available. infection of mice. Arenaviruses are also responsible for
Argentinian and Bolivian haemorrhagic fevers and Lassa
Postexposure prophylaxis. The wound should be fever.
cleaned carefully and thoroughly with soap and water
and left open. Human rabies immunoglobulin should be
given immediately (20 IU/kg); half should be injected Lassa fever
around the area of the wound and the other half should This illness was first documented in the town of Lassa,
be given intramuscularly. Five 1.0 mL doses of HDCV Nigeria, in 1969 and is confined to sub-Saharan West
should be given intramuscularly: the first dose is given on Africa (Nigeria, Liberia and Sierra Leone). The multi-
day 0 and is followed by injections on days 3, 7,14 and 28. mammate rat, Mastomys natalensis, is known to be the
Reaction to the vaccine is uncommon. reservoir. Humans are infected by ingesting foods
contaminated by rat urine or saliva containing the virus.
Control of rabies Person-to-person spread by body fluids also occurs. Only
Domestic animals should be vaccinated if there is any risk 10-30% of infections are symptomatic.
of rabies in the country. In the UK, control has been by
quarantine of imported animals and no indigenous case Clinical features
of rabies has been reported for many years. The quarantine The incubation period is 7-18 days. The disease is
laws are under revision at the present time. The Pet Travel insidious in onset and is characterized by fever, myalgia,
Scheme (PETS) introduced as a pilot scheme in 2000 severe backache, malaise and headache. A transient
enables certain pet animals to enter or re-enter Great maculopapular rash may be present. A sore throat,
Britain without quarantine if they come from qualifying pharyngitis and lymphadenopathy occur in over 50% of
countries via designated routes, are carried by authorized patients. In severe cases epistaxis and gastrointestinal
transport companies, and meet the conditions of the bleeding may occur - hence the classification of Lassa
scheme. Wild animals in 'at risk' countries must be fever as a viral haemorrhagic fever. The fever usually
handled with great care. lasts 1-3 weeks and recovery within a month of the onset
of illness is usual. However, death occurs in 15-20% of
hospitalized patients, usually from irreversible hypo-
RETROVIRUSES volaemic shock.

Retroviruses (Table 2.24) are distinguished from other Diagnosis


RNA viruses by their ability to replicate through a DNA The diagnosis is established by serial serological tests
intermediate using an enzyme, reverse transcriptase. (including the Lassa virus-specific IgM titre) or by
59
Infectious diseases, tropical medicine and sexually transmitted diseases

■m 60 culturing the virus from the throat, serum or urine. Treatment is supportive. In addition, clinical benefit
1 Molecular diagnosis by means of the reverse transcriptase and reduction in mortality can be achieved with
polymerase chain reaction has become available and this ribavirin therapy, if given in the first week.
provides a sensitive and reasonably rapid diagnostic test. In non-endemic countries, strict isolation
procedures should be used, the patient ideally being
Treatment nursed in a flexible-film isolator. Specialized units
for the natural reservoir of LCM virus being the house mouse. Treatment is symptomatic. Convalescent
manage- Infection is characterized by: human serum appears to decrease the severity of the
ment of attack.
■ non-nervous-system illness, with fever, malaise,
Lassa
myalgia, headache, arthralgia and vomiting
fever and
■ aseptic meningitis in addition to the above symptoms. POSTVIRAL/CHRONIC FATIGUE
other
haemorr Occasionally, a more severe form occurs, with encephalitis SYNDROME
leading to disturbance of consciousness. (see also p. 1281)
hagic
fevers This illness is generally self-limiting and requires no Viral illnesses have been implicated aetiologically,
have specific treatment. including those due to EBV, Coxsackie B viruses,
been echoviruses, CMV and hepatitis A virus. Non-viral
establish MARBURG VIRUS DISEASE AND EBOLA causes such as allergy to Candida spp. have also
ed in the VIRUS DISEASE been proposed.
UK. As The proportion of patients with 'organic'
Lassa These severe, haemorrhagic, febrile illnesses are dis- diagnoses remains uncertain. Studies have
fever cussed together because their clinical manifestations are suggested that two-thirds of patients with a
virus similar. The diseases are named after Marburg in symptom duration of more than 6 months have an
and Germany and the Ebola river region in the Sudan and underlying psychiatric disorder.
other Zaire where these viruses first appeared. The natural
causes ofreservoir for these viruses has not been identified and the
haemorr precise mode of spread from one individual to another TRANSMISSIBLE SPONGIFORM
has not been elucidated.
hagic
Epidemics have occurred periodically in recent years,
ENCEPHALOPATHIES (TSE OR
fever PRION DISEASE)
(Marbur mainly in sub-Saharan Africa. The mortality from Marburg
g/ Ebola and Ebola has ranged from 25% to 90% and recovery is Transmissible spongiform encephalopathies are
and slow in those who survive.
The illness is characterized by the acute onset of severe caused by the accumulation in the nervous system of
Congo- a protein, termed a 'prion', which is an abnormal
Crimean headache, severe myalgia and high fever, followed by isoform Pr Pres of a normal, host protein (Pr Pc).
haemorr prostration. On about the fifth day of illness a non- Although familial forms of prion disease are
pruritic maculopapular rash develops on the face and
hagic known to exist, these conditions can be transmissible,
then spreads to the rest of the body. Diarrhoea is profuse
fever particularly if brain tissue enters another host. There
and is associated with abdominal cramps and vomiting.
viruses) is no convincing evidence for the presence of nucleic
Haematemesis, melaena or haemoptysis may occur
have acid in association with prions; thus these agents
between the seventh and sixteenth day. Hepato-
been cannot be considered orthodox viruses and it is the
splenomegaly and facial oedema are usually present. In
transmitt abnormal prion protein itself that is infectious and
Ebola virus disease, chest pain and a dry cough are
ed from can trigger a conversion of the normal protein into
prominent symptoms.
patients the atypical isoform. After infection, a long
to staff incubation period is followed by CNS degeneration
in associated with dementia or ataxia which invariably
healthcar leads to death. Histology of the brain reveals
e spongiform change with an accumulation of the
situation abnormal prion protein in the form of amyloid
s, great plaques.
care The human prion diseases are Creutzfeldt-
should Jakob disease, including the sporadic, familial,
be taken iatrogenic and variant forms of the disease,
in Gerstmann-Straussler-Scheinker syndrome, fatal
handling familial insomnia, and kuru.
specime ■ Creutzfeldt-Jakob disease (CJD) usually
ns and occurs
clinical sporadically world-wide with an annual incidence
material of
from one per million of the population. Although, in
these most
patients. cases, the epidemiology remains obscure,
transmission
to others has occurred as a result of administration
Lymph
of
ocytic human cadaveric growth hormone or
chorio gonadotrophin,
menin from dura mater and corneal grafting, and in
gitis neuro-
(LCM)______________________________ surgery from reuse of contaminated instruments
and
This
electrodes (iatrogenic CJD).
infection
■ Variant CJD. In the UK, knowledge that large
is a
numbers
zoonosis,
of cattle with the prion disease, bovine
the
spong cases of variant CJD
iform
encep
halop
athy
(BSE)
had
gone
into
the
huma
n food
chain,
led to
enhan
ced
survei
llance
for
emerg
ence
of
the
diseas
e in
huma
ns.
The
evide
nce is
convi
ncing,
based
on
trans
missi
on
studie
s in
mice
and
on
glyco
sylati
on
patter
ns of
prion
protei
ns,
that
this
has
occurr
ed
and,
to
date,
there
have
been
appro
ximat
ely
150
confir
med
and
suspe
cted
Bacterial infections

(human BSE) in the UK and 12 in the rest of the world. 60- [ IvCJD confirmed | 1
In contrast to sporadic CJD, which presents with | Sporadic
dementia at a mean age of onset of 60 years, variant
CJD presents with ataxia, dementia, myoclonus and
chorea at a mean age of onset of 29 years (Fig. 2.21).
50-
■ 1
J[ i
■ Cerstmann-Straussler-Scheinker syndrome and fatal |
i

i
familial insomnia are rare prion diseases usually 40-
5
occurring in families with a positive history. The |
pattern of inheritance is as an autosomal dominant 30-

with some degree of variable penetrance.


■ Kuru was described and characterized in the Fore 20-
highlanders in NE New Guinea. Transmission was
associated with ritualistic cannibalism of deceased i i 1 1

CD
relatives. With the cessation of cannibalism by 1960, r
the disease has gradually diminished and recent cases

O
had all been exposed to the agent before 1960.
O ■<— CNJ CO ^f U} CO I— CO CD CD ■*— CM CO
The infectious agents of prion disease have remarkable CD CJ) CD CD CD CD Cn CD CD CD CD O O O
CD CD CD CD CD CD CD <D CD CD CD O CD CD
characteristics. In the infected host there is no evidence of
inflammatory, cytokine or immune reactions. The agent Fig. 2.21 Creutzfeldt-Jakob disease. Deaths of confirmed
and sporadic cases of CJD (* to 28/2/03) in the UK. Courtesy of
is highly resistant to decontamination, and infectivity is
Prof JW Ironside, Director National CJD Surveillance Unit,
not reliably destroyed by autoclaving or by treatment University of Edinburgh.
with formaldehyde and most other gas or liquid dis-
infectants. It is very resistant to y irradiation. Autoclaving
at a high temperature (134-137°C for 18 minutes) is used
for decontamination of instruments, and hypochlorite Bacteria have traditionally been classified according to
(20 000 p.p.m. available chlorine) or 1 molar sodium the Gram stain which distinguishes Gram-positive from
hydroxide are used for liquid disinfection. Uncertainty Gram-negative organisms. Using light microscopy, these
about the reliability of any methods for safe deconta - can then largely be divided into cocci and bacilli (rods).
mination of surgical instruments has necessitated the Some have a spiral appearance (spirochaetes) while
introduction of guidelines for patient management. others, such as Clostridium spp., may contain spores
(Table 2.25). The cell wall arrangement of Gram-positive
cocci contains a phospholipid bilayer surrounded by
FURTHER READING peptidoglycan made up of repeating units of N-
Banatvala JE, Brown DWG (2004) Rubella. Lancet 363: acetylglucosamine and N-acetylmuramic acid. In contrast,
1127-1136. Collins ST et al. (2004) Transmissible Gram-negative bacilli possess a second outer lipid bilayer
spongiform
containing protein and lipopolysaccharide (endotoxin).
encephalopathies. Lancet 363: 51-61. Hien TT,
dejong M, Farrar J (2005) Avian Influenza. Some pathogens are encapsulated, which is an anti-
New England Journal of Medicine 351: 2363-2365. phagocytic virulence factor.
Nicholson KG et al. (2003) Influenza. Lancet 362: Bacteria can often be cultured in broth or on solid agar.
1733-1745. Peiris JSM et al. (2003) The severe Those growing in the absence of oxygen are strict anaerobes
acute respiratory (e.g. Bacteroides spp.), whilst oxygen-dependent bacteria are
syndrome. New England Journal of Medicine 349: known as aerobes (e.g. Pseudomonas spp.). Many pathogens
2431-2441. Robertson SE, Hull BP, Tomori O et al. can tolerate reduced concentrations of oxygen (e.g. E. coli).
(1995) Yellow Some organisms are more demanding in their growth
fever. A decade of resurgence. Journal of the American requirements and require special laboratory media (e.g.
Medical Association 276:1157-1162. Warrell Mycoplasma spp. and Mycobacterium spp.); others require
MJ, Warrell DA (2004) Rabies and other
more prolonged incubation (e.g. Brucella spp.).
lyssavirus diseases. Lancet 363: 959-969.
Genetic classification is defining bacteria in terms of
DNA sequence information and has led to the
reclassification of several bacteria. DNA fingerprinting is
also being increasingly applied to distinguishing similar
isolates, which has applications in defining the epi
RIAL INFECTIONS demiology of infection. ■ . .■
Classification of bacteria
Diagnosis and management of bacterial
Bacteria are unicellular organisms (prokaryotes). A small infections
fraction are of medical importance. Unusual infections
may result from exposure under circumstances of altered The history and examination usually localizes the
host defences, notably in the severely immuno- infection to a specific organ or body site. A systemic
compromised patient. response may accompany such localized disease or, in the
Infectious diseases, tropical medicine and sexually transmitted diseases

Table 2.25 Classification of bacteria affecting humans


Aerobic bacteria Cocci Bacilli
Gram-positive Staphylococcus aureus Listeria monocytogenes
Staph. epidermidis Corynebacterium diphtheriae
Streptococcus pneumoniae Bacillus anthracis B. cereus
Strep, pyogenes (group A)
Strep, agalactiae (group B)
Enterococci Viridans
streptococci Neisseria Escherichia coli Klebsiella
Gram-negative gonorrhoeae N. spp. Proteus spp.
meningitidis Moraxella Haemophilus influenzae
catarrhalis Bordetella Legionella spp. Salmonella
pertussis spp. Shigella spp.
Campylobacter jejuni
Helicobacter pylori
Pseudomonas spp. Brucella
spp. Acinetobacter spp.
Burkholderia spp. Vibrio
cholerae Yesinia pestis
Gram-positive
Actinomyces spp.
Clostridium perfringens C.
difficile C. botulinum C.
tetani
Gram-negative
Anaerobes Peptococci
Peptostreptococci Bacteroides fragilis group
Fusobacterium spp.

Spirochaetes Treponema pallidum


Leptospira spp. Borrelia
spp. Mycobacterium spp.
Others Mycoplasma pneumoniae
Ureaplasma spp.
Chlamydia spp.
case of bloodstream infections, be the primary mode of Table 2.26 Bacterial causes of superficial skin and
presentation. The microbiological diagnosis is difficult to soft tissue infection
establish in most community-managed infections, and Specific risk factors Likely organisms
even in hospital where there is ready access to diagnostic
None Staphylococcus aureus
laboratories only a minority of infections are docu-
Streptococcus pyogenes
mented. For these reasons, a clinical approach to bacterial
Diabetes, peripheral Group B streptococci
diseases has been adopted. vascular disease
Animal bite Pasteurella multocida,
SKIN AND SOFT TISSUE INFECTION Capnocytophaga canimorsus
Fresh water exposure Aeromonas hydrophila
Sea water exposure Vibrio vulnificans Groups A,
Superficial infections Lymphoedema, stasis C and G streptococci
Infections of the skin and the soft tissues beneath are dermatitis Hot tub Pseudomonas aeruginosa
common. These are usually fungal (see p. 1322) or exposure Malignant Pseudomonas aeruginosa
otitis externa Human Fusobacterium spp.
bacterial. Although a wide range of bacteria have been
bite
recovered from skin and soft tissue infections (Table 2.26),
the majority are caused by the Gram-positive cocci Staphy-
lococcus aureus and Streptococcus pyogenes. Staphylococci
are part of the normal microflora of the human skin and
62
Bacterial infections

Table 2.27 Classification of bacterial skin and superficial soft tissue infections
Infection Subgroup Site Common cause
Pyoderma Impetigo Skin Streptococcus pyogenes
Staphylococcus aureus
Bullous impetigo Skin Staph. aureus
Foiliculitis Furuncle Skin, hair follicles Staph. aureus
Abscesses (boil) Hidradenitis Subcutaneous tissue Staph. aureus
suppurativa Multiple apocrine glands Staph. aureus, anaerobes
(acne inversa) (axillae, groins) Dense group of (secondary infection)
Carbuncle furuncles: back of Staph. aureus
neck, shoulders Skin and
Cellulitis subcutaneous tissue Staph. aureus
Strep, pyogenes
Group C and G streptococci
Erysipelas Skin Strep, pyogenes
Ecthyma Skin and subcutaneous tissue Strep, pyogenes
Staph. aureus
nasopharynx; up to 25% of people are carriers of S. aureus, Meticillin-resistant Staphylococcus aureus
which is the species responsible for the majority of (MRSA)
staphylococcal infections. Although soft tissue infections S. aureus are commonly resistant to penicillin, and
are the most common manifestation of S. aureus disease, isolated resistance to other P-lactam antibiotics such as
numerous other sites can be affected (Table 2.6). meticillin and flucloxacillin has been recognized since the
The classification of soft tissue infections is complex, development of the first semisynthetic penicillins in the
because imprecise and overlapping terms are in use. The early 1960s. However, in the last 25 years, strains
commonly encountered infections (Table 2.27) are of MRSA with resistance to a much wider range of
described in more detail on page 1318. antibiotics have emerged. In some cases only the
The majority of skin and superficial soft tissue glycopeptide antibiotics vancomycin and teicoplanin are
infections are due to bacteria on the skin surface effective, and a few organisms have been isolated with
penetrating the dermis or the subcutaneous tissues. decreased sensitivity even to these. Vancomycin-
Infection can take place via hair follicles, insect bites, cuts insensitive Staphylococcus aureus (VISA) develop because
and abrasions, or skin damaged by superficial fungal the organism produces a thick cell wall by changing the
infection. Sometimes infection is introduced by an animal synthesis of cell wall material. Vancomycin resistant
bite or a penetrating foreign body: in these cases more Staphylococcus aureus (VRSA) acquires resistance by
unusual organisms may be found. A number of factors receiving the van A gene from vancomycin-resistant
predispose to cellulitis and other soft tissue infections enterococci (see Fig. 2.2). Two classes of antibiotics, the
(Table 2.28). streptogramins (e.g. quinupristin with dalfopristin) and
the oxazolidinones (e.g. linezolid) are effective against
Pasteurellosis Gram-positive bacteria, including MRSA. They should
Pasteurella multocida is found in the oropharynx of up to usually be reserved for multi-resistant organisms. Control
90% of cats and 70% of dogs. It can cause soft tissue infec- of the use of antibiotics in hospitals and good infection
tions following animal bites. Although the infection control policies are vital to prevent spread.
initially resembles other forms of cellulitis, there is a MRSA is usually found as a harmless skin commensal,
much higher incidence of spread to deeper tissues, result- especially in hospitalized patients or nursing home
ing in osteomyelitis, tenosynovitis or septic arthritis. The residents. However, it can cause a variety of infections in
organism is sensitive to penicillin, but as infections soft tissues and elsewhere, and can cause death. It is parti
following animal bites are often polymicrobial, co- cularly associated with surgical wound infections.
amoxiclav is used. Eradication of the organism is difficult, and people who
are known to be colonized should be isolated from those
at risk of significant infection. Topical treatment with
Table 2.28 Predisposing factors for skin and soft antibiotics is often used, but is of limited efficacy. Hand-
tissue infection washing is more effective. .
Diabetes mellitus •.■..<-.■,
Chronic lymphoedema
Peripheral vascular disease Cat scratch disease
Steroid treatment Cat scratch disease is a zoonosis caused by Bartonella
Malnutrition henselae. Asymptomatic bacteraemia is relatively common
Some immunodeficiency states (e.g. Job's syndrome) in domestic and especially feral cats, and human infection
Nasal carriage of Staphylococcus aureus is probably due to direct inoculation from the claws or via
cat flea bites. Regional lymphadenopathy appears
63
Infectious diseases, tropical medicine and sexually transmitted diseases
1-2 weeks after infection; the nodes become tender and followed by tissue necrosis. Infection tracks rapidly along
may suppurate. Histology of the nodes shows granuloma the tissue planes, causing spreading erythema, pain and
formation, and the illness may be mistaken for myco- sometimes crepitus. The only chance of survival is with
bacterial infection or lymphoma. There are usually few urgent surgical debridement and aggressive antibiotic
systemic symptoms in immunocompetent patients, therapy. Type 2 necrotizing fasciitis is treated with high
although more severe disease may be seen in the doses of benzylpenicillin and clindamycin; type 1 with a
immunocompromised. In these patients tender cutaneous broad-spectrum combination.
or subcutaneous nodules are seen (bacillary angiomatosis)
which may ulcerate. The lymphadenopathy resolves Gas gangrene
spontaneously over weeks or months, although surgical Gas gangrene is caused by deep tissue infection with
drainage of very large suppurating nodes may be necess- Clostridium spp., especially C. perfringens, and follows
ary. B. henselae is sensitive to doxycycline, but the clinical contaminated penetrating injuries. It is particularly
benefit of treatment is unproven. associated with battlefield wounds, but is also seen in
intravenous drug users, and following surgery. The initial
infection develops in an area of necrotic tissue caused by
Toxin-mediated skin disease the original injury; toxins secreted by the bacteria kill
A number of skin conditions, although caused by surrounding tissue and enable the anaerobic organism to
bacteria, are mediated by exotoxins rather than direct spread rapidly. Toxins are also responsible for the severe
local tissue damage. systemic features of gas gangrene. Treatment consists of
urgent surgical removal of necrotic tissue, and treatment
Staphylococcal scalded skin syndrome with benzylpenicillin and clindamycin.
The scalded skin syndrome is caused by a toxin-secreting
strain of S. aureus. It principally affects children under the
age of 5. The toxin, exfoliatin, causes intra-epidermal FURTHER READING
cleavage at the level of the stratum corneum leading to Bisno AL, Stevens DL (1996) Streptococcal infections in
the formation of large flaccid blisters that shear readily. It skin and soft tissues. New England Journal of
Medicine 334: 240-245. Huskins WC,
is a relatively benign condition, and responds to treat-
Goldmann DA (2005) Controlling
ment with flucloxacillin. meticillin-resistant Staph aureus. The Lancet
365: 273-275. Seal KV (2001) Necrotizing fasciitis.
Toxic shock syndrome (TSS) Current Opinion in
TSS is usually due to toxin-secreting staphylococci, but Infectious Disease 14: 127-132.
toxin-secreting streptococci have also been implicated.
Although historically associated with vaginal colonization
and tampon use in women, this is not always the case.
The exotoxin (normally toxic shock syndrome toxin 1,
TSST-1) causes abrupt onset of fever and shock, with a RESPIRATORY TRACT INFECTIONS
diffuse macular rash and desquamation of the palms and Infections of the respiratory tract are divided into
soles. Many patients are severely ill and mortality is infections of the upper and lower respiratory tract, which
about 10%. Treatment is mainly supportive, although the are separated by the carina. In health, the lower
organism should be eradicated. respiratory tract is normally sterile owing to a highly
efficient defence system (p. 881). Infections of the upper
Scarlet fever (see p. 65) respiratory tract are particularly common in childhood
when they are usually the result of virus infection. The
Deep soft tissue infections paranasal sinuses and middle ear are contiguous
structures and can be involved secondary to viral
Infections of the deeper soft tissues are much less infections of the nasopharynx. The lower respiratory tract
common than superficial infections, and tend to be more is frequently compromised by smoking, air pollution,
serious. Usually they are related to penetrating injuries or aspiration of upper respiratory tract secretions and
to surgery, and the causative organisms relate to the chronic lung disease, notably chronic bronchitis and
nature of the wound. chronic obstructive pulmonary disease. Infections of the
respiratory tract are defined clinically, sometimes radio-
Necrotizing fasciitis logically, as in the case of pneumonia, and by appropriate
Necrotizing fasciitis is a fulminant, rapidly spreading microbiological sampling.
infection associated with widespread tissue destruction
and a high mortality. There are two forms. Type 1, caused
by a mixture of aerobic and anaerobic bacteria, is usually
Upper respiratory tract infections
seen following abdominal surgery or in diabetics. Type 2, ■ The common cold (acute coryza) (p. 895)
caused by group A streptococci, arises spontaneously in ■ Sinusitis (p. 1158)
previously healthy people. Both types are characterized ■ Rhinitis (p. 895)
by severe pain at the site of initial infection, rapidly ■ Pharyngitis (p. 898).
64
Bacterial infections
streptococcal nephritis may also complicate streptococcal
skin infection.

Prevention
Chemoprophylaxis with penicillin or erythromycin
should be given in epidemics.

Diphtheria
Diphtheria caused by Corynebacterium diphtheriae occurs
world-wide. Its incidence in the West has fallen
dramatically following widespread active immunization,
but it is epidemic in Russia and Eastern Europe. Trans-
mission is mainly through airborne droplet infection and
rarely through fomites.
C. diphtheriae is a Gram-positive bacillus. Only strains
Fig. 2.22 Scarlet fever rash, showing desquamation. which carry the tox+ gene, are capable of toxin pro-
duction. The toxin has two subunits, A and B. Subunit A
Scarlet fever is responsible for clinical toxicity. Subunit B serves only to
Scarlet fever occurs when the infectious organism transport the toxin component to specific receptors,
(usually a group A streptococcus) produces erythrogenic present chiefly on the myocardium and in the peripheral
toxin in an individual who does not possess neutralizing nervous system. Humans are the only natural hosts.
antitoxin antibodies.
Clinical features
Clinical features Diphtheria was formerly a disease of childhood but is
The incubation period of this relatively mild disease, increasingly affecting adults in countries where child-
which mainly affects children, is 2-4 days following a hood immunization has been interrupted as in Russia and
streptococcal infection, usually in the pharynx. Regional Eastern Europe. The incubation period is 2-7 days. The
lymphadenopathy, fever, rigors, headache and vomiting manifestations may be regarded as local (due to the
are present. The rash, which blanches on pressure, membrane) or systemic (due to exotoxin). The presence of
usually appears on the second day of illness; it initially a membrane, however, is not essential to the diagnosis.
occurs on the neck but rapidly becomes punctate, The illness is insidious in onset and is associated with
erythematous and generalized. It is typically absent from tachycardia but only low-grade fever. If complicated by
the face, palms and soles, and is prominent in the infection with other bacteria such as Strep, pyogenes, fever
flexures. The rash usually lasts about 5 days and is is high and spiking.
followed by extensive desquamation of the skin (Fig. Nasal diphtheria is characterized by the presence of a
2.22). The face is flushed, with characteristic circumoral unilateral, serosanguineous nasal discharge that crusts
pallor. Early in the disease the tongue has a white coating around the external nares.
through which prominent bright red papillae can be seen Pharyngeal diphtheria is associated with the greatest
('strawberry tongue'). Later the white coating disappears, toxicity and is characterized by marked tonsillar and
leaving a raw-looking, bright red colour ('raspberry pharyngeal inflammation and the presence of a mem-
tongue'). The patient is infective for 10-21 days after the brane. This tough greyish yellow membrane is formed by
onset of the rash, unless treated with penicillin. fibrin, bacteria, epithelial cells, mononuclear cells and
Scarlet fever may be complicated by peritonsillar or polymorphs, and is firmly adherent to the underlying
retropharyngeal abscesses and otitis media. tissue. Regional lymphadenopathy, often tender, is
prominent and produces the so-called 'bull-neck'.
Diagnosis Laryngeal diphtheria is usually a result of extension of
The diagnosis is established by the typical clinical the membrane from the pharynx. A husky voice, a brassy
features and culture of a throat swab. Elevated anti- cough, and later dyspnoea and cyanosis due to respir-
streptolysin O and anti-DNase B levels in convalescent atory obstruction are common features.
serum are indicative of streptococcal infection. Clinically evident myocarditis occurs, often weeks
later, in patients with pharyngeal or laryngeal diphtheria.
Treatment Acute circulatory failure due to myocarditis may occur in
Penicillin is the drug of choice and is given orally as convalescent individuals around the tenth day of illness
phenoxymethylpenicillin 500 mg four times daily for and is usually fatal. Neurological manifestations occur
10 days. Individuals allergic to penicillin can be treated either early in the disease (palatal and pharyngeal wall
effectively with erythromycin 250 mg four times daily for paralysis) or several weeks after its onset (cranial nerve
10 days. Treatment is usually effective in preventing palsies, paraesthesiae, polyneuropathy or, rarely,
rheumatic fever (p. 76) and acute glomerulonephritis encephalitis).
(p. 629), which are non-suppurative complications of Cutaneous diphtheria is increasingly being seen in
streptococcal pharyngitis. Unlike acute rheumatic fever, association with burns and in individuals with poor
65
Infectious diseases, tropical medicine and sexually transmitted diseases
Box 2.7 Antitoxin administration Epidemic disease occurred in the UK when the safety of the
Many antitoxins are heterologous and therefore whooping cough vaccine was questioned. Currently,
dangerous uptake exceeds 95% and the disease is uncommon.
Hypersensitivity reactions are common
Clinical features
Prior to treatment
Question patient about: The incubation period is 7-10 days. It is a disease of
(a) allergic conditions (e.g. asthma, hay fever) childhood, with 90% of cases occurring below 5 years of
(b) previous antitoxin administration. age. However, no age is exempt.
During the catarrhal stage the patient is highly
Read instructions on antitoxin package carefully.
infectious, and cultures from respiratory secretions are
Always give a subcutaneous test dose.
positive in over 90% of patients. Malaise, anorexia,
mucoid rhinorrhoea and conjunctivitis are present. The
paroxysmal stage, so called because of the characteristic
personal hygiene. Typically the ulcer is punched-out with
paroxysms of coughing, begins about a week later.
undermined edges and is covered with a greyish white to
Paroxysms with the classic inspiratory whoop are seen
brownish adherent membrane. Constitutional symptoms only in younger individuals in whom the lumen of the
are uncommon. respiratory tract is compromised by mucus secretion and
mucosal oedema. The whoop results from air being
Diagnosis
forcefully drawn through the narrowed tract. These
This must be made on clinical grounds since therapy is paroxysms usually terminate in vomiting. Conjunctival
usually urgent and bacteriological results of culture studies suffusion and petechiae and ulceration of the frenulum of
and toxin production cannot be awaited. the tongue are usual. Lymphocytosis due to the elabor -
ation of a lymphocyte-promoting factor by B. pertussis is
Treatment characteristic; lymphocytes may account for over 90% of
The patient should be isolated and bed rest advised. the total white blood cell count. This stage lasts approxi -
Antitoxin therapy is the only specific treatment. It must mately 2 weeks and may be associated with several
be given promptly to prevent further fixation of toxin to complications, including pneumonia, atelectasis, rectal
tissue receptors, since fixed toxin is not neutralized by prolapse and inguinal hernia. Cerebral anoxia may occur,
antitoxin. Depending on the severity, 20 000-100 000 units especially in younger children, resulting in convulsions.
of horse-serum antitoxin should be administered Bronchiectasis is a rare sequel.
intramuscularly after an initial test dose to exclude any
allergic reaction. Intravenous therapy may be required in Diagnosis
a very severe case. There is a risk of acute anaphylaxis The diagnosis is suggested clinically by the characteristic
after antitoxin administration and of serum sickness whoop and a history of contact with an infected indivi-
2-3 weeks later (Box 2.7). However, the risk of death out- dual. It is confirmed by isolation of the organism. Cultures
weighs the problems of anaphylaxis. Antibiotics should of swabs of nasopharyngeal secretions result in a higher
be administered concurrently to eliminate the organisms positive yield than cultures of 'cough plates'.
and thereby remove the source of toxin production.
Benzylpenicillin 1.2 g four times daily is given for 1 week. Treatment
The cardiac and neurological complications need
If the disease is recognized in the catarrhal stage,
intensive therapy.
erythromycin will abort or decrease the severity of the
Prevention infection. In the paroxysmal stage, antibiotics have little
role to play in altering the course of the illness.
Diphtheria is prevented by active immunization in
childhood (see p. 42). Booster doses should be given to Prevention and control
those travelling to endemic areas if more than 10 years
Affected individuals should be isolated to prevent contact
has elapsed following their primary course of immu-
with others, e.g. in hostels and boarding schools.
nization. All contacts of the patient should have throat
Pertussis is an easily preventable disease and effective
swabs sent for culture; those with a positive result should
active immunization is available (Box 2.6). Convulsions
be treated with penicillin or erythromycin and active
and encephalopathy have been reported as rare compli-
immunization or a booster dose of toxoid given.
cations of vaccination but they are probably less frequent
than after whooping cough itself. Any exposed susceptible
Pertussis (whooping cough)
infant should receive prophylactic erythromycin.
Pertussis occurs world-wide. Humans are both the natural
hosts and reservoirs of infection. The disease is caused by
Acute epiglottitis (p. 898)
Bordetella pertussis which is a Gram-negative coccobacillus.
This has been virtually eliminated among children in
B. parapertussis and B. bronchiseptica produce milder
those countries which have introduced Haemophilus
infections. Pertussis is highly contagious and is spread by
influenzae vaccine, as in the UK. Occasionally, infections
droplet infection. In its early stages it is indistinguishable
are being recognized in adults. The clinical features are
from other types of upper respiratory tract infection.
described on page 898.
66
Bacterial infections
Acute laryngotracheobronchitis (p.
Lung abscess (p. 929).
Influenza (pp. 55 and
Tuberculosis (pp. 86 and 930).
Lower respiratory tract infections FURTHER READING
Munoz FM, Keitel Wa (2003) Progress in the diagnosis,
Pneumonia: community-acquired (p. 922); hospital-acquired
prevention and treatment of pertussis. Current
(p. 929); in immunocompromised persons (p. 926). Infectious Disease Reports 5: 213-219.

Psittacosis (ornithosis)
Although originally thought to be limited to the psittacine
birds (parrots, parakeets and macaws), it is known that the
GASTROINTESTINAL INFECTIONS
disease is widely spread amongst many species of birds,
including pigeons, turkeys, ducks and chickens (hence the
Gastroenteritis
broader term 'ornithosis'). Human infection is related to
'
exposure to infected birds and is therefore a true zoonosis.
The causative organism, Chlamydia psittaci, is excreted in The most common form of acute gastrointestinal infection
avian secretions; it can be isolated for prolonged periods is gastroenteritis, causing diarrhoea with or without
from birds who have apparently recovered from infection. vomiting. Children in the developing world can expect,
The organism gains entry to the human host by inhalation. on average, three to six bouts of severe diarrhoea every
year. Although oral rehydration programmes have cut the
Clinical features and treatment death toll significantly, at least 2.25 million people die
These are discussed on page 925. every year as a direct result of diarrhoeal disease. In the
western world diarrhoea is both less common and less
likely to cause death. However, it remains a major cause
Other respiratory infections (see also p. 925) of morbidity, especially in the elderly. Other groups who
Chlamydia pneumoniae causes a relatively mild pneumonia are at increased risk of infectious diarrhoea include
in young adults, clinically resembling infection caused travellers to developing countries, homosexual men, and
by Mycoplasma pneumoniae. Diagnosis can be confirmed infants in day care facilities. Viral gastroenteritis (p. 51) is
by specific IgM serology. Treatment is with erythromycin a common cause of diarrhoea and vomiting in young
500 mg 6-hourly, tetracycline 500 mg every 6—8 hours, or a children but is rarely seen in adults. Protozoal and
fluoroquinolone, e.g. ciprofloxacin 500 mg twice daily. helminthic gut infections (p. 109) are rare in the West but
Other chlamydial infections include trachoma (p. 84), relatively common in developing countries. The most
lymphogranuloma venereum (p. 122) and other genital common cause of significant adult gastroenteritis world-
infections. wide is bacterial infection.

Legionnaires' disease. This is caused by Legionella Mechanisms


pneumophila and other Legionella spp. It is described on Bacteria can cause diarrhoea in three different ways
page 925. (Table 2.29). Some species may employ more than one of
these methods.
Table 2.29 Pathogenic mechanisms of bacterial gastroenteritis
Pathogenesi Mode of action Clinical presentation Examples
s
Mucosal adherence Effacement of intestinal mucosa Moderate watery diarrhoea Enteropathogenic E coli (EPEC)
Mucosal invasion Penetration and destruction of Dysentery Shigella spp. Campylobacter
mucosa spp. Enteroinvasive E coli
(EIEC)
Toxin production
Enterotoxin Fluid secretion without mucosal Profuse watery diarrhoea Vibrio cholerae Salmonella spp.
damage Campylobacter spp.
Enterotoxigenic E coli (ETEC)
Bacillus cereus Staphylococcus
aureus producing
enterotoxin B
Clostridium perfringens type A
Salmonella spp. Campylobacter
Cytotoxin Damage to mucosa Dysentery spp. Enterohaemorrhagic E. coli
0157
(EHEC)
67
2 Infectious diseases, tropical medicine and sexually transmitted
diseases
.1 Mucosal adherence
Most bacteria causing diarrhoea must first adhere to
specific receptors on the mucosa. A number of different
Box 2.8 Bacterial causes of watery diarrhoea
and dysentery

molecular adhesion mechanisms have been elaborated; or toxin production but others such as
for example, adhesions at the tip of the pili or fimbriae enteropathogenic Escherichia coli (EPEC) cause
which protrude from the bacterial surface aid adhesion. attachment-effacement mucosal lesions on EM and
For some pathogens this is merely the prelude to invasion produce a secretory diarrhoea directly as a result of
adherenc intestinal mucosa. They destroy the epithelial cells and Watery diarrhoea
e. produce the symptoms of dysentery: low-volume bloody Bacillus cereus plus profuse vomiting
Enteroag diarrhoea, with abdominal pain.
Staphylococcus aureus
gregative Vibrio cholerae
E. coli Toxin production Enterotoxigenic Escherichia coli (ETEC)
(EAggE Gastroenteritis can be caused by different types of Enteropathogenic Escherichia coli (EPEC)
C) bacterial toxins: Salmonella spp.
adhere in Campylobacter jejuni
■ Enterotoxins, produced by the bacteria adhering to the Clostridium perfringens
an intestinal epithelium, induce excessive fluid secretion
aggregat Clostridium difficile
into the bowel lumen, leading to watery diarrhoea,
ive without physically damaging the mucosa, e.g. cholera, Dysentery
pattern enterotoxigenic E. coli (ETEC). Some enterotoxins Shigella spp.
with the preformed in the food primarily cause vomiting, e.g. Salmonella spp.
bacteria Campylobacter spp.
Staph. aureus and Bacillus cereus. A typical example of Enteroinvasive Escherichia coli (EIEC)
clumping this is 'fried rice poisoning', in which B. cereus toxin is
Enterohaemorrhagic Escherichia coli (EHEC)
on the present in cooked rice left standing overnight at room
Yersinia enterocolitica
cell temperature. Vibrio parahaemolyticus
surface ■ Cytotoxins damage the intestinal mucosa and, in some Clostridium difficile
and its cases, vascular endothelium as well.
toxin
causes
persisten
t
Clinical syndromes Salmonellae can affect both the large and small
diarrhoe Bacterial gastroenteritis can be divided on clinical grounds bowel, and induce diarrhoea both by production of
a in into two broad syndromes: watery diarrhoea (usually due enterotoxins and by epithelial invasion. The
developi to enterotoxins, or adherence), and dysentery (usually due typical symptoms commence abruptly 12-48 hours
ng to mucosal invasion and damage) (Box 2.8). With some after infection and consist of nausea, cramping
countries pathogens such as Campylobacter jejuni there may be abdominal pain, diarrhoea, and sometimes fever.
. overlap between the two syndromes. The diarrhoea can vary from profuse and watery to
Diffusel a bloody dysentery syndrome. Spontaneous
y Salmonella resolution usually occurs in 3-6 days, although the
Gastroenteritis can be caused by many of the numerous organism may persist in the faeces for several
adhering
serotypes of salmonella (all of which are members of a weeks. Bacteraemia occurs in 1-4% of cases and is
E. coli
single species, S. choleraesuis), but the most commonly more common in the elderly and the
(DAEC)
immunosuppressed. Occasionally bacteraemia is
adheres implicated are S. enteritidis and S. typhimurium. These
complicated by metastatic infection, especially of
in a organisms, which are found all over the world, are
atheroma on vascular endothelium, with potentially
uniform commensals in the bowels of livestock (especially
devastating consequences. In healthy adults
manner poultry) and in the oviducts of chicken. They are usually
salmonella gastroenteritis is usually a relatively
and may transmitted to man in contaminated foodstuffs. minor illness, but young children and the elderly are
also at risk of significant dehydration.
cause Specific diagnosis is made by culturing the
diarrhoe organism from blood or faeces, but management is
a in usually empirical. Antibiotic therapy (ciprofloxacin
children 500 mg twice daily) may decrease the duration and
and in severity of symptoms, but is rarely warranted (see
developi Box 2.10).
ng
countries Campylobacter jejuni
. C. jejuni is also a zoonotic infection, existing as a
bowel commensal in many species of livestock. It is
Mucosa found world-wide, and is a common cause of
l childhood gastroenteritis in developing countries.
invasion Adults in these countries may be tolerant of the
Invasive organism, excreting it asymptomatically. In the West
pathogen it is a common cause of sporadic food-borne
s such as outbreaks of diarrhoea, especially in the summer
Shigella when barbecued beefburgers are a frequent vehicle.
spp., Like salmonella, campylobacter can affect large
enteroin and small bowel and can cause a wide variety of
vasive E. symptoms. The incubation period is usually 2-4
coli days, after which
(EIEC)
and
Campylo
bacter
spp.
penetrate
into the
Bacterial infections
there is an abrupt onset of nausea, diarrhoea and Enterotoxigenic Escherichia coli (ETEC)
abdominal cramps. The diarrhoea is usually profuse and ETEC produce both heat-labile and heat-stable
watery, but an invasive haemorrhagic colitis is sometimes enterotoxins which stimulate secretion of fluid into the
seen. Bacteraemia is very rare, and infection is usually intestinal lumen. The result is watery diarrhoea of
self-limiting in 3-5 days. Diagnosis is made from stool varying intensity, which usually resolves within a few
cultures. If symptoms are severe, azithromycin 500 mg days. Transmission is normally from person to person via
once daily is the drug of choice (see Box 2.10). contaminated food. The organism is common in develop-
ing countries, and is a major cause of travellers' diarrhoea
Shigella (see below).
Shigellae are enteroinvasive bacteria which cause
classical bacillary dysentery. The principal species Vibrio
causing gastroenteritis are S. dysenteriae, S. flexneri and Cholera, due to Vibrio cholerae is the prototypic pure
S. sonnet, which are found with varying prevalence in enterotoxigenic diarrhoea: it is described on page 84.
different parts of the world. All cause a similar syndrome, Vibrio parahaemolyticus causes acute watery diarrhoea
as a result of damage to the intestinal mucosa. Some after eating raw fish or shellfish that has been kept for
strains of S. dysenteriae also secrete a cytotoxin affecting several hours without refrigeration. Explosive diarrhoea,
vascular endothelium. Although shigellae are found abdominal cramps and vomiting occurs with a fever in
world-wide, transmission is strongly associated with 50%. It is self-limiting, lasting up to 10 days.
poor hygiene. The organism is spread from person to
person, and only small numbers need to be ingested to Yersiniosis
cause illness (< 200, compared to 10 4 for campylobacter Yersinia enterocolitica infection is a zoonosis of a variety of
and > 105 for salmonella). Bacillary dysentery is far more domestic and wild mammals. Human disease can arise
prevalent in the developing world, where the main either via contaminated food products, e.g. pork, or from
burden falls on children. direct animal contact. Y enterocolitica can cause a range
Symptoms start 24-48 hours after ingestion and of gastroenteric symptoms including watery diarrhoea,
typically consist of frequent small-volume stools contain- dysentery, and mesenteric adenitis. The illness is usually
ing blood and mucus. Dehydration is not as significant as self-limiting, but ciprofloxacin may shorten the duration.
in the secretory diarrhoeas, but systemic symptoms and Y pseudotuberculosis is a much less common human
intestinal complications are worse. The illness is usually pathogen: it causes mesenteric adenitis and terminal
ileitis.
self-limiting in 7-10 days, but in children in developing
countries the mortality may be as high as 20%. Antibiotic
treatment decreases the severity and duration of Staphylococcus aureus
Some strains of Staph. aureus can produce a heat-stable
diarrhoea, and possibly reduces the risk of further
toxin (enterotoxin B) which causes massive secretion of
transmission (see Box 2.10). Resistance to antibiotics is
fluid into the intestinal lumen. It is a common cause of
widespread: in some areas amoxicillin or co-trimoxazole
food-borne gastroenteritis in Europe and the USA,
may still be effective, but in many places nalidixic acid or
outbreaks usually occurring as a result of poor food
ciprofloxacin is needed.
hygiene. Because the toxin is preformed in the conta-
minated food, onset of symptoms is rapid, often within
Enteroinvasive Escherichia coli (EIEC) 1-A hours of consumption. There is violent vomiting,
This causes an illness indistinguishable from shigellosis.
followed within hours by profuse watery diarrhoea.
Definitive diagnosis is made by stool culture. Symptoms have usually subsided within 24 hours.
Enterohaemorrhagic Escherichia coli (EHEC) Bacillus cereus
EHEC (usually serotype O157:H7, and also known as B. cereus produces two toxins. One produces watery
verotoxin-producing E. coli, or VTEC) is a well recognized diarrhoea up to 12 hours after ingesting the organism.
cause of gastroenteritis in man. It is a zoonosis usually The other toxin is preformed in food and causes severe
associated with cattle, and there have been a number of vomiting, e.g. 'fried rice poisoning' (p. 72).
major outbreaks (notably in Scotland and Japan)
associated with contaminated food. EHEC secrete a toxin
Clostridial infections
(Shiga-like toxin 1) which affects vascular endothelial
C. difficile is found as part of the normal bowel flora in
cells in the gut and in the kidney. After an incubation
3—5% of the population and even more commonly in
period of 12-48 hours it causes diarrhoea (frequently
hospitalized people. C. difficile produces two toxins: toxin
bloody), associated with abdominal pain and nausea.
A is an enterotoxin and toxin B is cytotoxic and causes
Some days after the onset of symptoms the patient may
bloody diarrhoea. It usually causes illness after other
develop thrombotic thrombocytopenic purpura (p. 471)
bowel commensals have been eliminated by antibiotic
or haemolytic uraemic syndrome (HUS, p. 636). This is
therapy. Almost all antibiotics have been linked with
more common in children, and may lead to permanent
C. difficile diarrhoea, which can begin anything from
renal damage or death. Treatment is mainly supportive:
2 days to a month after taking antibiotics. Elderly
there is evidence that antibiotic therapy might precipitate
hospitalized patients are most frequently affected.
HUS by causing increased toxin release.
69
Infectious diseases, tropical medicine and sexually transmitted diseases
Symptoms can range from mild diarrhoea to haemor- Table 2.30 Common causes of travellers'
rhagic colitis: sometimes the ulcerated colonic mucosa diarrhoea (TD)
may be covered by a membrane-like material (pseudo- Organism Frequency
membranous colitis). The diagnosis is made by detecting (varies from country to country)
A or B toxins in the stools by ELBA techniques. Treatment
ETEC 30-70%
is with metronidazole 400 mg three times daily or oral
vancomycin 125 mg four times daily; causative antibiotics Shigella spp. 0-15%
should be discontinued if possible. The disease is usually Salmonella spp. 0-10%
more severe in the elderly, and can cause intractable Campylobacter spp. 0-15%
diarrhoea leading to death. Viral pathogens 0-10%
Giardia intestinalis 0-3%
Clostridium perfringens infection is due to inadequately
cooked food, usually meat or poultry allowed to cool for ETEC, enterotoxigenic Escherichia coli
a long time during which the spores germinate. The
ingested organism produces an enterotoxin causing
watery diarrhoea with severe abdominal pain, usually elderly. The mainstay of treatment for all types of gastro-
without vomiting. enteritis is oral rehydration solutions (ORS): antibiotics
have a subsidiary role in some cases (Fig. 2.23; Boxes 2.9
Travellers' diarrhoea and 2.10 and p. 85). The use and formulation of ORS
Travellers' diarrhoea is defined as the passage of three or are discussed under cholera on p. 85. It should also be
more unformed stools per day in a resident of an remembered that other diseases, notably urinary tract
industrialized country travelling in a developing nation. infections and chest infections in the elderly, and malaria
Infection is usually food- or water-borne, and younger at any age, can present with acute diarrhoea.
travellers are most often affected (probably reflecting
behaviour patterns). Reported attack rates vary from
country to country, but approach 50% for a 2-week stay in Food poisoning_______
many tropical countries. The disease is usually benign Food poisoning is a legally notifiable disease in England
and self-limiting: treatment with quinolone antibiotics and Wales, and is defined as 'any disease of an infective
may hasten recovery but is not normally necessary. or toxic nature caused by or thought to be caused by the
Prophylactic antibiotic therapy may also be effective for
consumption of food and water'. Not all cases of gastro-
short stays, but should not be used routinely. The
enteritis are food poisoning, as the pathogens are not
common causative organisms are listed in Table 2.30.
always food- or water-borne. Common bacterial causes of
Management of acute gastroenteritis food poisoning are listed in Table 2.31. Food poisoning
In children, untreated diarrhoea has a high mortality due may also be caused by a number of non-infectious
to dehydration, especially in hot climates. Death and organic and inorganic toxins (Table 2.32). Illnesses such as
serious morbidity are less common in adults but still botulism (p. 73) are also classified as food poisoning, even
occur, particularly in developing countries and in the though they do not primarily cause gastroenteritis.
Listeriosis is described on p. 78.
Is the patient Is the patient YES Is there access YES M
significantly taking oral to adequate an
dehydrated? fluids? clean water? ag
e
at
ho
m
e
wi
th
O
R
S
r NO

r
f
Manage at hospital/treatment centre
Fluid management Investigations
(where available) Antibiotic therapy Other measures
Is patient severely dehydrated? Urea Empirical therapy if: Watch for complications:
NO

Is patient taking oral


I YES
Electrolytes Stool
microscopy Stool
culture Clostridium
Dysenteric symptoms
Severely dehydrated Severe
systemic symptoms
Renal failure Perforation
Septicaemia

Inform appropriate public


fluids? difficile toxin Blood Immunosuppressed
health authorities
I culture Underlying illness Cholera
likely Try to trace source (especially
YES NO Treat on basis of stool culture if cholera suspected)

Oral rehydration i.v. infusion + if symptoms not improving Avoid anti-motility agents
solution + fluid fluid balance
balance
70 Fig. 2.23 Gastroenteritis - management plan. ORS, oral rehydration
solution.
Bacterial infections

Box 2.9 Oral rehydration solutions (ORS) and intravenous solutions in moderate and severe diarrhoea
Salts (mmol per litre) Substance added (per litre of water)
Oral Na+ K+ ci- Glucose
WHO New 75 20
reduced 65 75 NaCI 2.6 g
osmolality
2.9 g
formulation
1.5 g
13.5 g
Cereal-based 85 - Na citrate
80 KCI Glucose
Household 85 - 80 g cooked rice
80 111 5 g salt (NaCI)
UK/Europe 35-60 20
37 90-200 0 20 g glucose
Intravenous 5 g salt (NaCI) Pre-
131 4
Ringer's lactate prepared solutions
109

Pre-prepared
o Box 2.10 Antibiotics in adult acute bacterial
gastroenteritis Alternatives Benefits
Condition Indications Drug of choice Nalidixic acid 1 g Relieve symptoms
Dysentery Most patients four times daily Shorten illness
Ciprofloxacin 500 mg
Ampicillin 500 mg Decrease transmission
twice daily
four times daily
Co-trimoxazole 960 mg
twice daily
Tetracycline 250 mg Relieve symptoms
four times daily Shorten illness
Cholera All patients Ciprofloxacin
Nalidixic acid Co- Decrease transmission
trimoxazole
Azithromycin 500 mg Relieve symptoms
Empirical therapy once daily Co- Shorten illness May
Ciprofloxacin
of watery trimoxazole decrease
diarrhoea complications
Severe symptoms
Co-trimoxazole Relieve symptoms
Prolonged illness
Shorten illness
Ciprofloxacin
Erythromycin Co- May shorten illness
trimoxazole
Ciprofloxacin
Azithromycin
Elderly patients
Immunosuppressed
Vancomycin 125 mg Relieve symptoms
four times daily Shorten illness
Symptoms not
improving (rarely
needed)
Travellers' diarrhoea Rarely used

Treatment of
confirmed
Salmonella,
Shigella,
Campylobacter
Clostridium difficile
Most cases Metronidazole 400 mg
(unless symptoms three times daily
resolved)
The increase in reported food poisoning in developed contamination. The internationalization of food supply
countries is at least in part due to changes in the encourages widespread and distant transmission of the
production and distribution of food. Livestock raised resulting infections.
and slaughtered under modern intensive farming
conditions is frequently contaminated with salmonella or
campylobacter. However, the main problem is not at this Enteric fever (p
stage. Only 0.02-0.1% of the eggs from a flock of chickens
infected with S. enteritidis will be affected, and then only
at a level of less than 20 cells per egg - harmless to most Other gastrointestinal infections
healthy individuals. It is flaws in the processing, storage Gastric infection with Helicobacter pylori is discussed on
and distribution of food products which allow massive page 283, Whipple's disease on page 305, and bacterial
amplification of the infection, resulting in extensive peritonitis on page 344.
Infectious diseases tropical medicine and sexually transmitted diseases

1 Table 2.31 Bacterial causes of food poisoning


Organism Source/vehicles Incubation Symptoms Diagnosis Recovery
period
Staphylococcus aureus Man - contaminated 2-4 h Diarrhoea, Culture organism < 24 h
food and water vomiting and in vomitus or
dehydration remaining food
E. coli Salads, water, ice 24 h Watery diarrhoea Stool culture 1-4 days
E. coli 0157:H7 Cattle - meat, milk 12-48 h Watery diarrhoea Stool culture 10-12 days
± haemorrhagic
colitis, HUS
Yersinia enterocolitica Milk, pork 2-14 h Abdominal pain, Stool culture 2-30 days
vomiting, diarrhoea
Bacillus cereus Environment - rice, 1-6 h Vomiting Culture organism in Rapid
ice-cream, chicken 6-14 h Diarrhoea faeces and food
Clostridium perfringens Environment - 8-22 h Watery diarrhoea Culture organism in 2-3 days
contaminated food and cramping pain faeces and food
Listeria monocytogenes Environment - milk, 9 Colic, diarrhoea and Stool culture ?
raw vegetables vomiting
dairy products,
unpasteurized cheese
Vibrio parahaemolyticus Seafood 2-48 h Diarrhoea, vomiting Stool, food 2-10 days
Clostridium botulinum Environment - bottled 18-24h Brief diarrhoea and Demonstrate toxin 10-14 days
or canned food paralysis due to in food or faeces
neuromuscular
blockade
Salmonella spp. Cattle and poultry - 12-48h Abrupt diarrhoea, Stool culture Usually
eggs, meat fever and vomiting 3-6 days,
but may be
up to
2 weeks
Campylobacter jejuni Cattle and poultry - 48-96 h Diarrhoea ± blood, Stool culture 3-5 days
meat, milk fever, malaise and
abdominal pain
Shigella spp. Man - contaminated 24-48 h Acute watery, Stool culture 7-10 days
food and water bloody diarrhoea
HUS, haemolytic uraemic syndrome
Table 2.32 Organic toxins causing food poisoning FURTHER READING
(see p. 1020)
Bartlett JG (2002) Antibiotic associated diarrhoea. New
Toxin Source Illness England Journal of Medicine 346: 334-339.
Scombotoxin Tuna, mackerel Histamine fish De Bruyn G, Hahn S, Borwick A (2001) Antibiotic
treatment for travellers' diarrhoea. Cochrane database
poisoning of systematic reviews, Issue 1. Oxford: Update
Ciguatoxin Barracuda, Ciguatera Software.
snapper (diarrhoea and Musher DM, Musher BL (2004) Contagious acute
paraesthesia) gastrointestinal infections. New England Journal of
Dinoflagellate Shellfish Neurotoxic Medicine 351: 2417-2427.
plankton toxin shellfish
poisoning
Haemagglutinins Inadequately- Diarrhoea and
prepared dried vomiting INFECTIONS OF THE CARDIOVASCULAR
kidney beans SYSTEM
Unknown Buffalo fish Haff disease Infective endocarditis (p.
(toxic
rhabdomyolysis)
Phallotoxins, Mushrooms Various INFECTIONS OF THE NERVOUS SYSTEM
amatoxins
The central and peripheral nervous systems can be
affected by a variety of microorganisms either directly or
via toxins, e.g. viral (p. 1239), protozoal (p. 95) and prion
diseases (pp. 60 and 1242).
72
Bacterial infections

Bacterial meningitis (see p. 1236) high, but patients who survive the acute paralysis can
_______________________________________ make a full recovery.
The most common bacterial disease affecting the central Botulism may also follow the contamination of
nervous system is acute meningitis, which causes about wounds and street heroin injection with C. botulinum, and
175 000 deaths per year, predominantly in the developing in infants may be related to bowel colonization by the
world. Epidemic meningitis due to Neisseria meningitidis organism.
(usually group A) is common in a broad belt across sub-
Saharan Africa and is also seen in parts of Asia. In Europe Tetanus
and North America bacterial meningitis is usually Tetanus is also due to a toxin-secreting clostridium:
sporadic, with B and C strains predominating. A con- C. tetani. The organism is found in soil, and illness usually
jugate vaccine for serogroup C meningococcus has results from a contaminated wound. The injury itself may
resulted in a fall in the number of cases of C meningitis in be trivial and disregarded by the individual. It has also
those countries where it is now part of the childhood complicated intravenous drug misuse. In developing
immunization schedule, such as the UK. countries neonatal tetanus follows contamination of
Streptococcus pneumoniae is the other major cause the umbilical stump, often after dressing the area with
throughout the world, while tuberculous meningitis dung.
(p. 1238) is common in sub-Saharan Africa and parts of The organism is not invasive, and clinical manifes-
Asia. tations of the disease are due to the potent neurotoxin,
Haemophilus influenzae b (Hib) was once a common tetanospasmin. Tetanospasmin acts on both the a and 8
cause of meningitis in children, but since an effective motor systems at synapses, resulting in disinhibition. It
vaccine has been available, serious H. influenzae infections also produces neuromuscular blockade and skeletal
have become rare in western countries. Many developing muscle spasm, and acts on the sympathetic nervous
countries have also instituted immunization programmes, system. The end result is marked flexor muscle spasm
but invasive H. influenzae infection remains common in and autonomic dysfunction.
some parts of the world.
Other less common causes of meningitis in adults
Clinical features
include group B streptococci, Listeria monocytogenes (see The incubation period varies from a few days to several
p. 78), Staph. aureus, and Gram-negative bacilli. These weeks. The most common form of the disease is
organisms are usually associated with an underlying generalized tetanus. General malaise is rapidly followed
illness or immunocompromising condition, or with a by trismus (lockjaw) due to masseter muscle spasm.
cerebrospinal fluid leak. Spasm of the facial muscles produces the characteristic
grinning expression known as risus sardonicus. If the
disease is severe, painful reflex spasms develop, usually
Cerebral abscess within 24-72 hours of the initial symptoms. The interval
between the first symptom and the first spasm is referred
This is covered on page 1243. to as the 'onset time'. The spasms may occur sponta-
neously but are easily precipitated by noise, handling of
the patient, or by light. Respiration may be impaired
Toxin-mediated infections because of laryngeal spasm; oesophageal and urethral
spasm lead to dysphagia and urinary retention, respec-
Botulism tively, and there is arching of the neck and back muscles
Clostridium botulinum is a common environmental (opisthotonus). Autonomic dysfunction produces
organism, and produces spores which can survive tachycardia, a labile blood pressure, sweating and cardiac
heating to 100°C. It causes botulism, an illness caused by arrhythmias. Patients with tetanus are mentally alert.
contamination of canned or bottled foodstuff, in which Death results from aspiration, hypoxia, respiratory
the anaerobic organism can multiply and elaborate a failure, cardiac arrest or exhaustion. Mild cases with
neurotoxin. After ingestion the toxin causes profound rigidity usually recover. Poor prognostic indicators
neuromuscular blockade, leading to autonomic and include short incubation period, short onset time, and
motor paralysis. The first symptoms, occurring 18-24 extremes of age.
hours after ingestion, are nausea and diarrhoea. These are
Localized tetanus is a milder form of the disease. Pain
followed by cranial nerve palsies and then progressive
and stiffness are confined to the site of the wound, with
symmetrical paralysis, leading to respiratory failure.
increased tone in the surrounding muscles. Recovery
The diagnosis is usually clinical, and is confirmed by
usually occurs.
detection of toxin in faeces or in the contaminated food.
Cephalic tetanus is uncommon but invariably fatal. It
Treatment is mainly supportive, with mechanical
usually occurs when the portal of entry of C. tetani is the
ventilation if necessary. Antitoxin is available in some
middle ear. Cranial nerve abnormalities, particularly of
countries (including the UK); the risk of anaphylaxis is
the seventh nerve, are usual. Generalized tetanus may or
relatively high, and it should only be used in severe cases.
may not develop.
A subcutaneous test dose should be given before
intravenous or intramuscular injection. Antibiotics have Neonatal tetanus is usually due to infection of the
no proven role. The overall mortality from botulism is umbilical stump. Failure to thrive, poor sucking,

I 7
3
Infectious diseases, tropical medicine and sexually transmitted diseases
grimacing and irritability are followed by the rapid
FURTHER READING
development of intense rigidity and spasms. Mortality
Begg N, Cartwright KA, Cohen J et al. (1999) Overview
approaches 100%. One aim of the WHO Expanded of acute and chronic meningitis. Neurologic Clinics
Programme on Immunization (EPI) is to eliminate this 17(4): 691-710. Gold R (1999) Epidemiology of
condition by immunizing all women of childbearing age, bacterial meningitis.
providing clean delivery facilities and strengthening Infectious Disease Clinics of North America 13(3):
surveillance in high-risk areas. 515-525.

Diagnosis
Few diseases resemble tetanus in its fully developed
BONE AND JOINT INFECTIONS
form, and the diagnosis is therefore usually clinical.
Rarely, C. tetani is isolated from wounds. Phenothiazine ■ Infective arthritis (p. 571)
overdosage, strychnine poisoning, meningitis and tetany ■ Osteomyelitis (p. 573).
can occasionally mimic tetanus.

Management URINARY TRACT INFECTIONS


Suspected tetanus. Any wound must be cleaned and m Complicated versus uncomplicated infections (p. 638)
debrided if necessary, to remove the source of toxin. ■ Acute pyelonephritis (p. 639)
Human tetanus immunoglobin 250 units should be given ■ Reflux nephropathy (p. 639)
along with an intramuscular injection of tetanus toxoid. ■ Perinephric abscess (renal carbuncle) (p. 642)
If the patient is already protected a single booster dose ■ Bacterial prostatitis (p. 642)
of the toxoid is given; otherwise the full three-dose course ■ Tuberculosis of the urinary tract (p. 642)
of adsorbed vaccine is given (see below). ■ Peritonitis complicating continuous ambulatory
Established tetanus management is supportive peritoneal dialysis (p. 677).
medical and nursing care. Improvement in this area has
contributed more than any other single measure to the
SYSTEMIC/MULTISYSTEM INFECTIONS
decrease in the mortality rate from 60% to nearer 20%.
Patients are nursed in a quiet, isolated, well-ventilated, Many infections are confined to a particular body organ
darkened room. Benzodiazepines are used to control or system, owing to the metabolic requirements of the
spasm and sedate the patient; if the airway is com- organism, the route of infection, or the response of host
promised intubation and mechanical ventilation may be defences. Other infections can potentially affect several
necessary. systems or the entire body. Under unusual circumstances
Antibiotics and antitoxin should be administered, such as altered host immunity, infections which are
even in the absence of an obvious wound. Intravenous normally circumscribed may become systemic. This
metronidazole is the drug of choice, although penicillin is section describes those infections which commonly cause
also effective. Human tetanus immunoglobulin (HTIG) multisystem disease in an immunocompetent host.
500 IU should be given by intramuscular injection to
neutralize any circulating toxin. If HTIG is not available,
immune equine tetanus immunoglobulin 10 000 IU Bacteraemia and septicaemia
should be given intramuscularly: this is probably as Bacteraemia, the transient presence of organisms in the
effective as HTIG, but there is a high incidence of severe blood, can occur in healthy people without causing
allergic reactions. If the patient recovers, active immun- symptoms. It can follow surgery, dental treatment, and
ization should be instituted, as immunity following even tooth-brushing. Bacteraemia can also occur from the
tetanus is incomplete. bowel or bladder, especially in the presence of local
inflammation. Unless a site of metastatic infection is
Prevention established (such as the heart valves), most organisms are
Tetanus is an eminently preventable disease and all rapidly cleared from the blood.
persons should be immunized regardless of age. Those
who work in a contaminated environment, such as Septicaemia. Some invading bacteria such as Staph.
farmers, are particularly at risk and should have regular aureus or E. coli are less likely to be dealt with by the
booster injections. Active immunization with the alum- immune system and more likely to cause disease. Illness
adsorbed toxoid should be given. Initially two doses of arising from such blood-borne infection is called
0.5 mL of the toxoid are given intramuscularly with an 8- septicaemia, and may occur in isolation or secondary to a
week interval. The third dose is given 6-12 months focal infection. Septicaemia usually causes severe systemic
later as a booster. Subsequent boosters are required at 5- symptoms including high fever, rigors, hypotension,
year intervals. Infant immunization schedules in all myalgia and headache. It can also lead to the establish-
countries include tetanus (Box 2.6). Protection by passive ment of metastatic foci of infection and, in its most severe
immunization with either the equine or human anti- form, to septic shock.
tetanus immunoglobulin is short-lived, lasting only about Patients presenting with symptoms and signs suggest-
2 weeks. ing septicaemia should be examined carefully for
74
Bacterial infections
2
Table 2.33 Causes of septicaemia in a previously Meningococcal septicaemia
healthy adult
Site of origin
Neisseria meningitidis is found world-wide, in five major
Usual pathogen(s)
serogroups. In sub-Saharan Africa and parts of Asia
Skin Urinary where group A meningococcus is prevalent it usually
causes epidemic disease. Groups Y and W can also cause
tract epidemic infection, while groups B and C (which are the
predominant strains in Europe and North America) tend
Respiratory tract Gall
bladder or bowel

Staphylococcus aureus and other


Gram-positive cocci Escherichia
coli and other aerobic
Gram-negative rods
Streptococcus pneumoniae
Enterococcus faecalis, E. coli and
other Gram-negative rods
Bacteroides fragilis Neisseria
Clinical problem gonorrhoeae, anaerobes

Urinary catheter
Pelvic organs

Intravenous catheter
Table 2.34 Causes of septicaemia in hospitalized

Peritoneal catheter
Post-surgery:
Wound infection

Deep infection
Burns

patients
Usual pathogen(s)

Escherichia coli, Klebsiella spp.,


Proteus spp., Serratia spp.,
Pseudomonas spp.
Staphylococcus aureus and Staph.
epidermidis, Klebsiella spp.,
Pseudomonas spp., Candida
albicans
Staph. epidermidis

Staph. aureus, E. coli, anaerobes


(depending on site) Depends on
anatomical location Gram-positive
cocci,
Pseudomonas spp., Candida
albicans Any of the
above
Immunocompromised
patients

evidence of a source: common sites of infection and


organisms leading to septicaemia are listed in Tables 2.33
and 2.34. Because of the potential severity of septicaemia,
treatment with antibiotics should usually be started
empirically as soon as appropriate cultures have been
taken. The choice of agent is governed by the likely
pathogen: if there are no clues, a broad-spectrum regimen ny. 2.24 Meningococcal infections, showing a purpuric
should be used (e.g. piperacillin plus gentamicin, or rash.
cefotaxime, with or without metronidazole). In hospital
units with epidemic MRSA infection, it is common
practice to add vancomycin or teicoplanin to this empiric
regimen. Antibiotic therapy should be reviewed daily as
the illness progresses and the results of investigations
become available. The general management of septic
shock is covered on page 978.
to be sporadic. In England and Wales approximately 2000 tension (p. 967), and may be accompanied by a petechial
cases of meningococcal disease are reported annually. or haemorrhagic rash (Fig. 2.24). In some cases the patient
Man is the only known reservoir for the organism, can deteriorate rapidly, with shock, disseminated
which is carried asymptomatically in the nasopharynx of intravascular coagulation, and multiorgan failure.
5-20% of the general population. Meningococcal disease
occurs when the bacteria invade the nasal mucosa and Diagnosis
enter the bloodstream: this only happens in a small The presence of meningitis and septicaemia with a typical
percentage of those colonized. Invasion depends on both rash is strongly suggestive of meningococcal disease.
host and bacterial factors. It is more likely to take place Gram-negative diplococci may be seen on Gram stain of
soon after colonization has taken place, and following CSF or of aspirate from petechiae, and meningococci can
viral upper respiratory infections. also be cultured from CSF or blood, or detected by PCR.
A rising titre of antibody to meningococcal outer
Clinical features membrane protein (OMP) can also be used in diagnosis.
Invasive meningococcal infection may cause meningitis,
septicaemia, or both. Meningitic disease (see p. 1236) Management
usually presents with the classical triad of headache, N. meningitidis is sensitive to benzylpenicillin, chloram-
fever, and neck stiffness. Vomiting, diminished conscious- phenicol, and third-generation cephalosporins: antibiotic
ness, and focal neurological signs occur, although some treatment for meningococcal meningitis should be started
patients, especially in the early stages, only have mild immediately (see emergency box 21.1, page 1238) and
symptoms. Meningococcal septicaemia causes the typical continued parenterally for 7 days. Meningococcal
features of septic shock such as fever, myalgia, and hypo- septicaemia should be managed in the same way as any
75
Infectious diseases, tropical medicine and sexually transmitted diseases
other septicaemic illness (p. 973). The mortality from Table 2.35 Revised Duckett Jones criteria for the
meningococcal septicaemia in developed countries is diagnosis of rheumatic fever. The diagnosis is made on
currently approximately 10%, while that from meningo- the basis of two or more major criteria or one major
coccal meningitis alone is less than 5% (see below). Mild plus two or more minor criteria
neurological sequelae (especially vestibular nerve
Major criteria
damage) are common, but serious brain damage is
Carditis
relatively unusual. Polyarthritis
The meningococcal C conjugate vaccine has led to an Chorea
overall reduction of meningococcal C disease in the UK but Erythema marginatum
unfortunately an increase in infection of other serotypes Subcutaneous nodules
may occur. A serogroup B vaccine is not available. A
Minor criteria
combined A and C vaccine is also available (p. 42). Fever
For close contacts of a case of meningococcal disease, Arthralgia
household and 'kissing' contacts should be given pro- Previous rheumatic fever
phylaxis with oral rifampicin or ciprofloxacin to eradicate Raised ESR/C-reactive protein
the bacteria from the nasopharynx. In the case of group C Leucocytosis
disease, contacts should be offered immunization. Prolonged PR interval on ECG
Plus evidence of antecedent streptococcal infection, e.g.
Rheumatic fever______________________ positive throat cultures for group A streptococci, elevated
antistreptolysin O titre (> 250 U) or other streptococcal
Rheumatic fever is an inflammatory disease that occurs in antibodies, or a history of recent scarlet fever
children and young adults (the first attack usually occurs ESR, erythrocyte sedimentation rate
at between 5 and 15 years of age) as a result of infection
with group A streptococci. It affects the heart, skin, joints
and central nervous system. It is common in the Middle one major manifestation plus two or more minor features.
and Far East, eastern Europe and South America. It is rare These are known as the Duckett Jones criteria (Table 2.35).
in the UK, western Europe and North America. This Carditis manifests as:
decline in the incidence of rheumatic fever (from 10% of ■ new or changed heart murmurs
children in the 1920s to 0.01% today) parallels the ■ development of cardiac enlargement or cardiac failure
reduction in all streptococcal infections and is largely due ■ appearance of a pericardial effusion and ECG changes
to improved hygiene and the use of antibiotics. of pericarditis (raised ST segments) or myocarditis
Pharyngeal infection with group A streptococcus is (inverted or flattened T waves), first-degree or greater
followed by the clinical syndrome of rheumatic fever. AV block or other cardiac arrhythmias
This is thought to develop because of an autoimmune ■ transient diastolic mitral (Carey-Coombs) murmur
reaction triggered by molecular mimicry between the due to mitral valvulitis.
cell wall M proteins of the infecting Strep, pyogenes and
cardiac myosin and laminin. The condition is not due Non-cardiac features include the following:
to direct infection of the heart or to the production of a
■ There is usually a fever with an apparently excessive
toxin.
tachycardia.
■ The arthritis associated with rheumatic fever is
Pathology
classically a fleeting migratory polyarthritis affecting
All three layers of the heart may be affected. The large joints such as the knees, elbows, ankles and
characteristic lesion of rheumatic carditis is the Aschoff wrists. The joints are swollen, red and tender. As the
nodule, which is a granulomatous lesion with a central inflammation in one joint recedes, another becomes
necrotic area occurring in the myocardium, particularly affected. Once the acute inflammation disappears, the
in the subendocardium of the left ventricle. Small, warty rheumatic process leaves the joints normal.
vegetations may develop on the endocardium, parti- ■ Sydenham's chorea (or St Vitus' dance, see p. 1232) is
cularly on the heart valves. This leads to some degree of involvement of the central nervous system that
valvular regurgitation. A serofibrinous effusion character- develops late after a streptococcal infection. Sufferers
izes the acute pericarditis that occurs. are noticeably 'fidgety' and display spasmodic,
The synovial membranes are acutely inflamed during unintentional choreiform movements. Speech is often
rheumatic fever, and subcutaneous nodules (which are affected.
also granulomatous lesions) are seen in the acute stage of
■ Skin manifestations include erythema marginatum, a
the disease.
transient pink rash with slightly raised edges, which
occurs in 20% of cases. The erythematous areas found
Clinical features
mostly on the trunk and limbs coalesce into crescent-
The disease presents suddenly, with fever, joint pains, or ring-shaped patches. Subcutaneous nodules, which
malaise and loss of appetite. The clinical features depend are painless, pea-sized, hard nodules beneath the skin,
on the organs that are involved. Diagnosis relies on the may also occur, particularly over tendons, joints and
presence of two or more major clinical manifestations or bony prominences.
76
Bacterial infections
Investigations largely an occupational disease of farmers, vets, and
■ Throat swabs are cultured for the group A others who work with animals. In some parts of the
streptococcus. world (e.g. Hawaii, where the annual incidence is about
■ Serological changes may indicate a recent streptococcal 130/100 000) it is associated with a variety of recreational
infection. The antistreptolysin O titre, and sometimes activities which bring people into closer contact with
others such as the antistreptokinase titre, are performed. rodents. Outbreaks of leptospirosis have also been associ-
■ Non-specific indicators of inflammation such as the ated with flooding.
ESR and the C-reactive protein levels are usually
elevated. Clinical features
■ Cardiac investigations, e.g. ECG, echocardiogram. Weil, in 1886, described a severe illness consisting of
jaundice, haemorrhage, and renal impairment caused by
Treatment L. i. icterohaemorrhagiae, but fortunately 90-95% of
Patients with fever, active arthritis or active carditis infections are subclinical or cause only a mild fever. The
should be completely rested in bed. When the clinical incubation period of leptospirosis is usually 7-14 days,
syndrome has subsided (e.g. no pyrexia, normal pulse and the illness typically has two phases. A Ieptospiraemic
rate, normal ESR, normal white cell count) the patient phase, which lasts for up to a week, is followed after a
may be mobilized. couple of days' interval by an immunological phase. The
Residual streptococcal infections should be eradicated first phase is characterized by severe headache, malaise,
with oral phenoxymethylpenicillin 500 mg four times fever, anorexia and myalgia. Most patients have con-
daily for 1 week. This therapy should be administered junctival suffusion. Hepatosplenomegaly, lymph-
even if nasal or pharyngeal swabs do not culture the adenopathy and various skin rashes are sometimes seen.
streptococci. The second phase is usually mild. Fifty per cent of
High-dose salicylate (preferably acetylsalicylate, i.e. patients have meningism, about a third of whom have a
aspirin) therapy is given to the limit of tolerance CSF lymphocytosis. The majority of patients recover
determined by the development of tinnitus. If carditis is uneventfully at this stage.
present, systemic corticosteroids are given. Prednisolone In severe disease there may not be a clear distinction
60-120 mg in four divided doses each day is administered between phases. Following the initial symptoms, patients
until the clinical syndrome is improved and the ESR has progressively develop hepatic and renal failure, haemo-
fallen to normal. Steroids are then tapered off over lytic anaemia, and circulatory collapse. Cardiac failure
2-4 weeks. However, the efficacy of steroids is unproven. and pulmonary haemorrhage may also occur. Even with
Recurrences are most common when persistent cardiac full supportive care the mortality is around 10%, rising to
damage is present, and are prevented by the continued 15-20% in the elderly.
administration of oral phenoxymethylpenicillin 250 mg
twice daily until the age of 20 years or for 5 years after the Diagnosis
latest attack (see p. 32). A sulphonamide (e.g. sulfadiazine) The diagnosis is usually a clinical one. Leptospires can be
may be used if the patient is allergic to penicillin. Any cultured from blood or CSF during the first week of
streptococcal infection that does develop should be illness, but culture requires special media and may take
treated very promptly. several weeks. A minority of patients may also excrete the
organism in their urine from the second week onwards.
Prognosis Specific IgM antibodies start to appear from the end of the
More than 50% of those who suffer acute rheumatic fever first week and the diagnosis is often made retrospectively
with carditis will later (after 10-20 years) develop chronic with a microscopic agglutinating test (MAT) showing a
rheumatic valvular disease, predominantly affecting the four-fold rise. There is typically a leucocytosis and in
mitral and aortic valves (Table 13.35). severe infection, thrombocytopenia and an elevated
creatine phosphokinase.

Leptospirosis Management
Leptospirosis is a zoonosis caused by the spirochaete Early antibiotic therapy will limit the progress of the
Leptospim interrogans. There are over 200 serotypes: the disease, but treatment should still be initiated whatever the
main types affecting humans are L. i. icterohaemorrhagiae stage of the infection. Oral doxycycline may be used in mild
(rodents), L. i. canicola (dogs and pigs), L. i. hardjo (cattle), cases: intravenous penicillin or erythromycin is given in
and L.;'. pomona (pigs and cattle). Leptospires are excreted more severe disease. Intensive supportive care is needed for
in the animal urine, and enter the host through a skin those patients who develop hepatorenal failure.
abrasion or through intact mucous membranes.
Leptospirosis can also be caught by ingestion of contami-
Brucellosis
nated water. The organism can survive for many days in
warm fresh water, and for up to 24 hours in sea water. Brucellosis (Malta fever, undulant fever) is a zoonosis and
In England and Wales only about 30 cases of has a world-wide distribution, although it has been
leptospirosis are reported every year (although many virtually eliminated from cattle in the UK. The highest
mild infections probably go undiagnosed), and it remains incidence is in the Mediterranean countries, the Middle
77
Infectious diseases, tropical medicine and sexually transmitted diseases
East and the tropics; there are about 500 000 new cases infected animals, vaccination with the eradication of
diagnosed per year. infection in animals, and pasteurization of milk. No
The organisms usually gain entry into the human vaccine is available for use in humans.
body via the mouth; less frequently they may enter via
the respiratory tract, genital tract or abraded skin. The
bacilli travel in the lymphatics and infect lymph nodes.
Listeriosis____________________
This is followed by haematogenous spread with ultimate Listeria monocytogenes is an environmental organism
localization in the reticuloendothelial system. Spread is which is widely disseminated in soil and decayed matter.
usually by the ingestion of raw milk from infected cattle It affects both animals and man: the most common route
or goats, although occupational exposure is also common. of human infection is in contaminated foodstuffs. The
Person-to-person transmission is rare. -.■ ■ :• organism can grow at temperatures as low as 4°C, and the
most commonly implicated foods are unpasteurized soft
Clinical features cheeses, raw vegetables and chicken pates. Listeriosis is a
The incubation period of acute brucellosis is 1-3 weeks. rare but serious infection affecting mainly neonates, preg-
The onset is insidious, with malaise, headache, weakness, nant women, the elderly, and the immunocompromised.
generalized myalgia and night sweats. The fever pattern is L. monocytogenes has also been recognized as a cause of
classically undulant, although continuous and intermittent self-limiting food-borne gastroenteritis in healthy adults,
patterns are also seen. Lymphadenopathy, hepato- but the incidence of this is unknown.
splenomegaly and spinal tenderness sacro-iliitis (20-30%) In pregnant women listeria causes a flu-like illness, but
may be present; arthritis, osteomyelitis, epididymo-orchitis infection of the fetus can lead to septic abortion, pre-
(up to 40%), meningoencephalitis and endocarditis have all mature labour, and stillbirth. Early treatment of listeria in
been described. pregnancy may prevent this, but the overall fetal loss rate
Untreated brucellosis can give rise to chronic infection, is about 50%. Listeria in the elderly and the immuno-
lasting a year or more. This is characterized by easy compromised usually causes meningoencephalitis,
fatiguability, myalgia, and occasional bouts of fever and although septicaemia and a variety of other focal
depression. Splenomegaly is usually present. Occasion- infections have been described.
ally infection can lead to localized brucellosis. Bones and The diagnosis is established by culture of blood, CSF,
joints, spleen, endocardium, lungs, urinary tract and or other body fluids. The treatment of choice for adult
listeriosis is ampicillin plus gentamicin. Co-trimoxazole
nervous system may be involved. Systemic symptoms
is also effective, but the organism is resistant to
occur in less than one-third.
cephalosporins.
Diagnosis
Blood (or bone marrow) cultures are positive during the Q fever
acute phase of illness in 50% of patients (higher in
B. melitensis), but prolonged culture is needed. If using Q (query) fever is a zoonosis caused by the rickettsia-like
automated blood culture systems (BACTEC) incubate organism Coxiella burnetii. Infection is widespread in
longer than the usual 5-7 days. This is less helpful in domestic, farm and other animals, birds and arthropods:
chronic disease where serological tests are of greater spread is mainly by ticks. Modes of transmission to
value. The brucella agglutination test, which demon- humans are by dust, aerosol, and unpasteurized milk
strates a fourfold or greater rise in titre (> 1 in 160) over from infected cows. The formation of spores means that
a 4-week period, is highly suggestive of brucellosis. C. burnetii can survive in extreme environmental con-
However, non-agglutinating IgG and IgA molecules can ditions for long periods. The infective dose is very small,
block the agglutinating reaction (prozone phenomenon) so that minimal animal contact is required. One reported
and the test should be carried out to a high dilution to outbreak occurred among inhabitants of a village through
avoid this. An elevated serum IgG level is evidence of which infected sheep had passed.
current or recent infection; a negative test excludes
chronic brucellosis. In localized brucellosis antibody titres Clinical features
are low, and diagnosis is usually established by culturing Symptoms begin insidiously 2-A weeks after infection.
the organisms from the involved site. PCR for detection of Fever is accompanied by flu-like symptoms with myalgia
Brucella in blood gives a rapid diagnosis, and along with and headache. The acute illness usually resolves sponta-
measurement of IgG or IgM antibodies by ELISA, are neously but pneumonia or hepatitis may develop.
highly sensitive and specific. , : . ;.':;, Occasionally infection can become chronic, with
endocarditis, myocarditis, uveitis, osteomyelitis or other
Management and prevention focal infections.
Brucellosis is treated with a combination of doxycycline C. burnetii is an obligate intracellular organism, and
200 mg daily and rifampicin 600-900 mg daily for 6 weeks, does not grow on standard culture media. Diagnosis is
but relapses occur. Alternatively, tetracycline can be made serologically using an immunofluorescent assay.
combined with streptomycin, which is usually given for Antibody tests for two different bacterial antigens allow
only the first 2 weeks of treatment. Prevention and control distinction between acute and chronic infection; a nested
involve careful attention to hygiene when handling PCR assay is now available. , : >
78
Bacterial infections
Management ceftriaxone. However, treatment is unsatisfactory, and
Treatment with doxycycline 200 mg daily (or a quinolone preventative measures are necessary. In tick-infested
as an alternative) reduces the duration of the acute areas, repellents and protective clothing should be worn.
illness, but it is not known whether this correlates with Prompt removal of any tick is essential as infection is
eradication of the organism. For chronic Q fever, unlikely to take place until the tick has been attached for
including endocarditis, doxycycline is often combined more than 48 hours. Ticks should be grasped with forceps
with rifampicin or clindamycin. Even prolonged courses near to the point of attachment to the skin and then
of treatment may not clear the infection. withdrawn by gentle traction. Antibiotic prophylaxis
following a tick bite is not usually justified, even in areas
where Lyme disease is common. A vaccine was available
but has recently been withdrawn.
Lyme disease_________ '
____________________
Lyme disease is caused by a spirochaete Borrelia
burgdorferi, which has at least 11 different genomic Tularaemia
species. It is a zoonosis of deer and other wild mammals. Tularaemia is due to infection by Fmncisella tularensis, a
The syndrome was first recognized and named following Gram-negative organism. It is primarily a zoonosis,
an 'outbreak' of arthritis in the town of Lyme, acquired mainly from rodents. Infection is normally
Connecticut, in the mid-1970s. Since then the disease has transmitted by arthropod vectors, including ticks and
increased in both incidence and detection: it is now blood-sucking flies. Humans may be infected by this
known to be widespread in the USA, Europe, Russia and route or by handling infected animals, when the micro-
the Far East. Infection is transmitted from animal to man organisms enter through minor abrasions or mucous
by ixodid ticks, and is most likely to occur in rural membranes. Occasionally infection occurs from contami-
wooded areas in spring and early summer. nated water or from eating uncooked meat. The disease is
widely distributed in North America, Northern Europe
Clinical features and Asia. It is relatively rare, occurring mainly in hunters,
The first stage of the illness, which follows 7-10 days after trappers, and others in close contact with animals.
infection, is characterized by the skin lesion, erythema The incubation period of 2-7 days is followed by a
migrans at the site of the tick bite. This is often generalized illness. The most common presentation is
accompanied by headache, fever, malaise, myalgia, ulceroglandular tularaemia. A papule occurs at the site of
arthralgia and lymphadenopathy. Many people have inoculation. This ulcerates and is followed by tender,
no further illness after this. A second stage may follow suppurative lymphadenopathy. Rarely this can be fol-
weeks or months later, when some patients develop lowed by bacteraemia, leading to septicaemia, pneumonia,
neurological symptoms (meningoencephalitis, cranial or or meningitis. These forms of the disease carry a high
polyneuropathies), radiculopathies, cardiac problems mortality if untreated.
(conduction disorders, myocarditis) or arthritis. These Diagnosis is by culture of the organism or by a rising
manifestations, which are often fluctuant and changing, titre seen on a bacterial agglutination test.
usually resolve spontaneously over months or years. Tularaemia should be treated with streptomycin or
Some patients, however, develop chronic and persistent gentamicin.
neurological disease (e.g. paraparesis) or rheumatological
disease (Tate Lyme disease'). Acrodermatitis chronica
atrophicans, usually on the backs of the hands and feet FURTHER READING
can occur if the disease does not resolve spontaneously. Galvin JE, Hemric ME, Ward K, Cunningham MW
(2000) Cytotoxic Mab from rheumatic carditis
Diagnosis ~ recognizes heart valves and laminin. Journal of
The clinical features and epidemiological considerations Clinical Investigation 106: 217-224.
are usually strongly suggestive. The diagnosis can only Hotchkiss R, Karl I (2003) The pathophysiology and
rarely be confirmed by isolation of the organisms from treatment of sepsis. New England Journal of Medicine
348:138-150.
blood, skin lesions or CSF. IgM antibodies are detectable
Levett PN (1999) Leptospirosis: re-emerging or re-
in the first month, and IgG antibodies are invariably discovered disease? Journal of Medical Microbiology 48:
present late in the disease. Commercial tests (ELISA, 417-418.
immunofluorescence, haemagglutination) are available Parola P, Raoult D (2001) Ticks and tick-borne bacterial
but false positive results do occur. A genuine positive IgG diseases in humans. Clinical Infectious Diseases 32: 897-
may be a marker of previous exposure rather than of 928.
ongoing infection. Rosenstein NE et al. (2001) Meningococcal disease. New
England Journal of Medicine 344: 1378-1389.
Management Stanek G, Strle F (2004) Lyme borreliosis. Lancet 362: 1639-
Amoxicillin or doxycycline given early in the course of 1647.
Pappas G et al (2005) Brucellosis. New England Journal of
the disease shortens the duration of the illness in Medicine 352: 2325-2336.
approximately 50% of patients. Late disease should be
treated with 1-A weeks of intravenous benzylpenicillin or
79
Infectious diseases, tropical medicine and sexually transmitted diseases

BACTERIAL INFECTIONS SEEN IN destroy the bacilli (Thl response) but with associated
DEVELOPING AND TROPICAL destruction of the tissue. The lepromin test (see below)
is positive.
COUNTRIES ■ Lepromatous leprosy, a generalized disease that occurs
in individuals with impaired CMI (Fig. 2.25). Here the
SKIN, SOFT TISSUE AND EYE DISEASE tissue macrophages fail to be activated and the bacilli
multiply intracellularly. Th2 cytokines are produced
Leprosy (see p. 208). The lepromin test is negative.
Leprosy (Hansen's disease) is caused by the acid-fast The WHO classification of leprosy depends on the
bacillus Mycobacterium leprae. Unlike other mycobacteria, number of skin lesions and the number of bacilli detected
it does not grow in artificial media or even in tissue on the skin smears: paucibacillary leprosy has 5 or fewer
culture. Apart from the nine-banded armadillo, man is skin lesions with no bacilli; multibacillary leprosy has
the only natural host of M. leprae, although it can be 6 more lesions which may have bacilli.
grown in the footpads of mice. In practice many patients will fall between these two
The WHO campaign to control leprosy has been
extremes and some may move along the spectrum as the
hugely successful, with more than 13 million people
disease progresses or is treated.
having been cured of the disease. The number of people
with active leprosy has fallen from 5.4 million in 1985 to
about 600 000, largely as the result of supervised multi- Clinical features
drug treatment regimens. India has 70% of the world The incubation period varies from 2-6 years, although it
cases with Brazil having the next highest. It is also may be as short as a few months or as long as 20 years.
common across Africa and Asia. The onset of leprosy is generally insidious. Acute onset is
The precise mode of transmission of leprosy is still known to occur, and patients may present with a
uncertain but it is likely that nasal secretions play a role. transient rash, with features of an acute febrile illness,
Infection is related to poverty and overcrowding. Once an with evidence of nerve involvement, or with any combi-
individual has been infected, subsequent progression to nation of these. The major signs of leprosy are:
clinical disease appears to be dependent on several
factors. Males appear to be more susceptible than ■ Skin lesions, usually anaesthetic (generally tuberculoid).
females, and there is evidence from twin studies of a ■ Thickened peripheral nerves, nerves of predilection
genetic susceptibility. The main factor, however, is the which are superficial or lie in fibro-osseous tunnels -
response of the host's cell-mediated immune system. ulnar (elbow), median (wrist), radial cutaneous
Two polar types of leprosy are recognized (Ridley- (wrist), common peroneal (knee), posterior tibial and
Jopling system) (Fig. 2.25): sural (ankle), facial (crossing zygomatic arch) and
greater auricular (posterior triangle of the neck).
■ Tuberculoid leprosy, a localized disease that occurs in
individuals with a high degree of cell-mediated The spectrum of disease can be divided into five clinical
immunity (CMI). The T cell response to the antigen groups.
releases interferon which activates macrophages to
Tuberculoid leprosy (TT)
In tuberculoid leprosy the infection is localized because
Infection the patient has unimpaired cell-mediated immunity. The
characteristic, usually single, skin lesion is a hypo-
LEPROMATOUS pigmented, anaesthetic patch with thickened, clearly
NO DISEASE LEPROSY
(majority) INDETERMINATE demarcated edges, central healing, and atrophy. The face,
id. leprae) LEPROSY LL gluteal region and extremities are most commonly
TUBERCULOID affected. The nerve leading to the hypopigmented patch,
LEPROSY
and the regional nerve trunk, are often thickened and
TT BT BB BL
tender. Unlike other parts of the body, a tuberculoid patch
on the face is not anaesthetic. Nerve involvement leads to
marked muscle atrophy. Tuberculoid lesions are known
to heal spontaneously. The prognosis is good.

Borderline tuberculoid (BT) leprosy


This resembles TT but skin lesions are usually more
Fig. 2.25 Clinical spectrum of leprosy with the
numerous, smaller, and may be present as small 'satellite'
combined Ridley-Jopling and WHO classification. lesions around larger ones. Peripheral but not cutaneous
BT, borderline tuberculoid; BB, borderline; BL, borderline nerves are thickened, leading to deformity of hands and
lepromatous; CMI, cell-mediated immunity; AFB, acid-fast feet.
bacilli; PB, paucibacillary; MB, multibacillary. Modified from
Jacobson R (1999) Krahenbuhl JL Lancet 353: 655. Borderline (BB) leprosy
Skin lesions are numerous, varying in size and form
(macules, papules, plaques). The annular, rimmed lesion
Bacterial infections seen in developing and tropical countries

with punched-out, hypopigmented anaesthetic centre is on the face, the gluteal region and the upper and lower
characteristic (Fig. 2.26). There is widespread nerve limbs. They may be macules, papules, nodules or plaques:
involvement and limb deformity (Fig. 2.27). of these, the macule is the first to appear. Infiltration is
most noticeable in the ear lobes. Thinning of the lateral
Borderline lepromatous (BL) leprosy margins of the eyebrows is characteristic. The mucous
There are a large number of florid asymmetrical skin membranes are frequently involved, resulting in nasal
lesions of variable form, which are strongly positive for stuffiness, laryngitis and hoarseness of the voice. Nasal
acid-fast bacilli. Skin between the lesions is normal and septal perforation with collapse of the nasal cartilages
often negative for bacilli. produces a saddle-nose deformity. With progression of
the disease the typical leonine fades due to infiltration of
Lepromatous leprosy (LL) the skin becomes apparent. Glove and stocking anaes-
Although practically every organ can be involved, the thesia, gynaecomastia, testicular atrophy, ichthyosis and
changes in the skin are the earliest and most obvious nerve palsies (facial, ulnar, median and radial) develop
manifestation. Peripheral oedema and rhinitis are the late in the disease. Neurotrophic atrophy affecting the
earliest symptoms. The skin lesions predominantly occur phalanges leads to the gradual disappearance of fingers.
Nerve involvement is less pronounced than in TT.

Lepra reactions
These are immunologically mediated acute reactions that
occur in patients with the borderline or lepromatous
spectrum of disease, usually during treatment. Two forms
are recognized.

Non-lepromatous lepra reaction (type I lepra reaction).


This is seen following treatment of patients with
borderline disease; it is a type IV delayed hypersensitivity
reaction. Both upgrading (or reversal) reactions (i.e. a
clinical change towards a more tuberculoid form) and
downgrading reactions (i.e. a change towards the
lepromatous form) can occur. Neurological deficits such
as an ulnar nerve palsy may occur abruptly.

Erythema nodosum leprosum (ENL; type II lepra


reaction). This is a humoral antibody response to an
antigen-antibody complex (i.e. a type III hypersensitivity
reaction). It is seen in 50% of patients with treated LL.
ENL is characterized by fever, arthralgia, iridocyclitis,
crops of painful, subcutaneous erythematous nodules,
and other systemic manifestations. It may last from a few
days to several weeks.

Diagnosis
The diagnosis of leprosy is essentially clinical with:
Fig. 2.26 Multiple asymmetrical hypopigmented
anaesthetic patches. Courtesy of Dr P Matondo, Zambia. ■ hypopigmented/reddish patches with loss of sensation
■ thickening of peripheral nerves
■ acid-fast bacilli (AFB) seen on skin-slit smears/ biopsy.
Small slits are made in pinched skin and the fluid
obtained is smeared on a slide and stained for AFB.
Patients should be examined carefully for skin lesions in
adequate natural light. Occasionally nerve biopsies are
helpful. Detection of M. leprae DNA is possible in all
forms of leprosy using the polymerase chain reaction, and
can be used to assess the efficacy of treatment.

Management
Multidrug therapy (MDT) is essential because of develop-
ing drug resistance (up to 40% of bacilli in some areas are
resistant to dapsone). Much shorter courses of treatment
are now being used: the current WHO recommended

I
Fig. 2.27 Leprosy - claw hand due to median and ulnar
nerve damage. drug regimens for leprosy are shown in Box 2.11 but
8
1
Infectious diseases, tropical medicine and sexually transmitted diseases
Box 2.11 Recommended treatment regimens for with an infected animal; infection is most frequently seen
leprosy in adults (modified WHO guidelines) in farmers, butchers, and dealers in wool and animal
Multibacillary leprosy (LL, BL, BB) hides. Spores can also be ingested or inhaled. There have
Rifampicin 600 mg once-monthly, supervised been recent cases in the USA due to the deliberate release
Clofazimine 300 mg once-monthly, supervised of anthrax spores as a bioterrorist weapon (p. 1031).
Clofazimine 50 mg daily, self-administered
Dapsone 100 mg daily, self-administered Clinical features
Treatment continued for 12 months The incubation period is 1-10 days. Cutaneous anthrax is
Paucibacillary leprosy (BT, TT) the most common. The small, erythematous, maculo-
Rifampicin 600 mg once-monthly, supervised papular lesion is initially painless. It may subsequently
Dapsone 100 mg daily, self-administered vesiculate and ulcerate, with formation of a central black
Treatment continued for 6 months eschar. The illness is self-limiting in the majority of
Single lesion paucibacillary leprosy patients, but occasionally perivesicular oedema and
Rifampicin 600 mg regional lymphadenopathy may be marked, and
Ofloxacin 400 mg as a single dose toxaemia can occur.
Minocycline 100 mg j Inhalational anthrax (woolsorter's disease) follows
LL, lepromatous; BL, borderline lepromatous; BB, borderline; BT, inhalation of spores, and bioterrorism should be suspected.
borderline tuberculoid; TT, tuberculoid A febrile illness is accompanied by non-productive cough
and retrosternal discomfort; pleural effusions are common.
Untreated, the mortality is about 90%, and in the recent
cases in the USA it was 45% despite treatment.
longer therapy may be required in severe cases. Follow Gastrointestinal anthrax is due to consumption of
up including skin smears is essential. undercooked, contaminated meat. It presents as severe
Patient education is essential. Patients should be gastroenteritis; haematemesis and bloody diarrhoea can
taught self-care of their anaesthetic hands and feet to occur. Toxaemia, shock and death may follow.
prevent ulcers. If ulcers develop, no weight-bearing
should be permitted. Cheap canvas shoes with cushioned Diagnosis
insoles are protective. The diagnosis is established by demonstrating the
Leprosy should be treated in specialist centres with organism in smears from cutaneous lesions or by culture
adequate physiotherapy and occupational therapy of blood and other body fluids. Serological confirmation
support. Surgery and physiotherapy also play a role in can be made using ELISAs detecting antibodies to both
the management of trophic ulcers and deformities of the the organism and a toxin.
hands, feet and face.
Management
Treatment of lepra reactions. This is urgent, as Ciprofloxacin is considered the best treatment. In mild
irreversible eye and nerve damage can occur. Antileprosy cutaneous infections, oral therapy for 2 weeks is adequate
therapy must be continued. Type II lepra reactions (ENL) but therapy for 60 days was used in the recent outbreaks
can be treated with analgesics, chloroquine, clofazimine in the USA. In more severe infections high doses of intra-
and antipyretics. Thalidomide was prevously used for venous antibiotics are needed, along with appropriate
ENL and is effective. However, because of its terato- supportive care. Any suspected case should be reported
genicity, it is no longer recommended by WHO. Prednis- to the relevant authority.
olone 40-60 mg daily for 3-6 months is effective in type I
reactions. Control
Any infected animal that dies should be burned and the
Prevention area in which it was housed disinfected. Where animal
The prevention and control of leprosy depends on rapid husbandry is poor, mass vaccination of animals may
treatment of infected patients, particularly those with LL prevent widespread contamination, but needs to be
and BL, to decrease the bacterial reservoir. repeated annually. A human vaccine is available for those
at high risk, and prophylactic antibiotics may be indicated
following exposure. Some countries are establishing public
Anthrax health policies to deal with the deliberate release of
anthrax spores.
Anthrax is caused by Bacillus anthracis. The spores of
these Gram-positive bacilli are extremely hardy and
withstand extremes of temperature and humidity. The
organism is capable of toxin production and this property Mycobacterial ulcer (Buruli ulcer)________
correlates most closely with its virulence. The disease Buruli ulcer is seen world-wide in rural areas in the
occurs world-wide. Epidemics have been reported in The tropical rainforests. Mycobacterium ulcerans, the causative
Gambia, in both North and South America and in organism, is found in pools and rivers, and infection is
southern Europe. Transmission is through direct contact usually due to bathing, swimming or collecting water. A
82
Bacterial infections seen in developing and tropical countries
small subcutaneous nodule at the site of infection weeks or months a primary inflammatory reaction occurs
gradually ulcerates, involving subcutaneous tissue, at the inoculation site, from which organisms can be
muscle and fascial planes. The ulcers are usually large isolated. Dissemination of the organism leads to multiple
with undermined edges and markedly necrotic bases due papular lesions containing treponemes; these skin lesions
to mycolactone. Smears taken from necrotic tissue usually involve the palms and soles. There may also be
generally reveal numerous acid-fast bacilli. The only bone involvement, particularly affecting the long bones
effective treatment is wide surgical excision with skin and those of the hand.
grafts, but this is often unavailable in areas where Approximately 10% of those infected go on to develop
the disease is prevalent. Antituberculous therapy is late yaws. Bony gummatous lesions may progress to
ineffective. cause gross destruction and disfigurement, particularly of
the skull and facial bones, the interphalangeal joints and
the long bones. Plantar hyperkeratosis is characteristic.
Like syphilis, there may be a latent period between the
Endemic treponematoses (bejel, yaws early and late phases of the disease, but visceral,
and pinta) neurological and cardiovascular problems do not occur.
These diseases are found in various parts of the tropics
and subtropics, mainly in impoverished rural areas Bejel (endemic syphilis)
(Fig. 2.28). The WHO treated over 50 million cases in the Bejel is seen in Africa and the Middle East. The causative
1950s and 1960s, reducing the prevalence of these organism (Treponema endemicum) enters through abrasions
diseases, but subsequently there has been a resurgence in the skin or from contaminated drinking vessels. It
of infection. The latest estimate of global prevalence is differs from venereal syphilis in that a primary lesion is
2.5 million cases. Improvements in sanitation and an not commonly seen. The late stages resemble syphilis, but
increase in living standards will be required to eradicate cardiological and neurological manifestations are rare.
the diseases completely as organisms are transmitted by
bodily contact, usually in children. Pinta
Pinta, caused by Treponema carateum, is restricted mainly
Clinical features to Central and South America. It is milder than the other
Yaws trepanomatoses and is confined to the skin. The primary
Yaws (caused by Treponema pertenue) is the most wide- lesion is a pruritic red papule, usually on the hand or foot.
spread and common of the endemic treponemal diseases. It may become scaly but never ulcerates and is generally
It is spread by direct contact, the organism entering associated with regional lymphadenopathy. In the later
through damaged skin. After an incubation period of stages similar lesions can continue to occur for up to
I | Yaws
I | Pinta and yaws

| | Endemic syphilis (bejel)

Fig. 2.28 Bejel, yaws and pinta - geographical distribution.


1 year, associated with generalized lymphadenopathy.
FURTHER READING
Eventually the lesions heal leaving hyperpigmented or Barlett JG et al. (2002) Management of anthrax. Clinical
depigmented patches. Infectious Diseases 35: 851-858. Britton WJ, Lockwood
DNJ (2004) Leprosy. Lancet 363:
Diagnosis and management 1209-1219. Mabey D, Solomon A, Foster A (2003)
In endemic areas the diagnosis is usually clinical. The Trachoma. Lancet
causative organism can be identified from the exudative 362: 223-229. Swartz MN (2001) Recognition and
lesions under dark-ground microscopy. Serological tests management of
for syphilis are positive but do not differentiate between anthrax. 'New England Journal of Medicine 345:
1621-1626.
the conditions.
The treatment is with long-acting penicillin (e.g. intra-
muscular benzathine penicillin, 1.2 million units) given
as a single dose. Doxycycline is used when penicillin is GASTROINTESTINAL INFECTIONS
ineffective or contra-indicated. mm;

Cholera
Trachoma____________________________ Cholera is caused by the curved, flagellated Gram-
Trachoma, caused by the intracellular bacterium Chlamydia negative bacillus, Vibrio cholerae. The organism is killed by
trachomatis, is the most common cause of blindness in the temperatures of 100 °C in a few seconds but can survive
world. It is estimated that there are 150 million current in ice for up to 6 weeks. One major pathogenic serogroup
infections, and 6 million people who have been blinded possesses a somatic antigen (Ol) with two biotypes:
by trachoma. It is a disease of poverty which is found classical and El Tor. The El Tor biotype replaced the
mainly in the tropics and the Middle East: it is entirely classical biotype as the major cause of the seventh
preventable. Trachoma commonly occurs in children, and pandemic which began in the 1960s. Infection with the El
is spread by direct transmission or by flies. Isolated infec- Tor biotype generally causes milder symptoms, but can
tion is probably self-limiting, and it is repeated infection still cause severe and life-threatening disease.
which leads to chronic eye disease. The fertile, humid Gangetic plains of West Bengal have
traditionally been regarded as the home of cholera.
Clinical features However, a series of pandemics have spread the disease
Infection is bilateral and begins in the conjunctiva, with across the world, usually following trade routes. The
marked follicular inflammation and subsequent scarring. seventh pandemic has affected large areas of Asia, North
Scarring of the upper eyelid causes entropion, leaving the Africa, Kenya and southern Europe. It has spread to
cornea exposed to further damage with the eyelashes South and Central America in recent years, claiming
rubbing against it (trichiasis). The corneal scarring that thousands of lives. A new serogroup (O139 Bengal) is
eventually occurs leads to blindness. now responsible for an increasing number of cases in
Trachoma may also occur as an acute ophthalmic Bangladesh, India and South East Asia. It has a charac-
infection in the neonate. teristic pattern of antibiotic resistance (sulfamethoxazole,
trimethoprim and streptomycin), and may prove to be the
Diagnosis and management cause of the next pandemic.
The diagnosis is generally established by the typical Transmission is by the faeco-oral route. Contaminated
clinical picture. It can be confirmed by cell culture tech- water plays a major role in the dissemination of cholera,
niques or species-specific fluorescent monoclonal anti- although contaminated foodstuffs and contact carriers
bodies, but these are rarely available in endemic areas. may contribute in epidemics. Achlorhydria or hypo-
Tetracycline ointment applied locally each day for chlorhydria facilitates passage of the cholera bacilli into
6—8 weeks is effective but compliance is poor. Systemic the small intestine. Here they proliferate, elaborating an
therapy with a single dose of azithromycin 20 mg/kg is exotoxin which produces massive secretion of isotonic
the treatment of choice. In endemic areas repeated fluid into the intestinal lumen (see p. 332). Cholera toxin
courses of therapy are necessary. Once infection has been also releases serotonin (5-HT) from enterochromaffin cells
controlled, surgery may be required for eyelid recon- in the gut, which activates a neural secretory reflex in the
struction and for treatment of corneal opacities. enteric nervous system. This may account for at least 50%
of cholera toxin's secretory activity. V. cholerae also
Prevention produces other toxins (zona occludens toxin, ZOT, and
Community health education, improvements in water accessory cholera toxin, ACT) which contribute to its
supply and sanitation (pit latrines) and earlier case pathogenic effect.
reporting could have a substantial impact on disease
prevalence. This is reflected in the WHO 'SAFE' approach
Clinical features
to trachoma: surgery, antibiotics, facial cleanliness, The incubation period varies from a few hours to 6 days.
environmental improvement. A WHO target is global The majority of patients with cholera have a mild illness
eradication by 2020. that cannot be distinguished clinically from diarrhoea
84
Bacterial infections seen in developing and tropical countries
due to other infective causes. Classically, however, three of hydration is effectively carried out by oral rehydration
phases are recognized in the untreated disease. solutions.
The evacuation phase is characterized by the abrupt Antibiotics such as tetracycline 500 mg four times daily
onset of painless, profuse, watery diarrhoea, associated for 3 days help to eradicate the infection, decrease stool
with vomiting in the severe forms. 'Rice water' stools, so output, and shorten the duration of the illness. Drug
called because of mucus flecks floating in the watery resistance is becoming an increasing problem, and
stools, are typical of this stage. ciprofloxacin is now used more frequently.
If appropriate supportive treatment is not given, the Immunization is now recommended by the WHO in
patient passes on to the collapse phase. This is charac- potential or actual outbreak situations. Live attenuated
terized by features of circulatory shock (cold clammy and killed vaccine (both oral) are available: neither
skin, tachycardia, hypotension and peripheral cyanosis) protect against the 0139 strain. Chemoprophylaxis with
and dehydration (sunken eyes, hollow cheeks and a tetracycline 500 mg twice-daily for 3 days for adults, or
diminished urine output). The patient, though apathetic, 125 mg daily for children, is effective. The best prevent-
is usually lucid. Muscle cramps may be severe. Children ative measures, however, are good hygiene and improved
may present with convulsions owing to hypoglycaemia. sanitation.
At this stage renal failure and aspiration of vomitus
present major problems. Enteric fever
If the patient survives the collapse stage the recovery
phase starts, with a gradual return to normal clinical and Over 16 million new cases of enteric fever occur world -
biochemical parameters in 1-3 days. wide, mainly in India and Africa, causing 600 000 deaths
per year. Enteric fever is an acute systemic illness
Diagnosis characterized by fever, headache, and abdominal
This is largely clinical. Examination of freshly passed discomfort. Typhoid, the typical form of enteric fever, is
stools may demonstrate rapidly motile organisms. This is caused by Salmonella typhi. A similar but generally less
not diagnostic, as Cmnpylobacter jejuni may also give a severe illness known as paratyphoid is due to infection
similar appearance. However, demonstration of the with S. paratyphi A, B, or C. Man is the only natural host
rapidly motile vibrios by dark-field illumination and sub- for S. typhi, which is transmitted in contaminated food or
sequent inhibition of their movement with type-specific water. The incubation period is 10-14 days.
antisera is diagnostic. Stool and rectal swabs should be
taken for culture.
Clinical features
After ingestion, the bacteria invade the small bowel wall
Management via Peyer's patches, from where they spread to the regional
The mainstay of treatment is rehydration, and with lymph nodes and then to the blood. The onset of illness is
appropriate and effective rehydration therapy mortality insidious and non-specific, with intermittent fever, head-
has decreased to less than 1%. Oral rehydration is usually ache, and abdominal pain. Physical findings in the early
adequate, but intravenous therapy is occasionally stages include abdominal tenderness, hepatosplenomegaly,
required. lymphadenopathy, and a scanty maculopapular rash
Oral rehydration solutions (ORS) are based on the obser- ('rose spots'). Without treatment (and occasionally even
vation that glucose (and other carbohydrates) enhances after treatment) serious complications can arise, usually
sodium and water absorption in the small intestine, even in the third week of illness. These include meningitis,
in the presence of secretory loss due to toxins. Additions lobar pneumonia, osteomyelitis, intestinal perforation
such as amylase-resistant starch to glucose-based ORS and intestinal haemorrhage. The fourth week of the ill -
have been shown to increase the absorption of fluid. ness is characterized by gradual improvement, but in
Cereal-based electrolyte solutions have been found to be developing countries up to 30% of those infected will die,
as effective as sugar/salt ORS, and actually reduce stool and 10% of untreated survivors will relapse. This
volume as well as rehydrating. The WHO has recently compares with a mortality rate of 1—2% in the USA.
recommended the use of reduced osmolarity ORS for all After clinical recovery 5-10% of patients will continue
types of diarrhoea, although concerns remain about the to excrete S. typhi for several months: these are termed
risk of hyponatraemia. Suitable solutions for rehydration convalescent carriers. Between 1% and 4% will continue
are listed in Box 2.9 (p. 71). to carry the organism for more than a year: this is chronic
Mi ldly dehydra te d indi vi dua ls a re given ORS carriage. The usual site of carriage is the gall bladder,
50 mL/kg in the first 4 hours, followed by a maintenance and chronic carriage is associated with the presence of
dose of 100 mL/kg daily until the diarrhoea stops. For gallstones. However, in parts of the Middle East and
moderate dehydration, ORS 100 mL/kg is given within Africa where urinary schistosomiasis is prevalent, chronic
the first 4 hours followed by 10-15 mL/kg/hour. carriage of S. typhi in the urinary bladder is also common.
Intravenous rehydration is required only for severely
dehydrated individuals with features of collapse. Several Diagnosis
litres of intravenous fluid (Ringers Lactate) are usually The definitive diagnosis of enteric fever requires the
required to overcome the features of shock. Maintenance culture of S. typhi or S. paratyphi from the patient. Blood
185
Infectious diseases, tropical medicine and sexually transmitted diseases
culture is positive in most cases in the first 2 weeks. injectable inactivated or oral live attenuated vaccines
Culture of intestinal secretions, faeces, and urine is also gives partial protection.
used, although care must be taken to distinguish acute
infection from chronic carriage. Bone marrow culture is
more sensitive than blood culture, but is rarely required SYSTEMIC INFECTIONS
except in patients who have already received antibiotics.
Leucopenia is common but non-specific. Serological tests Tuberculosis
such as the Widal antigen test are of little practical value ____________________________________
and are easily misinterpreted. ■ Tuberculosis is caused by Mycobacterium tuberculosis, and
occasionally M. bovis or M. africanum. These are slow-
Management growing bacteria, and unlike other mycobacteria, are
Increasing antibiotic resistance is seen in isolates of S. typhi, facultative intracellular organisms. The prevalence of
especially in the Indian subcontinent. Chloramphenicol, tuberculosis increases with poor social conditions,
co-trimoxazole and amoxicillin may all still be effective in inadequate nutrition, and overcrowding. In developing
some cases, but quinolones (e.g. ciprofloxacin 500 mg countries it is most commonly acquired in childhood.
twice daily) are now the treatment of choice, although The impact of tuberculosis in the developing world
increased resistance to these agents is being seen: in such has been magnified in the past 20 years by the emergence
cases azithromycin may be effective. Infection from the of the HIV pandemic (p. 129) (Fig. 2.29).
Indian subcontinent, Middle East and South East Asia is Widespread misuse of antibiotics, combined with the
often resistant to multiple antibacterial agents. The breakdown of healthcare systems in parts of Africa,
patient's temperature may remain elevated for several Russia and East Europe, has led to the emergence of drug-
days after starting antibiotics, and this alone is not a sign resistant tuberculosis. The most serious form, known as
of treatment failure. Prolonged antibiotic therapy may multidrug-resistant tuberculosis (MDRTB), is caused by
eliminate the carrier state, but in the presence of gall bacteria that are resistant to both rifampicin and
bladder disease it is rarely effective. Cholecystectomy is isoniazid, two drugs which form the mainstay of treat-
not usually justified on clinical or public health grounds. ment. MDRTB is very difficult to treat, and has a signifi-
cant mortality even with the best medical care.
Prevention
In most people, the initial primary tuberculosis is
This is mainly through improved sanitation and clean asymptomatic or causes only a mild illness.
water. Travellers should avoid drinking untreated water, Occasionally the primary infection progresses locally
ice in drinks and eating ice creams. Vaccination with to a more widespread lesion. Haematogenous spread at
this stage may give rise to miliary tuberculosis.
Number of cases
| | No estimate

■I < 1000
r~Z 1000-9999
Lj 10 000-99 999
(62)
■ 100 000-999 999 (13)
rn > 1 ooo ooo

(2)
Fig. 2.29 Tuberculosis - geographical distribution. From Frieden TR, Sterling TR, Munsiff SS et al. (2003) Tuberculosis.
Reprinted with permission from Elsevier (Lancet 362: 888).
pveloping and tropical countries

Tuberculosis in the adult may be the result of Table 2.36 Non-tuberculous mycobacteria causing
reactivation of old disease (post-primary tuberculosis), disease in man
primary infection, or more rarely reinfection. Clinical Common cause Rare cause
Pulmonary tuberculosis is the most common form; this
is described on page 306, along with the chemotherapeutic Chronic lung Mycobacterium M. malmoense
regimens. Tuberculosis also affects other parts of the body: disease avium- M. xenopi
intracellulare
■ The gastrointestinal tract, mainly the ileocaecal area, M. kansasii
but occasionally the peritoneum, producing ascites Local M. avium- M. malmoense
(see p. 344). lymphadenitis intracellulare
■ The genitourinary system. The kidneys are most M. scrofulaceum M. fortuitum
commonly involved, but tuberculosis can also cause Skin and soft
painless, craggy swellings in the epididymis, and tissue infection
salpingitis, tubal abscesses, and infertility in females. Fish tank M. marinum
■ The central nervous system, causing tuberculous granuloma
meningitis and tuberculomas (p. 1238). Abscesses, M. fortuitum M. haemophilum
ulcers, sinuses M. chelonae
■ The skeletal system, leading to septic arthritis and Bone and joint M. kansasii M. scrofulaceum
osteomyelitis. infection M. avium-
■ The skin, giving rise to lupus vulgaris. intracellulare
■ The eyes, where it can cause choroiditis or Disseminated M. avium-
iridocyclitis. infection (in HIV) intracellulare
■ The pericardium, producing constrictive pericarditis
(p. 856).
■ The adrenal glands, causing destruction and producing
Addison's disease. Clinical features
■ Lymph nodes. This is a common mode of presentation, Four clinical forms are recognized: bubonic, pneumonic,
especially in young adults and children. Any group of septicaemic and cutaneous.
lymph nodes may be involved, but hilar and para-
tracheal lymph nodes are the most common. Initially Bubonic plague
the nodes are firm and discrete but later they become This is the most common form and occurs in about 90% of
matted and can suppurate with sinus formation. infected individuals. The incubation period is about
Scrofula is the term used to describe massive cervical 1 week. The onset of illness is acute, with high fever, chills,
lymph node enlargement with discharging sinuses. headache, myalgia, nausea, vomiting and, when severe,
Mycobacterial lymph node disease may also be caused prostration. This is rapidly followed by the development of
by non-tuberculous mycobacteria. lymphadenopathy (buboes), most commonly involving the
inguinal region. Characteristically these are matted and
Non-tuberculous mycobacterial tender, and suppurate in 1-2 weeks. Petechiae, ecchymoses
infections and bleeding from the gastrointestinal tract, the respiratory
tract and the genitourinary tract may occur. Mental
The majority of mycobacterial species are environmental confusion follows the development of toxaemia.
organisms, and are rarely pathogenic. Some have been
found to cause disease in man, particularly in immuno- Pneumonic plague
compromised patients or those with pre-existing chronic This is characterized by the abrupt onset of features of a
lung disease (Table 2.36). fulminant pneumonia with bloody sputum, marked
respiratory distress, cyanosis and death in almost all
Plague ______^ _ _ _ affected patients.
Plague is caused by Yersinia pestis, a Gram-negative Septicaemic plague
bacillus. Sporadic cases of plague (as well as occasional This presents as an acute fulminant infection with
epidemics) occur world-wide: about 2500 cases per year evidence of shock and disseminated intravascular
are reported to the WHO, with a 10% mortality. The coagulation (DIC). If left untreated, death usually occurs
majority of cases are seen in sub-Saharan Africa, although in 2—5 days. Lymphadenopathy is unusual.
the disease is occasionally seen in developed countries in
people undertaking outdoor pursuits. The main reservoirs Cutaneous plague
are woodland rodents, which transmit infection to
This presents either as a pustule, eschar or papule or an
domestic rats (Rattus rattus). The usual vector is the rat
extensive purpura, which can become necrotic and
flea, Xenopsylla cheopis. These fleas bite humans when
gangrenous.
there is a sudden decline in the rat population. Occasion-
ally, spread of the organisms may be through infected Diagnosis
faeces being rubbed into skin wounds, or through
inhalation of droplets. A rapid diagnostic test on samples (bubo aspirate,
sputum) has been developed. This is an easy to read,
Infectious diseases, tropical medicine and sexually transmitted diseases
hand held immunodermatographic dipstick assay relying generalized myalgia and headache. A petechial or
on conjugated gold particles to detect Y pesfi's-specific Fl ecchymotic rash may be seen. The general condition then
capsular antigen. It has an extremely high sensitivity and deteriorates, with delirium, hepatosplenomegaly,
specificity. The diagnosis can also be established by jaundice, haemorrhagic problems and circulatory
demonstrating the organism in lymph node aspirates, in collapse. Although complete recovery may occur at this
blood cultures or on examination of sputum. time, the majority experience one or more relapses of
diminishing intensity over the weeks following the initial
Management illness. The severity of the illness varies enormously, and
Treatment is urgent and should be instituted before the some cases have only mild symptoms. However, in some
results of culture studies are available. The treatment of epidemics mortality has exceeded 50%.
choice is intramuscular streptomycin 1 g twice daily or Tick-borne relapsing fever is caused by B. duttoni and
gentamicin 2 mg/kg i.v. three times daily for 10 days. Oral other Borrelia species, spread by soft (argasid) ticks.
tetracycline 500 mg four times daily and chloramphenicol Rodents are also infected, and humans are incidental
are also effective. hosts, acquiring the spirochaete from the saliva of the
infected tick. This disease is mainly found in countries
Prevention where traditional mud huts are the form of shelter, but is
Prevention of plague is largely dependent on the control occasionally associated with old houses and camp sites in
of the flea population. Outhouses, or huts, should be the USA. The illness is generally similar to the louse-
sprayed with insecticides that are effective against the borne disease, although neurological involvement is
local flea. During epidemics rodents should not be killed more common.
until the fleas are under control, as the fleas will leave
dead rodents to bite humans. Tetracycline 500 mg four Diagnosis and management
times daily or sulphonamides 2^1 g daily for 7 days are Spirochaetes can be demonstrated microscopically in the
effective chemoprophylactic agents. A partially effective blood during febrile episodes: organisms are more
formalin-killed vaccine is available for use by travellers to numerous in louse-borne relapsing fever. Treatment is
plague-endemic areas. usually with tetracycline or doxycycline (see p. 36). A
severe Jarisch-Herxheimer reaction (p. 124) occurs in
Relapsing fevers many patients, often requiring intensive nursing care and
intravenous fluids.
These conditions are so named because, after apparent
recovery from the initial infection, one or more Prevention
recurrences may occur after a week or more without Control of infection relies on elimination of the vector.
fever. They are caused by spirochaetes of the genus Borrelia. Ticks live for years and remain infected, passing the
infection to their progeny. These reservoirs of infection
Clinical features should be controlled by spraying houses with insecticides
Louse-borne relapsing fever (caused by B. recurrentis) is and by reducing the number of rodents. Patients infested
spread by body lice, and only humans are affected. with lice should be deloused by washing with a suitable
Classically it is an epidemic disease of armies and insecticide. All clothes must be thoroughly disinfected.
refugees, although it is also endemic in the highlands of
Ethiopia, Yemen and Bolivia. Lice are spread from person
to person when humans live in close contact in Typhus
impoverished conditions. Infected lice are crushed by Typhus is the collective name given to a group of diseases
scratching, allowing the spirochaete to penetrate through caused by Rickettsia species (Table 2.37). Rickettsia (and
the skin. Symptoms begin 3-10 days after infection and the closely related Orientiae) are small intracellular
consist of a high fever of abrupt onset with rigors, bacteria that are spread to humans by arthropod vectors,
88 Table 2.37 Infections caused by rickettsiae
Disease Organism Reservoir Vector
Typhus fever group
Epidemic typhus Rickettsia prowazekii Man Human body louse
Endemic (murine) typhus R. typhi Rodents Rat flea
Scrub typhus Orientia tsutsugamushi Trombiculid mite Trombiculid mite
Spotted fever group
African tick typhus R. africae Various mammals Hard tick
Mediterranean spotted fever R. conorii Rodents, dog Hard tick
Rocky Mountain spotted fever R. ricketsii Rodents Hard tick
Rickettsial pox R. akari Rodents Mite
Flea-borne spotted fever R. felis Various mammals Flea
Bacterial infections seen in developing and tropical countries

including body lice, fleas, hard ticks, and larval mites. illness vary from place to place the clinical course is
Rickettsiae inhabit the alimentary tract of these common to all. After an incubation period of 4—10 days an
arthropods and the disease is spread to the human host eschar may develop at the site of the bite in association
by inoculation of their faeces through broken human skin, with regional lymphadenopathy. There is abrupt onset of
generally produced by scratching. Rickettsiae multiply fever, myalgia and headache, accompanied by a maculo-
intracellularly and can enter most mammalian cells, papular rash which may become petechial. Neurological,
although the main lesion produced is a vasculitis due to haematological and cardiovascular complications occur
invasion of endothelial cells of small blood vessels. as in epidemic typhus, although these are uncommon.
Multisystem involvement is usual.
Diagnosis
Clinical features The diagnosis is generally made on the basis of the
Typhus fever group history and clinical course of the illness. It can be con-
Epidemic typhus firmed serologically by the indirect fluorescent antibody
The vector of epidemic typhus is the human body louse, test (the most sensitive and specific), or the latex
and like louse-borne relapsing fever, epidemics are agglutination test. The Weil-Felix agglutination test,
associated with war and refugees. Outbreaks have although previously widely used, is not specific or
occurred in Africa, Central and South America, and sensitive.
Asia.
The incubation period of 1-3 weeks is followed by an Treatment and prevention
abrupt febrile illness associated with profound malaise Doxycycline or tetracycline given for 5-7 days is the
and generalized myalgia. Headache is severe and there treatment of choice. Ciprofloxacin is also effective.
may be conjunctivitis with orbital pain. A measles-like Doxycycline 200 mg weekly protects against scrub
eruption appears around the fifth day, the macules typhus; it is reserved for highly endemic areas.
increasing in size and eventually becoming purpuric in Rifampicin is also used when resistance to tetracycline
character. At the end of the first week, signs of meningo- has occurred. Seriously ill patients need intensive care.
encephalitis appear and CNS involvement may progress Control of typhus is achieved by eradication of the
to stupor or coma, sometimes with extrapyramidal arthropod vectors. Lice and fleas can be eradicated from
involvement. At the height of the illness, splenomegaly, clothing by insecticides (0.5% malathion or DDT). Control
pneumonia, myocarditis, and gangrene at the peripheries of rodents is necessary in endemic typhus and some of
may be evident. Oliguric renal failure occurs in the spotted fevers. Areas of vegetation infested with
fulminating disease, which is usually fatal. Recovery trombiculid mites can be cleared by chemical spraying
begins in the third week but is generally slow. The disease from the air. Bites from ticks and mites should be avoided
may recur many years after the initial attack owing to by wearing protective clothing on exposed areas of the
rickettsiae that lie dormant in lymph nodes. The body. The likelihood of infection from ticks is related to
recrudescence is known as Brill-Zinsser disease. The the duration of feeding, and in high-risk areas the body
factors that precipitate recurrence are not clearly defined, should be inspected twice a day and any ticks removed
although other infections may play a role. (p. 79).

Endemic (murine) typhus


This is an infection of rodents that is inadvertently spread Bartonellosis and ehrlichiosis
to humans by rat fleas. The disease closely resembles
epidemic typhus but is much milder and rarely fatal. Bartonella spp. and Ehrlichia spp. are intracellular bacteria
closely related to the rickettsiae. A number of human
Scrub typhus diseases can be caused by these organisms; like rickettsial
Found throughout Asia and the Western Pacific, this disease, infection is usually spread from animals via an
disease is spread by larval trombiculid mites (chiggers). arthropod vector (Table 2.38).
An eschar (a black, crusted, necrotic papule) can often be
found at the site of the bite. The clinical illness is very Carrion's disease
variable, ranging from a mild illness to fulminant and This disease is restricted mainly to the habitat of its main
potentially fatal disease. The more severe cases resemble vector, the sandfly, in the river valleys of the Andes
epidemic typhus. Unlike other types of typhus the mountains at an altitude of 500-3000 m. Two clinical
organism is passed on to subsequent generations of mites, presentations are seen, which may occur alone or
which consequently act as both reservoir and vector. consecutively. Oroya fever is an acute febrile illness
causing myalgia, arthralgia, severe headache, and con-
Spotted fever group « v > fusion, followed by a haemolytic anaemia. Verruga peruana
A variety of Rickettsia species, collectively known as the consists of eruptions of reddish-purple haemangiomatous
spotted fever group rickettsiae, cause the illnesses known nodules, resembling bacillary angiomatosis. It may
as spotted fevers. In all except for rickettsial pox (which is follow 4-6 weeks after Oroya fever, or be the presenting
transmitted by a rodent mite) the vector is a hard tick. feature of infection. Spontaneous resolution may occur
Although the causative organism and the name of the over a period of months or years. Carrion's disease is

I 89
Infectious diseases, tropical medicine and sexually transmitted diseases

1 Table 2.38 Human infections caused by Bartonella spp. and Ehrlichia spp.
Disease Organism Reservoir Vector

Bartonella Bartonella bacilliformis Unknown Sandfly Cat


Carrion's disease Cat B. henselae B. henselae Cat Cat flea Cat flea
scratch disease Bacillary B. quintana Human Body louse
angiomatosis Trench
fever

Ehrlichia Ehrlichia chafeensis A. Deer Small mammals and Hard ticks


Human ehrlichiosis 'Human phagocytophilum* deer Hard ticks
granulocytic ehrlichia' (HE)
"Formerly known as Ehrlichia phagocytophilia
frequently complicated by superinfection, especially with
Salmonella spp.
Actinomycosis
The diagnosis is made by culturing bacilli from blood Actinomyces spp. are Gram-positive, branching higher
or peripheral lesions. Serological tests have been bacteria which are normal mouth and intestine com-
developed but are not widely available. mensals; they are particularly associated with poor
Treatment with chloramphenicol or tetracycline is very mouth hygiene. Actinomyces have a world-wide distri-
effective in acute disease, but less so in verruga peruana. bution but are a rare cause of disease in the West.

Cat-scratch disease and bacillary angiomatosis


These are described on page 63. Clinical features
■ Cervicofacial actinomycosis, the most common form,
Trench fever usually occurs following dental infection or extraction.
Trench fever is caused by Bartonella quintana, and It is often indolent and slowly progressive, associated
transmitted by human body lice. It is mainly seen in with little pain, and results in induration and localized
refugees and the homeless. It is characterized by cyclical swelling of the lower part of the mandible. Lymph-
fever (typically every 5 days), chills, and headaches, adenopathy is uncommon. Occasionally acute inflam
accompanied by myalgia and pretibial pain. The disease mation occurs. Sinuses and tracts develop with dis
is usually self-limiting but it can be treated with charge of 'sulphur' granules.
erythromycin or doxycycline if symptoms are severe. ■ Thoracic actinomycosis follows inhalation of organisms,
usually into a previously damaged lung. The clinical
picture is not distinctive and is often mistaken for
Melioidosis malignancy or tuberculosis. Symptoms such as fever,
The term melioidosis refers to infections caused by the malaise, chest pain and haemoptysis are present.
Gram-negative bacteria Burkholderia pseudomallei. This Empyema occurs in 25% of patients and local exten
environmental organism, which is found in soil and sion produces chest-wall sinuses with discharge of
surface water, is distributed widely in the tropics and 'sulphur' granules.
subtropics. The majority of clinical cases of melioidosis ■ Abdominal actinomycosis most frequently affects the
occur in South East Asia. Infection follows inhalation or caecum. Characteristically, a hard indurated mass is
direct inoculation. More than half of all patients with felt in the right iliac fossa. Later, sinuses develop.
melioidosis have predisposing underlying disease: it is The differential diagnosis includes malignancy,
particularly common in diabetics. tuberculosis, Crohn's disease and amoeboma. The
B. pseudomallei causes a wide spectrum of disease, and incidence of pelvic actinomycosis appears to be
the majority of infections are probably subclinical. Illness increasing with wider use of intrauterine contraceptive
may be acute or chronic, localized or disseminated, but devices.
one form of the disease may progress to another and Occasionally actinomycosis becomes disseminated to
individual patients may be difficult to categorize. The involve any site.
most serious form is septicaemic melioidosis, which is
often complicated by multiple metastatic abscesses: this is
frequently fatal. Serological tests are available, but Diagnosis and management
definitive diagnosis depends on isolating the organism Diagnosis is by microscopy and culture of the organism.
from blood or appropriate tissue. B. pseudomallei has Treatment often involves surgery as well as antibiotics:
extensive intrinsic antibiotic resistance. The most effective penicillin is the drug of choice. Intravenous penicillin
agent is ceftazidime, which is given intravenously for 2.4 g 4-hourly is given for 4-6 weeks, followed by oral
2-4 weeks; this should be followed by several months of penicillin for some weeks after clinical resolution.
co-amoxiclav to prevent relapses. Tetracyclines are also effective.
90 j
Nocardia infections Table 2.39 Common fungal infections
Nocardia spp. are Gram-positive branching bacteria, Systemic
which are found in soil and decomposing organic matter. Histoplasmosis
Cryptococcosis
N. asteroides, and less often N. brasiliensis, are the main
Coccidioidomycosis
human pathogens. Blastomycosis
Zygomycosis
Clinical features (mucormycosis)
Mycetoma is the most common illness. This is a result of Candidiasis
local invasion by Nocardia spp. and presents as a painless Aspergillosis
swelling, usually on the sole of the foot (Madura foot). Pneumocystis carinii
The swelling of the affected part of the body continues (previously classed as
inexorably. Nodules gradually appear which eventually a protozoan)
rupture and discharge characteristic 'grains', which are Subcutaneous
colonies of organisms. Systemic symptoms and regional Sporotrichosis Subcutaneous
zygomycosis
lymphadenopathy are rare. Sinuses may occur several
Chromoblastomycosis
years after the onset of the first symptom. A similar Mycetoma
syndrome may be produced by other branching bacteria,
and also by species of eumycete fungi such as Madurella Superficial
Dermatophytosis
mycetomi (p. 95).
Superficial candidiasis
Pulmonary disease, which follows inhalation of the
Malassezia infections
organism, presents with cough, fever, and haemoptysis: it
is usually seen in the immunocompromised. Pleural
involvement and empyema occur. In severely immuno-
suppressed patients initial pulmonary infection may be ■ dimorphic fungi, which behave as yeasts in the host
followed by disseminated disease. but as moulds in vitro (e.g. Histoplasma capsulatum and
Sporothrix schenckii).
Diagnosis and management
The diagnosis is often difficult to establish, as Nocardia is Despite the fact that fungi are ubiquitous, systemic fungal
not easily detected in sputum cultures or on histological infections are uncommon, although increasing in selected
section. Severe pulmonary or disseminated infection may populations of patients such as the immunocompromised
require parenteral treatment: effective agents include and transplant patients, those managed in high depen-
ceftriaxone and amikacin. Local infection is usually treated dency units and in those with severe immunodeficiency,
with prolonged courses of oral sulphonamides, combined including HIV. Fungal infections are transmitted by
with surgical drainage of pus if necessary. inhalation of spores or by contact with the skin. Oppor-
tunistic mycoses can cause disease in immuno -
compromised patients. Fungi do not produce endotoxin,
FURTHER READING but exotoxin (e.g. aflatoxin) production has been docu-
Cole ST et al (eds) (2005) Tuberculosis and the Tubercle mented in vitro. Fungi may also produce allergic
Bacillus. Washington: ASM Press. Guerrant R, Carneiro
pulmonary disease. Some fungi such as Candida albicans
F, Dillingham R (2003) Cholera,
diarrhea, and oral rehydration therapy: triumph are human commensals. Diseases are usually divided into
and indictment. Clinical Infectious Diseases 37: systemic, subcutaneous or superficial (Table 2.39).
398-405. Parry CM et al. (2002) Typhoid fever. New
England
Journal of Medicine 347:1770-1782. Ustianowski A,
Lockwood D (2003) Leprosy: current SYSTEMIC FUNGAL INFECTIONS
diagnostic and treatment approaches. Current
Opinion in Infectious Disease 16: 421^27. Watt G, Candidiasis
Parola P (2003) Scrub typhus and tropical
Candidiasis is the most common fungal infection in
rickettsioses. Current Opinion in Infectious Disease 16:
429-436. humans and is predominantly caused by Candida albicans
although other species of Candida are increasingly
recognized. Candida are small asexual fungi. Most species
that are pathogenic to humans are normal oropharyngeal
FUNGAL INFECTIO, and gastrointestinal commensals. Candidiasis is found
world-wide. , „ . „....
Morphologically, fungi can be grouped into three major
categories: Clinical features
■ yeasts and yeast-like fungi, which reproduce by budding Any organ in the body can be invaded by Candida, but
■ moulds, which grow by branching and longitudinal vaginal infection and oral thrush are the most common
extension of hyphae forms. This latter is seen in the very young, in the elderly,
following antibiotic therapy and in those who are
immunosuppressed. Candidal oesophagitis presents with
painful dysphagia. Cutaneous candidiasis typically
occurs in intertriginous areas. It is also a cause of
paronychia. Balanitis and vaginal infection are also
common (see p. 127).
Chronic mucocutaneous candidiasis is a rare manifes-
tation, usually occurring in children, and is associated
with a T cell defect. It presents with hyperkeratotic
91
Infectious diseases, tropical medicine and sexually transmitted diseases
plaque-like lesions on the skin, especially the face, and on Clinical features
the fingernails. It is associated with several endocrino- Figure 2.30 summarizes the pathogenesis, main clinical
pathies, including hypothyroidism and hypopara- forms and sequelae of histoplasma infection. Primary
thyroidism. Dissemination of candidiasis may lead to pulmonary histoplasmosis is usually asymptomatic. The
haematogenous spread, with meningitis, pulmonary only evidence of infection is conversion of a histoplasmin
involvement, endocarditis or osteomyelitis. skin test from negative to positive, and radiological
features similar to those seen with the Ghon primary
Diagnosis and treatment complex of tuberculosis (see p. 930). Calcification in the
The fungi can be demonstrated in scrapings from infected lungs, spleen and liver occurs in patients from areas of
lesions, tissue secretions or in invasive disease, from high endemicity. When symptomatic, primary pulmon-
blood cultures. ary histoplasmosis generally presents as a mild influenza-
Treatment varies depending on the site and severity like illness, with fever, chills, myalgia and cough. The
of infection. Oral lesions respond to nystatin, oral systemic symptoms are pronounced in severe disease.
amphotericin B or fluconazole. For systemic infections, Complications such as atelectasis, secondary bacterial
parenteral therapy with fluconazole, itraconazole or pneumonia, pleural effusions, erythema nodosum and
amphotericin B is necessary. Polysymptomatic patients erythema multiforme may also occur.
often complaining of widespread candidiasis can have a Chronic pulmonary histoplasmosis is clinically
psychiatric disorder (see p. 1283). indistinguishable from pulmonary tuberculosis (see
p. 931). It is usually seen in white males over the age of 50
years. Radiologically, pulmonary cavities, infiltrates and
characteristic fibrous streaking from the periphery
Histoplasmosis ____________ towards the hilum are seen.
Histoplasmosis is caused by Histoplasma capsulatum, a The presentation of disseminated histoplasmosis
non-encapsulated, dimorphic fungus. Spores can survive resembles disseminated tuberculosis clinically. Fever,
in moist soil for several years, particularly when it is lymphadenopathy, hepatosplenomegaly, weight loss,
enriched by bird and bat droppings. Histoplasmosis leucopenia and thrombocytopenia are common. Rarely,
occurs world-wide but is only commonly seen in Ohio features of meningitis, hepatitis, hypoadrenalism, endo-
and the Mississippi river valley regions where over 80% carditis and peritonitis may dominate the clinical picture.
of the population have been subclinically exposed.
Transmission is mainly by inhalation of the spores, Diagnosis
particularly when clearing out attics, barns and bird Definitive diagnosis is possible only by culturing the
roosts or exploring caves. : fungi or by demonstrating them on histological sections.
Pathogenesis

Main clinical
forms and
sequelae
9Fig. 2.30
2Histopla
sma
infection.
Summar
y of
pathoge
nesis,
main
clinical
forms
and
sequela
e.
Fungal infections
The histoplasmin skin test is of limited diagnostic value The diagnosis and treatment are described in more detail
and can be negative in acute disseminated disease. on page 939.
Antibodies usually develop with 3 weeks of the onset of
illness and are best detected by complement-fixation,
immunodiffusion or radioimmunoassay.
Cryptococcosis
Definitive diagnosis is possible only by culturing the Cryptococcosis is caused by the yeast-like fungus,
fungi or by demonstrating them on histological sections. Cryptococcus neoformans. It has a world-wide distribution
The histoplasmin skin test is of limited diagnostic value and appears to be spread by birds, especially pigeons, in
and can be negative in acute disseminated disease. Anti- their droppings. The spores gain entry into the body
bodies usually develop within 3 weeks of the onset of through the respiratory tract, where they elicit a
illness and are best detected by the complement-fixation, granulomatous reaction. Pulmonary symptoms are,
immunodiffusion or the counter-immunoelectrophoretic however, uncommon; meningitis which usually occurs in
tests. those with HIV or lymphoma is the usual mode of
presentation and often develops subacutely. Less
commonly, lung cavitation, hilar lymphadenopathy,
Management pleural effusions and occasionally pulmonary fibrosis
Only symptomatic acute pulmonary histoplasmosis, occur. Skin and bone involvement is rare.
chronic histoplasmosis and acute disseminated histo-
plasmosis require therapy. Itraconazole or ketoconazole
are indicated for moderate disease. Severe infection is Diagnosis and treatment
treated with intravenous amphotericin B to a total dose of This is established by demonstrating the organisms in
1.5 g followed by itraconazole. Patients with AIDS appropriately stained tissue sections. A positive latex
usually require treatment with parenteral amphotericin B cryptococcal agglutinin test performed on the CSF is
followed by lifelong maintenance therapy with diagnostic of cryptococcosis.
itraconazole 200 mg twice daily. Surgical excision of histo- Amphotericin B (0.7mg/kg daily i.v.) alone or in
plasmomas (pulmonary granuloma due to H. capsuhtum) combination with flucytosine (100-200 mg/kg daily) for
or chronic cavitatory lung lesions and release of ad- 2 weeks followed by fluconazole 400 mg daily has
hesions following mediastinitis are often required. reduced the mortality of this once universally fatal con-
dition. Therapy should be continued for 3 months if
African histoplasmosis meningitis is present. Fluconazole has greater CSF
This is caused by Histoplasma duboisii, the spores of which penetration and is used when toxicity is encountered
are larger than those of H. capsulatum. Skin lesions (e.g. with amphotericin B and flucytosine and as maintenance
abscesses, nodules, lymph node involvement and lytic therapy in immunocompromised patients, especially
bone lesions) are prominent. Pulmonary lesions do not those with HIV in whom the recommended treatment is
occur. Treatment is similar to that for H. capsulatum followed by lifelong fluconazole 200 mg daily, unless they
infection. are responding to HAART.

Aspergillosis_________________________ Coccidioidomycosis
Aspergillosis is caused by one of several species of Coccidioidomycosis is caused by the non-budding
dimorphic fungi of the genus Aspergillus. Of these, spherical form (spherule) of Coccidioides immitis. This is a
A. fumigatus is the most common, although A. flavus and soil saprophyte and is found in the southern USA,
A. niger are also recognized. These fungi are ubiquitous in Central America and parts of South America. Humans are
the environment and are commonly found on decaying infected by inhalation of the thick-walled barrel-shaped
leaves and trees. Humans are infected by inhalation spores called arthrospores. Occasionally epidemics of
of the spores. Disease manifestation depends on the coccidioidomycosis have been documented following
dose of the spores inhaled as well as the immune dust storms.
response of the host. Three major forms of the disease are
recognized:
■ Bronchopulmonary allergic aspergillosis (see p. 939) Clinical features
shows symptoms suggestive of bronchial asthma. The majority of patients are asymptomatic and the
■ Aspergilloma (see p. 940) is sometimes referred to as a infection is only detected by the conversion of a skin test
pulmonary mycetoma. using coccidioidin (extract from a culture of mycelial
■ Invasive aspergillosis, which occurs in immuno- growth of C. immitis) from negative to positive. Acute
suppressed patients and presents as acute pneumonia, pulmonary coccidioidomycosis presents, after an
meningitis or an intracerebral abscess, lytic bone incubation period of about 10 days, with fever, malaise,
lesions, and granulomatous lesions in the liver; less cough and expectoration. Erythema nodosum, erythema
commonly endocarditis, paranasal Aspergillus multiforme, phlyctenular conjunctivitis and, less com-
granuloma or keratitis may occur. Urgent treatment monly, pleural effusions may occur. Complete recovery is
with intravenous amphotericin B is required. usual.
93
Infectious diseases, tropical medicine and sexually transmitted diseases
Pulmonary cavitation with haemoptysis, pulmonary natives. In severe or unresponsive disease and in the
fibrosis, meningitis, lytic bone lesions, hepatosplenomegaly, immunocompromised, amphotericin B is indicated.
skin ulcers and abscesses may occur in severe disease.

Diagnosis Invasive zygomycosis__________


Because of the high infectivity of this fungus, and con- Invasive zygomycosis (mucormycosis) is rare and is
sequent risk to laboratory personnel, serological tests caused by several fungi, including Mucor spp., Khizopus
(rather than culture of the organism) are widely used for spp. and Absidia spp. It occurs in severely ill patients. The
diagnosis. These include the highly specific latex aggluti- hallmark of the disease is vascular invasion with marked
nation and precipitin tests (IgM) which are positive haemorrhagic necrosis.
within 2 weeks of infection and decline thereafter. Rhinocerebral mucormycosis is the most common
A positive complement-fixation test (IgG) performed form. Nasal stuffiness, facial pain and oedema, and
on the CSF is diagnostic of coccidioidomycosis meningitis necrotic, black nasal turbinates are characteristic. It is rare
within 4-6 weeks and may remain positive for many and is mainly seen in diabetics with ketoacidosis. Other
years. forms include pulmonary and disseminated infection
(immunosuppressed), gastrointestinal infection (in
Treatment malnutrition), and cutaneous involvement (in burns).
Mild pulmonary infections are self-limiting and require Treatment is with amphotericin B and sometimes
no treatment, but progressive and disseminated disease judicious debridement. This condition is invariably fatal
requires urgent therapy. Ketoconazole or itraconazole if left untreated.
400 mg daily for 6 months is the treatment of choice for
primary pulmonary disease with more prolonged courses
for cavitating or fibronodular disease. Fluconazole in FURTHER READING
Chapman SW, Bradsher RW Jr, Campbell GD Jr et al.
high dose (600-1000 mg daily) is given for meningitis.
(2000) Practice guidelines for the management of
Amphotericin B is indicated for life-threatening infection. patients with blastomycosis. Clinical Infectious
Surgical excision of cavitatory pulmonary lesions or Diseases 30: 679-683. Pappas PG, Rex JH, Sobel JD
localized bone lesions may be necessary. When occurring et al. (2004) Guidelines
in those with HIV, amphotericin B, followed by main- for treatment of candidiasis. Clinical Infectious
tenance itraconazole or fluconazole is indicated. Diseases 38:161-189. Saag MS, Graybill RJ,
Larsen RA (2000) Practice
guidelines for the management of cryptococcal
Blastomycosis disease. Clinical Infectious Diseases 30: 710-718.
Blastomycosis is a systemic infection caused by the Singh N (2001) Trends in the epidemiology of
opportunistic fungal infections: predisposing factors
biphasic fungus Blastomyces dermatitidis. Although and the impact of antimicrobial use practices.
initially believed to be confined to certain parts of North Clinical Infectious Diseases 33:1692-1696. Stevens
America, it has been reported in Canada, Africa, Israel, DA, Kan VL, Judson MA (2000) Practice
Eastern Europe and Saudi Arabia. guidelines for disease caused by Aspergillus. Clinical
Infectious Diseases 30: 696-709. Wheat LJ, Sarosi
Clinical features GA, McKinsey DS (2000) Practice
Blastomycosis primarily involves the skin, where it guidelines for the management of patients with
presents as non-itchy papular lesions that later develop histoplasmosis. Clinical Infectious Diseases 30:
into ulcers with red verrucous margins. The ulcers are 688-695.
initially confined to the exposed parts of the body but
later involve the unexposed parts as well. Atrophy and
scarring may occur. Pulmonary involvement presents as a
solitary lesion resembling a malignancy or gives rise to
SUBCUTANEOUS INFECTIONS
radiological features similar to the primary complex of
tuberculosis. Systemic symptoms such as fever, malaise,
Sporotrichosis
cough and weight loss are usually present. Bone lesions
are common and present as painful swellings. Sporotrichosis is due to the saprophytic fungus Sporothrix
schenckii, which is found world-wide. Infection usually
Diagnosis and treatment . follows cutaneous inoculation, at the site of which a
The diagnosis is confirmed by demonstrating the organism reddish, non-tender, maculopapular lesion develops
in histological sections or by culture, although results can -referred to as 'plaque sporotrichosis'. Pulmonary involve-
be negative in 30-50% of cases. Enzyme immunoassay may ment and disseminated disease rarely occur.
be helpful although there is some cross-reactivity of
antibodies to blastomyces with histoplasma. Treatment with saturated potassium iodide (10-12 mL
Itraconazole is preferred for treating mild to moderate daily orally for adults) is curative in the cutaneous form.
disease in the immunocompetent for periods up to Itraconazole 100-200 mg/day for 3-6 months is a useful
6 months. Ketoconazole or fluconazole are useful alter- alternative.
941
Protozoal infections
Subcutaneous zygomycosis Malassezia infection
Subcutaneous zygomycosis, a disease seen in children in Malassezia spp. are found on the scalp and greasy skin
Africa and Indonesia, is caused by several filamentous and are responsible for seborrhoeic dermatitis, pityriasis
fungi of the Basidiobolus genus. The disease usually versicolor (hypo- or hyperpigmented rash on trunk) and
remains confined to the subcutaneous tissues and muscle Malassezia folliculitis (itchy rash on back).
fascia. It presents as a brawny, woody infiltration
involving the limbs, neck and trunk. Less commonly, the Treatment is with topical antifungals or oral ketoconazole
pharyngeal and orbital regions may be affected. - : if infection is extensive. .-.. : . ...

Treatment is with saturated potassium iodide solution


FURTHER READING
given orally. . . . . . . . .., ................................................. Ribes JA, Vanover-Sams CL, Baker DJ (2000).
Zygomycetes in human disease. Clinical Microbiology
Chromoblastomycosis_________________ Reviews 13: 236-301. Richardson MD, Warnock DW
(eds) (2003) Fungal
Chromoblastomycosis (chromomycosis) is caused by fungi Infection: Diagnosis and Management, 3rd edition.
of the genera Phialophora, Cladosporium and Fonsecaea. Oxford: Blackwell Science. Silveira F, Nucci M (2001).
These are found mainly in tropical and subtropical Emergence of black moulds
countries. It presents initially as a small papule, usually at in fungal disease: epidemiology and therapy.
the site of a previous injury. This persists for several Current Opinion in Infectious Disease 14: 679-684.
months before ulcerating. The lesion later becomes warty
and encrusted and gradually spreads. Satellite lesions
may be present. Itching is frequent. The drug of choice is
flucytosine, sometimes in combination with ketoconazole PROTOZOAL INFECTIONS
or amphotericin B. Itraconazole may also prove effective.
Cryosurgery is used to remove local lesions. Protozoa are unicellular eukaryotic organisms. They are
more complex than bacteria, and belong to the animal
Mycetoma (Madura foot) __ __ _ kingdom. Although many protozoa are free-living in the
environment some have become parasites of vertebrates,
Mycetoma may be due to subcutaneous infection with including man, often developing complex life cycles
fungi (Eumycetes spp.) or bacteria (see p. 91). Infection involving more than one host species. In order to be trans-
results in local swelling which may discharge through mitted to a new host, some protozoa transform into hardy
sinuses. Bone involvement may follow. cyst forms which can survive harsh external conditions.
Others are transmitted by an arthropod vector, in which a
Treatment is with ketoconazole or antibacterials accord- further replication cycle takes place before infection of a
ing to the aetiological agent. new vertebrate host. Major protozoan parasites of man
are listed in Table 2.40.
Pneumocystis carinii infection
Genetic analysis has shown this organism to be BLOOD AND TISSUE PROTOZOA
homologous with fungi. It exists as a trophozoite which is
probably motile and reproduces by binary fission. After Malaria
invasion the trophozoite wall thickens and forms a cyst. Human malaria can be caused by four species of the
On maturation further division takes place to yield eight genus Plasmodium: P. falciparum, P. vivax, P. ovale, P.
merozoites which after cell wall rupture develop into malariae. Ocassionally other species of malaria usually
trophozoites. Infection probably occurs in infancy but in found in primates can affect man. Malaria probably
otherwise healthy infants it remains undetected. It is originated from animal malarias in central Africa, but was
usually cleared from the lungs. P. carinii disease in adults spread around the globe by human migration. Public
is associated with immunodeficiency states, particularly health measures and changes in land use have eradicated
AIDS, and is discussed on page 136. malaria in most developed countries, although the
potential for malaria transmission still exists in many
areas. Five hundred million people are infected every year,
SUPERFICIAL INFECTIONS

Dermatophytosis Blood
Dermatophytoses are chronic fungal infections of
Tissues
keratinous structures such as the skin, hair or nails.
Table 2.40 Major protozoal diseases of man
Trichophyton spp., Microsporum spp., Epidermophyton spp. Gastrointestinal tract
and Candida spp. can also infect keratinous structures.
Malaria Leishmaniasis Giardiasis
Trypanosomiasis Toxoplasmosis Amoebiasis
Cryptosporidiosis
95
Infectious diseases, tropical medicine and sexually transmitted diseases
and over one million die yearly. Twenty five thousand when the local mosquito population becomes infected by
international travellers per year are infected. a returning traveller.

Epidemiology Parasitology
Malaria is transmitted by the bite of female anopheline The female mosquito becomes infected after taking a
mosquitoes. The parasite undergoes a temperature- blood meal containing gametocytes, the sexual form of
dependent cycle of development in the gut of the insect, the malarial parasite (Fig. 2.32). The developmental cycle
and its geographical range therefore depends on the in the mosquito usually takes 7-20 days (depending on
presence of the appropriate mosquito species and on temperature), culminating in infective sporozoites
adequate temperature. The disease occurs in endemic migrating to the insect's salivary glands. The sporozoites
or epidemic form throughout the tropics and subtropics are inoculated into a new human host, and those which
(Fig. 2.31) except for areas above 2000 m: Australia, the are not destroyed by the immune response are rapidly
USA, and most of the Mediterranean littoral are also taken up by the liver. Here they multiply inside
malaria-free. In hyperendemic areas (51-75% rate of para- hepatocytes as merozoites: this is pre-erythrocytic (or
sitaemia, or palpable spleen in children 2-9 years of age) hepatic) sporogeny. After a few days the infected
and holoendemic areas (> 75% rate) where transmission hepatocytes rupture, releasing merozoites into the blood
of infection occurs year round, the bulk of the mortality is from where they are rapidly taken up by erythrocytes. In
seen in infants. Those who survive to adulthood acquire the case of P. vivax and P. ovale, a few parasites remain
significant immunity; low-grade parasitaemia is still dormant in the liver as hypnozoites. These may reactivate
present, but causes few symptoms. In mesoendemic areas at any time subsequently, causing relapsing infection.
(11-50%) there is regular seasonal transmission of Inside the red cells the parasites again multiply,
malaria. Mortality is still mainly seen in infants, but older changing from merozoite, to trophozoite, to schizont, and
children and adults may develop chronic ill health due to finally appearing as 8-24 new merozoites. The erythro-
repeated infections. In hypoendemic areas (0-10%), where cyte ruptures, releasing the merozoites to infect further
infection occurs in occasional epidemics, little immunity cells. Each cycle of this process, which is called
is acquired and the whole population is susceptible to erythrocytic schizogony, takes about 48 hours in
severe and fatal disease. P. falciparum, P. vivax and P. ovale, and about 72 hours in
Malaria can also be transmitted in contaminated blood P. malariae. P. vivax and P. ovale mainly attack reticulocytes
transfusions. It has occasionally been seen in injecting and young erythrocytes, while P. malariae tends to attack
drug users sharing needles and as a hospital-acquired older cells; P. falciparum will parasitize any stage of
infection related to contaminated equipment. Rare cases erythrocyte.
are acquired outside the tropics when mosquitoes are A few merozoites develop not into trophozoites but
transported from endemic areas ('airport malaria'), or into gametocytes. These are not released from the red
96
Fig. 2.31
reserved.
Malaria - geographical distribution. From Baird 2005, Copyright: © Massachusetts Medical Society. All rights
Protozoal infections
6 Migration of 5 Completion of Duffy antigen on the red cell membrane (a common
sporozoites to gametogony finding in West Africa) are not susceptible to infection
mosquito with P. vivax. Certain haemoglobinopathies (including
salivary gland sickle cell trait) also give some protection against the
severe effects of malaria: this may account for the
persistence of these otherwise harmful mutations in
tropical countries. Iron deficiency may also have some
Fertilization and protective effect. The spleen appears to play a role in
development of
sporozoites in controlling infection, and splenectomized people are at
mosquito stomach risk of overwhelming malaria. Some individuals appear
to have a genetic predisposition for developing cerebral
4 Formation of malaria following infection with P. falciparum. Pregnant
gametocytes women are especially susceptible to severe disease.
(gametogony)

Clinical features
Typical malaria is seen in non-immune individuals. This
includes children in any area, adults in hypoendemic
areas, and any visitors from a non-malarious region.
The normal incubation period is 10-21 days, but can
be longer. The most common symptom is fever, although
malaria may present initially with general malaise,
headache, vomiting, or diarrhoea. At first the fever may
%% & —Merozoites be continual or erratic: the classical tertian or quartan
fever only appears after some days. The temperature
3 Invasion and often reaches 41 °C, and is accompanied by rigors and
multiplication drenching sweats.
in red blood
cells
P. vivax or P. ovale infection
Fig. 2.32 A schematic life cycle of Plasmodium vivax. The illness is relatively mild. Anaemia develops slowly,
and there may be tender hepatosplenomegaly. Spontaneous
recovery usually occurs within 2-6 weeks, but hypno-
zoites in the liver can cause relapses for many years after
cells until taken up by a feeding mosquito to complete the infection. Repeated infections often cause chronic ill
life cycle. health due to anaemia and hyperreactive splenomegaly.

P. malariae infection
Pathogenesis
This also causes a relatively mild illness, but tends to run
The pathology of malaria is related to anaemia, cytokine a more chronic course. Parasitaemia may persist for years,
release, and in the case of P. falciparum, widespread organ with or without symptoms. In children, P. malariae
damage due to impaired microcirculation. The anaemia infection is associated with glomerulonephritis and
seen in malaria is multifactorial (Table 2.41). In
nephrotic syndrome.
P. falciparum malaria, red cells containing schizonts
adhere to the lining of capillaries in the brain, kidneys,
P. falciparum infection
gut, liver and other organs. As well as causing mechanical
This causes, in many cases, a self-limiting illness similar
obstruction these schizonts rupture, releasing toxins and
to the other types of malaria, although the paroxysms of
stimulating further cytokine release.
fever are usually less marked. However it may also cause
After repeated infections partial immunity develops,
serious complications (Box 2.12), and the vast majority of
allowing the host to tolerate parasitaemia with minimal
malaria deaths are due to P. falciparum. Patients can
ill effects. This immunity is lost if there is no further
deteriorate rapidly, and children in particular progress
infection for a couple of years. Certain genetic traits also
from reasonable health to coma and death within hours.
confer some immunity to malaria. People who lack the
A high parasitaemia (> 1% of red cells infected) is an
indicator of severe disease, although patients with
Table 2.41 Causes of anaemia in malaria infection apparently low parasite levels may also develop compli-
cations. Cerebral malaria is marked by diminished
Haemolysis of infected red cells
consciousness, confusion, and convulsions, often pro-
Haemolysis of non-infected red cells (blackwater fever)
Dyserythropoiesis
gressing to coma and death. Untreated it is universally
Splenomegaly and sequestration fatal. Blackwater fever is due to widespread intravascular
Folate depletion haemolysis, affecting both parasitized and unparasitized
red cells, giving rise to dark urine.
97
Infectious diseases, tropical medicine and sexually transmitted diseases
Box 2.12 Some features of severe falciparum Diagnosis
malaria
Malaria should be considered in the differential diagnosis
CNS of anyone who presents with a febrile illness in, or having
Cerebral malaria (coma convulsion) recently left, a malarious area. Falciparum malaria is
Renal unlikely to present more than 3 months after exposure,
Haemoglobinuria (blackwater fever) even if the patient has been taking prophylaxis, but vivax
Oliguria malaria may cause symptoms for the first time up to a
Uraemia (acute tubular necrosis) year after leaving a malarious area.
Blood Diagnosis is usually made by identifying parasites on
Severe anaemia (haemolysis and dyserythropoiesis) a Giemsa-stained thick or thin blood film (thick films are
Disseminated intravascular coagulation (DIC) more difficult to interpret, and it may be difficult to
speciate the parasite, but they have a higher yield). At
Respiratory
least three films should be examined before malaria is
Acute respiratory distress syndrome
declared unlikely. An alternative microscopic method is
Metabolic quantitative buffy coat analysis (QBC), in which the
Hypoglycaemia (particularly in children) centrifuged buffy coat is stained with a fluorochrome
Metabolic acidosis which Tights up' malarial parasites. A number of antigen-
Gastrointestinal/liver detection methods for identifying malarial proteins and
Diarrhoea enzymes have been developed. Some of these are
Jaundice available in card or dipstick form, and are potentially
Splenic rupture suitable for use in resource-poor settings. Serological tests
Other are of no diagnostic value.
Shock - hypotensive Parasitaemia is common in endemic areas, and the
Hyperpyrexia presence of parasites does not necessarily mean that
malaria is the cause of the patient's symptoms. Further
investigation, including a lumbar puncture, may be
needed to exclude bacterial infection.
Hyperreactive malarial splenomegaly (tropical
splenomegaly syndrome, TSS) Management
This is seen in older children and adults in areas where The drug of choice for susceptible parasites is chloroquine
malaria is hyperendemic. It is associated with an exagger- (Box 2.13). P. vivax, P. ovale and P. malariae are almost
ated immune response to repeated malaria infections, always sensitive to this drug, the only exception being
and is characterized by anaemia, massive splenomegaly, some strains of P. vivax from Oceania.
and elevated IgM levels. Malaria parasites are scanty or There is now widespread chloroquine resistance
absent. TSS usually responds to prolonged treatment among P. falciparum, and there are few parts of the world
with prophylactic antimalarial drugs. where all infections will be susceptible. Despite this, cost
Box 2.13 Drug treatment of uncomplicated malaria in adults
Type of malaria Drug treatment
Plasmodium vivax, P. ovale, P. malariae, CQ-sensitive Chloroquine: P. 600 mg
falciparum 300 mg 6 hours later
300 mg 24 hours later
300 mg 24 hours later
CQ-resistant, SP-sensitive P. falciparum Fansidar (SP): 3 tablets as single dose
CQ- and SP-resistant P. falciparum Quinine: 600 mg 3 times daily for 7 days plus
Tetracycline: 500 mg 4 times daily for 7 days or
Fansidar (SP): 3 tablets as single dose
Alternative therapies
Mefloquine: 20 mg/kg in 2 doses 8 hours apart
or Malarone: 4 tablets daily for 3 days
or Coartemether: 4 tablets 12-hourly for 3 days
or Lapdap (chlorproguanil/dapsone)
CQ, chloroquine; SP, Fansidar = pyrimethamine/sulfadoxine; Malarone = atovaquone/proguanil; Coartemether = artemether lamufantrine
Chloroquine doses quoted are for base drug
Quinine dose applies to sulphate, hydrochloride or dihydrochloride
98
Protozoal infections
and availability mean that chloroquine is still the most 1% in a non-immune patient, is a medical emergency.
commonly used antimalarial. Quinine should be given intravenously as shown in
Treatment should ideally be based on a knowledge of Emergency box 2.1: the loading dose should be omitted if
local sensitivity, but this is often not known. In developed the patient has already received quinine or mefloquine.
countries P. falciparum is commonly treated with quinine, Intensive care facilities may be needed, including
usually as quinine sulphate. In mild cases this can be mechanical ventilation and dialysis. Severe anaemia may
given orally, but in more severe illness it is given by require transfusion. Careful monitoring of fluid balance is
intravenous infusion. Tinnitus and nausea are predictable essential: both pulmonary oedema and prerenal failure
side-effects of quinine, and do not require dose reduction are common. Hypoglycaemia can be induced both by the
unless severe. Some resistance to quinine is emerging, and infection itself and by quinine treatment. Superadded
another antimalarial (either Fansidar (pyrimethamine/ bacterial infection is common. In very heavy infections
sulfadoxine) or tetracycline) should be given at the end of (parasitaemia > 10%), there may be a role for exchange
the course of quinine. transfusion, if the facilities are available.
Other available antimalarial drugs include mefloquine, Following successful treatment of P. vivax or P. ovale
artemisinin derivatives, and the fixed-dose combination malaria, it is necessary to give a 2- to 3-week course of
preparations Malarone (atovaquone/proguanil), primaquine (15 mg daily) to eradicate the hepatic
coartemether (artemether/lamufantrine), and Lapdap hypnozoites and prevent relapse. This drug can precipitate
(chlorproguanil/dapsone). The way in which these drugs haemolysis in patients with G6PD deficiency (p. 446).
should be distributed and used, particularly in the poorer
developing countries, is still a matter for debate. Prevention and control
Multidrug combinations are available but costly (e.g. As with many vector-borne diseases, control of malaria
Artemisinin combination therapy ACT). These extend the relies on a combination of case treatment, vector
usefulness of existing drugs and limit the development of eradication, and personal protection from vector bites,
resistance to new agents. Trials of these combination e.g. insecticide treated nets. Mosquito eradication is
therapies are being completed. usually achieved either by the use of insecticides, house
Severe malaria, indicated by the presence of any of the spraying with DDT, or by manipulation of the habitat
complications discussed above, or a parasite count above (e.g. marsh drainage). After some initial successes, a
T Emergency Box 2.1
Drug treatment of severe Plasmodium falciparum malaria in adults
Full hospital No infusion No injection
facilities available available
CQ-sensitive P. falciparum Chloroquine: 10 mg/kg Chloroquine: 2.5 mg/kg Chloroquine: by nasogastric
infused over 8 hours, every 4 hours by tube (as in oral regimen)
followed by 15 mg/kg intramuscular injection or
over 24 hours (to total of 25 mg/kg)
CQ-resistant P. falciparum Quinine salt: 20 mg/kg Quinine dihydrochloride Artemisinin rectal
infused over 4 hours, given by divided suppositories
followed by 10 mg/kg intramuscular injection (limited availability)
over 4 hours every (regimen as for i.v.)
8 hours
or
Artesunate 2.4 mg/kg by
intravenous injection,
then 1.2 mg/kg
r Chloroquine (CQ) doses quoted are for base drug. Quinine doses apply to sulphate, hydrochloride and dihydrochloride.
C
Box 2.14 Malaria prophylaxis for adult travellers
C
Area visited h P Prophylactic regimen
p D
lP o
o
No
rM rM
chlo
roq e e
D
uine o
o
resi rM
stan a
ce
Limi
ted
chlo
roq
uine
resi
stan
ce

Sig
nific
ant
chlo
roq
uine
resi
stan
ce
Infectious diseases, tropical medicine and sexually transmitted diseases
WHO campaign to eliminate malaria foundered in the Clinical features
mid-1960s. Since then the emergence of both parasite
T. b. gambiense causes a chronic, slowly progressive
resistance to drugs and mosquito resistance to insecticides
illness. Episodes of fever and lymphadenopathy occur
has rendered the task more difficult. However, malaria is
over months or years, and hepatosplenomegaly may
once again a priority for the WHO, which announced a
develop. Eventually infection reaches the central nervous
new 'Roll Back Malaria' campaign in 1998.
system, causing headache, behavioural changes, con-
Non-immune travellers to malarious areas should take
fusion, and daytime somnolence. As the disease pro-
measures to avoid insect bites, such as using insect
gresses patients may develop tremors, ataxia, convulsions
repellent and sleeping under mosquito nets. Antimalarial
and hemiplegias; eventually coma and death supervene.
prophylaxis should also be taken in most cases, although
Histologically there is a lymphocytic meningoencephalitis,
this is never 100% effective (Box 2.14). The precise choice
with scattered trypanosomes visible in the brain
of prophylactic regimen depends both on the individual
substance.
traveller and on the specific itinerary; further details can
T. b. rhodesiense sleeping sickness is a much more acute
be found in National Formularies or from travel advice
disease. Early systemic features may include myocarditis,
centres. Despite considerable efforts, there is still no
hepatitis and serous effusions, and patients can die before
effective vaccine available for malaria.
the onset of CNS disease. If they survive, cerebral
involvement occurs within weeks of infection, and is
Trypanosomiasis rapidly progressive.
African trypanosomiasis (sleeping sickness)
Sleeping sickness is caused by trypanosomes transmitted Diagnosis
to humans by the bite of the tsetse fly (genus Glossina). It Trypanosomes may be seen on Giemsa-stained smears of
is endemic in a belt across sub-Saharan Africa, extending thick or thin blood films, or of lymph node aspirate.
to about 14° N and 20° S: this marks the natural range of Blood films are usually positive in T. b. rhodesiense, but
the tsetse fly. Two subspecies of trypanosome cause human may be negative in T. b. gambiense: concentration tech-
sleeping sickness: Trypanosoma brucei gambiense (Gambian niques may increase the yield. The quantitative buffy coat
sleeping sickness'), and T. b. rhodesiense (Rhodesian sleeping test (QBC, see p. 98) developed for diagnosing malaria is
sickness'). also used to identify trypanosomes. Serological tests are
useful for screening for infection: the card agglutination
Epidemiology test for trypanosomiasis (CATT) is a robust and easy-to-
West African sleeping sickness is found from Uganda in use field assay. Examination of cerebrospinal fluid is
Central Africa, west to Senegal and south as far as essential in patients with evidence of trypanosomal
Angola. Man is the major reservoir, and infection is trans- infection. CNS involvement causes lymphocytosis and
mitted by riverine Glossina species (e.g. G. palpalis). elevated protein in the CSF, and parasites may be seen in
Sleeping sickness due to T. b. rhodesiense occurs in East concentrated specimens.
and Central Africa from Ethiopia to Botswana. It is a
zoonosis of both wild and domestic animals. In endemic
situations it is maintained in game animals and trans- Management
mitted by savanna flies such as G. morsitans. Epidemics The treatment of sleeping sickness has remained largely
are usually related to cattle, and the vectors are riverine unchanged for more than 40 years, although there have
flies. been developments in the management of T. b. gambiense
Recent political upheavals and wars have both infection. In both forms, treatment is usually effective if
disrupted established treatment and control programmes, given before the onset of CNS involvement, but much less
and led to large population movements. This has resulted so in neurological disease. The drug of choice in early
in major epidemics of T. b. gambiense disease in Angola and trypanosomiasis is suramin, given intravenously at a
the Democratic Republic of Congo, and T. b. rhodesiense in dose of 20 mg/kg at 5 to 7-day intervals up to a total dose
Uganda. Although the majority of cases are unreported of 5 g. Severe reactions are relatively common, and a test
the prevalence may be as high as 500 000 cases per year, dose of 100 mg is usually given prior to this regimen.
with about 65 000 deaths. Intramuscular pentamidine is effective against T. b.
gambiense only: a number of different regimens are in use.
Parasitology A single dose of suramin should be given to patients with
Tsetse flies bite during the day, and unlike most arthropod parasitaemia prior to lumbar puncture, to avoid inocu-
vectors both males and females take blood meals. An lation into the CSF.
infected insect may deposit metacyclic trypomastigotes The only effective drugs which penetrated the CSF in
(the infective form of the parasite) into the subcutaneous trypanocidal concentrations were the arsenicals, of which
tissue. These cause local inflammation ('trypanosomal the most widely used is melarsoprol. These are given
chancre') and regional lymphadenopathy. Within 2- intravenously; a variety of dosing schedules are in use.
3 weeks the organisms invade the bloodstream, Melarsoprol is extremely toxic: 2-10% of patients develop
subsequently spreading to all parts of the body including an acute encephalopathy, with a 50-75% mortality, and
, the brain. peripheral neuropathy and hepatorenal toxicity are also
100
Protozoal infections
common. Prednisolone 1 mg/kg/day decreases the leads to progressive dilatation of parts of the gastro -
treatment-related mortality by 50% in T. b. gambiense intestinal tract: this commonly results in megaoesophagus
infection; it has not been fully assessed in T. b. rhodesiense (causing dysphagia and aspiration pneumonia) and mega-
disease. Between 3-6% of patients relapse following colon (causing severe constipation).
melarsoprol treatment. In T. b. gambiense sleeping sick-
ness, eflornithine (difluoromethylornithine) is effective, Diagnosis
clearing parasites from blood and CSF: it has a variable Trypanosomes may be seen on a stained blood film
effect on T. b. rhodesiense infection. Eflornithine is much during the acute illness. In chronic disease, parasites may
less toxic than the arsenical drugs, but cost prevents it be detected by xenodiagnosis: infection-free reduviid
from being used as a first-line treatment in most cases. bugs are allowed to feed on the patient, and the insect gut
subsequently examined for parasites. Serological tests can
Control detect both acute and chronic Chagas' disease.
The morbidity and mortality of sleeping sickness could
be considerably reduced by early detection and treatment Management and control
of cases. Control programmes have been effective in some Nifurtimox is the drug of choice for treating Chagas'
areas, but many have been discontinued because of lack disease, but it is variably available throughout the world.
of funding, or political upheaval. As in many vector- Benznidazole (5-10 mg/kg/day for 60 days) is also used.
borne diseases, prevention depends largely on elimi- The cure rate is about 80% in acute infection. Both are
nation, control or avoidance of the vector. Again this toxic with adverse reactions in up to 50% of patients. The
requires considerable coordination and money, and has drug treatment of chronic infection is controversial, as
only been implemented in a few places. most of the tissue damage is thought to be immune-
mediated and there is little clinical evidence that parasite
South American trypanosomiasis (Chagas' elimination influences the outcome. Antiarrhythmic
disease) drugs and pacemakers may be needed in cardiac disease,
Chagas' disease is widely distributed in rural areas of and surgical treatment is sometimes needed for gastro-
South and Central America. It is caused by Trypanosoma intestinal complications. In the long term, prevention of
cruzi, which is transmitted to humans in the faeces of Chagas' disease relies on improved housing and living
blood-sucking reduviid bugs (also called cone-nose, or conditions. In the interim, local vector control pro -
assassin bugs). The bugs, which live in mud or thatch grammes may be effective and the countries of the
buildings, feed on a variety of vertebrate hosts at night, 'Southern Cone' of South America have a joint pro-
defecating as they do so. Faeces infected with T. cruzi gramme to control the disease by spraying houses with
insecticide.
trypomastigotes are rubbed in through skin abrasions,
mucosa or conjunctiva. The parasites spread in the
bloodstream, before entering host cells and multiplying. Leishmaniasis
Cell rupture releases them back into the circulation,
This group of diseases is caused by protozoa of the genus
where they can be taken up by a feeding bug. Further
Leishmania, which are transmitted by the bite of the
multiplication takes place in the insect gut, completing
female phlebotomine sandfly (Table 2.42). Leishmaniasis
the trypanosome life cycle. Human infection can also
occur via contaminated blood transfusion, or occasionally
by transplacental spread. Table 2.42 Leishmania species causing visceral and
cutaneous disease in man
Clinical features Species complex Species
Acute infection, which usually occurs in children, often Visceral L donovani L. donovani
passes unnoticed. A firm reddish papule is sometimes
leishmania L. infantum
seen at the site of entry, associated with regional
L. chagasi
lymphadenopathy. In the case of conjunctival infection
there is swelling of the eyelid, which may close the eye Cutaneous L. tropica L. tropica
(Romana's sign). There may be fever, lymphadenopathy, leishmania L major L major
hepatosplenomegaly, and rarely meningoencephalitis. L aethiopica L. aethiopica
Acute Chagas' disease is occasionally fatal in infants, but L. mexicana L mexicana
normally there is full recovery within a few weeks or L. amazonensis
L. garnhami
months.
L. pifanoi
After a latent period of many years, some people go on L. venezuelensis
to develop chronic Chagas' disease. The pathogenesis of this L. braziliensis L braziliensis
is unclear: it is possibly due to an autoimmune response L. guyanensis
triggered by the initial infection, although recently the L. panamanensis
demonstration of parasites on PCR has thrown doubt on L peruviana
this mechanism. The heart is commonly affected, with Mucocutaneous L braziliensis
conduction abnormalities, arrhythmias, aneurysm forma- leishmania
tion and cardiac dilatation. Gastrointestinal involvement
101
Infectious diseases, tropical medicine and sexually transmitted diseases
is seen in localized areas of Africa, Asia (particularly India leishmanin skin test is negative, indicating a poor cell-
and Bangladesh), Europe, the Middle East and South and mediated immune response. ■ ; r j
Central America. Certain parasite species are specific to
each geographical area. The clinical picture is dependent Management
on the species of parasite, and on the host's cell-mediated The most widely used drugs for visceral leishmaniasis are
immune response. Asymptomatic infection, in which the the pentavalent antimony salts (e.g. sodium stibogluconate,
parasite is suppressed or eradicated by a strong immune which contains 100 mg of antimony per mL), given intra-
response, is common in endemic areas, as demonstrated venously or intramuscularly at a dose of 20 mg of anti-
by a high incidence of positive leishmanin skin tests. mony per kg for 21 days. In India, meglumine antimonate
Symptomatic infection may be confined to the skin is used. Resistance to antimony salts is increasing, and
(sometimes with spread to the mucous membranes), or relapses may occur following treatment. The drug of choice
widely disseminated throughout the body (visceral where resources permit is intravenous amphotericin B
leishmaniasis). Relapse of previously asymptomatic (preferably given in the liposomal form). However, this
infection may be seen in patients who become immuno- drug is expensive and not widely available in many areas
compromised, especially those with HIV infection. where the disease is prevalent. Intravenous pentamidine
In some areas leishmania is primarily zoonotic, is also effective, and an oral drug, miltefosine, has been
whereas in others, man is the main reservoir of infection. shown in India to be highly effective. Intercurrent
In the vertebrate host the parasites are found as oval bacterial infections are common and should be treated
amastigotes (Leishman-Donovan bodies). These multiply with antibiotics. Blood transfusion may occasionally be
inside the macrophages and cells of the reticulo- required.
endothelial system, and are then released into the Successful treatment may be followed in a small
circulation as the cells rupture. Parasites are taken into proportion of patients by a skin eruption called post-kala
the gut of a feeding sandfly (genus Phlebotomus in the Old azar dermal leishmaniasis (PKDL). It starts as a macular
World, genus Lutzomyia in the New World), where they maculopapular nodular rash which spreads over the
develop into the flagellate promastigote form. These body. It is most often seen in the Sudan and India.
migrate to the salivary glands of the insect, where they Current trials are looking at the use of miltefosine for
;
can be inoculated into a new host. . treating PKDL.

Cutaneous leishmaniasis
Visceral leishmaniasis Cutaneous leishmaniasis is caused by a number of
Clinical features geographically localized species, which may be zoonotic
Visceral leishmaniasis (kala azar) is caused by L. donovani, or anthroponotic. Following a sandfly bite, leishmania
L. infantum or L. chagasi, and is prevalent in localized amastigotes multiply in dermal macrophages. The local
areas of Asia, Africa, the Mediterranean littoral and South response depends on the species of leishmania, the size of
America. In India, where man is the main host, the the inoculum, and the host immune response. Single or
disease occurs in epidemics. In most other areas it is multiple painless nodules occur on exposed areas within
endemic, and it is mainly children and visitors to the area 1 week to 3 months following the bite. These enlarge and
who are at risk. The main animal reservoirs in Europe and ulcerate with a characteristic erythematous raised border.
Asia are dogs and foxes, while in Africa it is carried by An overlying crust may develop. The lesions heal slowly
various rodents. over months or years, sometimes leaving a disfiguring
The incubation period is usually 1-2 months, but may scar.
be several years. The onset of symptoms is insidious, and L. major and L. tropica are found in Russia and Eastern
the patient may feel quite well despite markedly Europe, the Middle East, Central Asia, the Mediterranean
abnormal physical findings. Fever is common, and littoral, and sub-Saharan Africa. The reservoir for L. major
although usually low-grade, it may be high and inter- is desert rodents, while L. tropica has a mainly urban
mittent. The liver, and especially the spleen, become distribution with dogs and humans as reservoirs.
enlarged; lymphadenopathy is common in African kala L. aethiopica is found in the highlands of Ethiopia and
azar. The skin becomes rough and pigmented. If the Kenya, where the animal reservoir is the hyrax. The skin
disease is not treated, profound pancytopenia develops, lesions usually heal spontaneously with scarring: this
and the patient becomes wasted and immunosuppressed. may take a year or more in the case of L. tropica.
Death usually occurs within a year, and is normally due Leishmaniasis recidivans is a rare chronic relapsing form
to bacterial infection or uncontrolled bleeding. caused by L. tropica.
L. mexicana is found predominantly in Mexico,
Diagnosis Guatemala, Brazil, Venezuela and Panama: infection
Specific diagnosis is made by demonstrating the parasite usually runs a benign course with spontaneous healing
in stained smears of aspirates of bone marrow, lymph within 6 months. L. braziliensis infections (which are seen
node, spleen or liver. The organism can also be cultured throughout tropical South America) also usually heal
from these specimens. Specific serological tests are spontaneously, but may take longer.
positive in 95% of cases. Pancytopenia, hypoalbuminaemia L. mexicana amazonensis and L. aethiopica may occasion-
and hypergammaglobulinaemia are common. The ally cause diffuse cutaneous leishmaniasis. This is rare,
102I
Protozoal infections
and is characterized by diffuse infiltration of the skin by Following a successful immune response the infection is
Leishman-Donovan bodies. Visceral lesions are absent. controlled, but dormant parasites remain encysted in host
tissue for many years. The life cycle is completed when
Diagnosis and treatment carnivorous felines eat infected animal tissue. Humans
The diagnosis can often be made clinically in a patient are infected either from contaminated cat faeces, or by
who has been in an endemic area. Giemsa stain on a split- eating undercooked infected meat; transplacental
skin smear will demonstrate leishmania parasites in 80% infection may also occur. '. . .
of cases. Biopsy tissue from the edge of the lesion can be
examined histologically, and parasites identified by PCR; Clinical features
culture is less often successful. The leishmanin skin test is Toxoplasmosis is common: seroprevalence in adults in
positive in over 90% of cases, but does not distinguish the UK is about 25%, rising to 90% in some parts of
between active and resolved infection. Serology is Europe. Most infections are asymptomatic or trivial.
unhelpful. Symptomatic patients usually present with lymph-
Small lesions usually require no treatment. Large adenopathy, mainly in the head and neck. There may be
lesions or those in cosmetically sensitive sites can some- fever, myalgia, and general malaise; occasionally there
times be treated locally, by curettage, cryotherapy or are more severe manifestations including hepatitis,
topical antiparasitic agents. In other cases, systemic pneumonia, myocarditis, and choroidoretinitis. Lymph-
treatment (as for visceral leishmaniasis) is required, adenopathy and fatigue can sometimes persist for
although treatment is less successful as antimonials are months after the initial infection.
poorly concentrated in the skin; L. aethiopica is not sensi- Congenital toxoplasmosis may also be asymptomatic,
tive to antimonials. but can produce serious disease. Clinical manifestations
include microcephaly, hydrocephalus, encephalitis,
Mucocutaneous leishmaniasis convulsions and mental retardation. Choroidoretinitis is
Mucocutaneous leishmaniasis occurs in 3-10% of common; occasionally this may be the only feature.
infections with L. b. braziliensis, and is commonest in Immunocompromised patients, especially those with
Bolivia and Peru. The cutaneous sores are followed HIV infection, are at risk of serious infections with
months or years later by indurated or ulcerating lesions T. gondii. In acquired immunodeficiency states this is
affecting mucosa or cartilage, typically on the lips or nose usually due to reactivation of latent disease (p. 137).
('espundia'). The condition can remain static, or there
may be progression over months or years affecting the Diagnosis
nasopharynx, uvula, palate and upper airways. Diagnosis is usually made serologically. IgG antibodies
detectable by the Sabin-Feldman dye test remain positive
Diagnosis and treatment for years; acute infection can be confirmed by demon-
Biopsies usually show only very scanty organisms, strating a rising titre of specific IgM.
although parasites can be detected by PCR; serological
tests are frequently positive. Management
Amphotericin B is the treatment of choice if available, Acquired toxoplasmosis in an immunocompetent host
although systemic antimonial compounds are widely rarely requires treatment. In those with severe disease
used; miltefosine may also be effective. Relapses are (especially eye involvement) sulfadiazine 2-^1 g daily and
common following treatment. Patients may die because pyrimethamine 25 mg daily are given for 4 weeks, along
of secondary bacterial infection, or occasionally laryngeal with folinic acid. The management of pregnant women
obstruction. with toxoplasmosis aims to decrease the risk of fetal
complications. Treatment of early infection (before the
Prevention i parasite has crossed the placenta) with spiramycin cuts
Prevention of leishmaniasis relies on control of vectors the rate of fetal infection significantly. If the fetus has
and/ or reservoirs of infection. Insecticide spraying, control already been infected, treatment with sulfadiazine and
of host animals, and treating infected humans may all be spiramycin (± pyrimethamine, which is itself teratogenic)
helpful. Personal protection against sandfly bites is also appears to decrease the severity of complications.
necessary, especially in travellers visiting endemic areas. Infected infants should be treated from birth. The treat-
ment of toxoplasmosis in HIV-positive patients is covered
on page 137.
Toxoplasmosis
Toxoplasmosis is caused by the intracellular protozoan Babesiosis
parasite Toxoplasma gondii. The sexual form of the parasite ____________________________________
lives in the gut of the definitive host, the cat, where it Babesiosis is a tick-borne parasitic disease, diagnosed
produces oocysts. After a period of maturing in the most commonly in North America and Europe. It is a
environment, these oocysts become the source of zoonosis of rodents and cattle, and is occasionally
infection for secondary hosts which may ingest them. In transmitted to humans: infection is more common and
the secondary hosts (which include man, cattle, sheep, more severe in those who are immunocompromised
pigs, rodents, and birds) there is disseminated infection. following splenectomy. The causative organisms are the
103
Infectious diseases, tropical medicine and sexually transmitted diseases
plasmodium-like Babesia microti (rodents) and B. divergens Clinical features
(cattle). It is believed that many individuals can carry the pathogen
The incubation period averages 10 days. In patients without obvious evidence of clinical disease (asymp-
with normal splenic function, the symptoms are mild and tomatic cyst passers). However, this may be due in some
usually comprise fever, nausea, myalgia, chills, vomiting cases to the misidentification of non-pathogenic E. dispar
and abdominal pain. Hepatosplenomegaly and haemolytic as E. histolytica, and it is not clear how often true
anaemia may also be present. In splenectomized indivi- E. histolytica infection is symptomless. In affected people
duals, systemic symptoms are more pronounced and E. histolytica trophozoites invade the colonic epithelium,
haemolysis is associated with haemoglobinuria, jaundice probably with the aid of their own cytotoxins and
and renal failure. Examination of a peripheral blood proteolytic enzymes. The parasites continue to multiply
smear may reveal the characteristic plasmodium-like and finally frank ulceration of the mucosa occurs. If
organisms. penetration continues, trophozoites may enter the portal
The standard treatment was a combination of quinine vein, via which they reach the liver and cause intra-
650 mg and clindamycin 600 mg orally three times daily hepatic abscesses. This invasive form of the disease is
for 7 days but a regimen of atovaquone and azithromycin serious and may even be fatal.
is as effective, with fewer adverse reactions. The incubation period of intestinal amoebiasis is
highly variable and may be as short as a few days or as
long as several months. The usual course is chronic, with
mild intermittent diarrhoea and abdominal discomfort.
GASTROINTESTINAL PROTOZOA This may progress to bloody diarrhoea with mucus, and
mm*
The major gastrointestinal parasites of man are shown in is sometimes accompanied by systemic symptoms such
Table 2.43. as headache, nausea and anorexia. Less commonly, infec-
tion may present as acute amoebic dysentery, resembling
bacillary dysentery or acute ulcerative colitis.
Amoebiasis Complications are unusual, but include toxic
S^s>r ''^3MMHMaM^HMMHMaHHHMMMMHHinBnMHiMMMMHMMi^^HHi^Hi
dilatation of the colon, chronic infection with stricture
Amoebiasis is caused by Entamoeba histolytica. The
formation, severe haemorrhage, amoeboma, and amoebic
organism formerly known as E. histolytica is now known
liver abscess. Amoebomas, which develop most com-
to consist of two distinct species: E. histolytica, which is
monly in the caecum or rectosigmoid region, are some-
pathogenic, and E. dispar, which is non-pathogenic. Cysts
times mistaken for carcinoma. They may bleed, cause
of the two species are identical, but can be distinguished
obstruction or intussuscept. Amoebic liver abscesses
by molecular techniques after culture of the trophozoite.
often develop in the absence of a recent episode of colitis.
E. histolytica can be distinguished from all amoebae
Tender hepatomegaly, a high swinging fever and
except E. dispar, and from other intestinal protozoa, by
profound malaise are characteristic, although early in the
microscopic appearance. Amoebiasis occurs world-wide,
course of the disease both symptoms and signs may be
although much higher incidence rates are found in the
minimal. The clinical features are described in more detail
tropics and subtropics.
on page 392.
The organism exists both as a motile trophozoite and
as a cyst that can survive outside the body. Cysts are
transmitted by ingestion of contaminated food or water, Diagnosis
or spread directly by person-to-person contact. Trophozoites Microscopic examination of fresh stool or colonic exudate
emerge from the cysts in the small intestine and then pass obtained at sigmoidoscopy is the simplest way of diag-
on to the colon, where they multiply. nosing colonic amoebic infection. To confirm the
diagnosis motile trophozoites containing red blood cells
must be identified: the presence of amoebic cysts alone
Table 2.43 Pathogenic human intestinal protozoa
does not imply disease. Sigmoidoscopy and barium
Amoebae enema examination may show colonic ulceration but are
Entamoeba histolytica rarely diagnostic.
Flagellates The amoebic fluorescent antibody test is positive in at
Giardia intestinalis least 90% of patients with liver abscess and in 60-70%
with active colitis. Seropositivity is low in asymptomatic
Ciliates
Balantidium coli
cyst passers.

Coccidia
Cryptosporidium parvum Management
Isospora belli Sarcocystis Metronidazole 800 mg three times daily for 5 days is
spp. Cyclospora given in amoebic colitis; a lower dose (400 mg three times
cayetanensis daily for 5 days) is usually adequate in liver abscess.
Microspora Tinidazole is also effective: dehydroemetine and
Enterocytozoon bieneusi chloroquine are alternative drugs, but are rarely used.
Encephalitozoon spp. After treatment of the invasive disease, the bowel should
104
Protozoal infections
be cleared of parasites with a luminal amoebicide such as is evidence that the morphological damage may be
diloxanide furoate. , immune-mediated. Bacterial overgrowth has also been
found in association with giardiasis and may contribute
Prevention to fat malabsorption.
Amoebiasis is difficult to eradicate because of the
substantial human reservoir of infection. The only Clinical features
progress will be through improved standards of hygiene Many individuals excreting giardia cysts have no symp-
and better access to clean water. Cysts are destroyed by toms. Others become ill within 1-3 weeks after ingesting
boiling, but chlorine and iodine sterilizing tablets are not cysts: symptoms include diarrhoea, often watery in the
always effective. , early stage of the illness, nausea, anorexia, and abdominal
discomfort and bloating. In most people affected, these
resolve after a few days, but in some the symptoms
Giardiasis persist. Stools may then become paler, with the charac-
____________________________________ teristic features of steatorrhoea. If the illness is prolonged,
Giardia intestinalis is a flagellate (Fig. 2.33) that is found weight loss ensues, which can be marked. Chronic
world-wide. It causes small intestinal disease, with giardiasis frequently seen in developing countries can
diarrhoea and malabsorption. Prevalence is high result in growth retardation in children.
throughout the tropics, and it is the most common para-
sitic infection in travellers returning to the UK. In certain Diagnosis
parts of Europe, and in some rural areas of North Both cysts and trophozoites can be found in the stool, but
America, large water-borne epidemics have been reported. negative stool examination does not exclude the
Person-to-person spread may occur in day nurseries and diagnosis since the parasite may be excreted at irregular
residential institutions. Like E. histolytica, the organism intervals. The parasite can also be seen in duodenal
exists both as a trophozoite and a cyst, the latter being the aspirates (obtained either at endoscopy or with an
form in which it is transmitted. Enterotest capsule), and in histological sections of jejunal
The organism sometimes colonizes the small intestine mucosa.
and may remain there without causing detriment to the
host. In other cases, severe malabsorption may occur Management
which is thought to be related to morphological damage Metronidazole 2 g as a single dose on 3 successive days
to the small intestine. The changes in villous architecture will cure the majority of infections, although sometimes a
are usually mild partial villous atrophy; subtotal villous
second or third course is necessary. Alternative drugs
atrophy is rare. The mechanism by which the parasite
include tinidazole, mepacrine and albendazole. Pre-
causes alteration in mucosal architecture and produces
ventative measures are similar to those outlined above for
diarrhoea and intestinal malabsorption is unknown: there
E. histolytica.
Cryptosporidiosis
This organism is found world-wide, cattle being the
major natural reservoir. It has also been demonstrated in
supplies of drinking water in the UK. The parasite is able
to reproduce both sexually and asexually; it is transmitted
by oocysts excreted in the faeces.
In healthy individuals cryptosporidiosis is a self-
limiting illness. Acute watery diarrhoea is associated with
fever and general malaise lasting for 7-10 days. In
immunocompromised patients, especially those with
HIV, diarrhoea is severe and intractable (see p. 138).
Diagnosis is usually made by faecal microscopy,
although the parasite can also be detected in intestinal
biopsies. As yet there is no effective antimicrobial treat-
ment for this infection.

Balantidiasis
Balantidium coli is the only ciliate that produces clinically
significant infection in humans. It is found throughout
Fig. 2.33 Giardia intestinalis on small intestinal the tropics, particularly in Central and South America,
mucosa. Courtesy of Dr A Phillips, Department of Electron Iran, Papua New Guinea and the Philippines. It is usually
Microscopy, Royal Free Hospital, London. carried by pigs, and infection is most common in those
105
Infectious diseases, tropical medicine and sexually transmitted diseases
communities that live in close association with swine. Its although once the adults are established in their defini-
life cycle is identical to that of E. histolytica. B. coli causes tive site they rarely migrate further. Adult helminths may
diarrhoea, and sometimes a dysenteric illness with be very long-lived: up to 30 years in the case of the
invasion of the distal ileal and colonic mucosa. schistosomes.
Trophozoites rather than cysts are found in the stool. Many helminths have developed complex life
Treatment is with tetracycline or metronidazole. cycles, involving more than one host. Both primary
and intermediate hosts are often highly specific to a
particular species of worm. In some cases of human
Blastocystis hominis infection
infection man is the primary host, while in others,
B. hominis is a strictly anaerobic protozoan pathogen that humans are a non-specific intermediary or coincidentally
inhabits the colon. For decades its pathogenicity for infected.
humans was questioned, but there is increasing evidence
that it may cause diarrhoea. It is sensitive to metronidazole.
NEMATODES
Cyclospora cayetanensis infection Human infections can be divided into:
____________________________________ ■ Tissue-dwelling worms including the filarial worms,
Cyclospom cayetanensis, a coccidian protozoal parasite, and the Guinea worm Dracunculus medinensis.
was originally recognized as a cause of diarrhoea in ■ Human intestinal worms, including the human hook
travellers to Nepal. It has been detected in stool speci- worms, the common roundworm (Ascaris lumbricoides)
mens from immunocompetent and immunodeficient and Strongyloides stercoralis, which are the most
people world-wide. Infection is usually self-limiting, but common helminthic parasites of man. The adult
can be treated with co-trimoxazole. worms live in the human gut, and do not usually
invade tissues, but many species have a complex life
Microsporidiosis cycle involving a migratory larval stage.
■ Zoonotic nematodes which accidentally infect man
Protozoa of the phylum Microsporea can cause diarrhoea and are not able to complete their normal life cycle.
in patients with HIV/AIDS (see p. 138). They often become 'trapped' in the tissues, causing a
potentially severe local inflammatory response.
FURTHER READING
Baird JK (2005) Effectiveness of anti-malarial drugs. Tissue-dwelling worms
Neiv England Journal of Medicine 352:1565-1577. Barrett
M et al. (2003) Trypanosomiasis. Lancet 362: Filariasis
1469-1478. Duffy PE, Mutabingwa TK (2004) Drug Several nematodes belonging to the superfamily
combinations Filarioidea can infect humans. The adult worms are long
for malaria - time to ACT? Lancet 363: 3-4. and threadlike, ranging from 2 cm to 50 cm in length;
Greenwood BM et al (2005) Malaria. Lancet females are generally much larger than males. Larval
365:1487-1498. Maitland K, Bejon P, Newton-Charles R
stages are inoculated by various species of biting flies,
(2003) Malaria.
Current Opinion in Infectious Disease 16: 389-395. each specific to a particular parasite. The adult worms
Stanley SL (2003) Amoebiasis. Lancet 361: 1025-1034. which develop from these larvae mate, producing
Sundar S, Jha T, Thakur C et al. (2002) Oral miltefosine millions of offspring (microfilariae), which migrate in the
for Indian visceral leishmaniasis. New England blood or skin. These are taken up by feeding flies, in
Journal of Medicine 347: 1739-1746. which the remainder of the life cycle takes place. Disease,
WHO Tropical Diseases Research page: which may be caused by either the adult worms or by
http://www.who.int/tdr. microfilariae, is caused by host immune response to the
parasite and is characterized by massive eosinophilia.
Adult worms are long-lived (10—15 years), and reinfection
is common, so that disease tends to be chronic and
HELMINTHIC INFECTIONS progressive.

Worm infections are very common in developing Lymphatic filariasis


countries, causing much disease in both humans and Lymphatic filariasis, which may be caused by different
domestic animals. They are frequently imported into species of filarial worm, has a scattered distribution in the
industrialized countries. The most common human tropics and subtropics (Table 2.45). Nearly 1 billion
helminth infections are listed in Table 2.44. people in developing countries are at risk. Wuchereria
Helminths are the largest internal human parasite. bancrofti is transmitted to man by a number of mosquito
They reproduce sexually, generating millions of eggs or species, mainly Culex fatigans. Adult female worms
larvae. Nematodes and trematodes have a mouth and (which are 5—10 cm long) live in the lymphatics, releasing
intestinal tract, while cestodes absorb nutrients directly large numbers of microfilariae into the blood. Generally
through the outer tegument. All worms are motile, this occurs at night, coinciding with the nocturnal feeding
106
Helminthic infections

Table 2.44 Helminths commonly infecting man


Helminth Common name/disease caused
Nematodes (roundworms)
Tissue-dwelling worms Wuchereria bancmfti Filariasis
Brugia malayi/timori Loa Filariasis
loa Loiasis
Onchocerca volvulus River blindness
Dracunculus medinensis Dracunculiasis
Mansonella perstans Mansonellosis
Intestinal human nematodes Enterobius vermicularis Threadworm
Ascaris lumbricoides Roundworm
Trichuris trichiura Whipworm
Necator americanus Hookworm
Ancylostoma duodenale Hookworm
Strongyloides stercoralis Strongyloidosis
Zoonotic nematodes Toxocara canis Toxocariasis
Trichinella spiralis Trichinellosis
Trematodes (flukes)
Blood flukes Lung Schistosoma species Schistosomiasis
flukes Intestinal/hepatic Paragonimus species Paragonimiasis
flukes Fasciolopsis buski
Fasciola hepatica
Clonorchis sinensis
Opisthorchis felineus
Cestodes (tapeworms)
Intestinal adult worms Taenia saginata Taenia Beef tapeworm
solium Diphyllobothrium Pork tapeworm
latum Hymenolepis nana Fish tapeworm
Taenia solium Dwarf tapeworm
Larval tissue cysts Echinococcus granulosus Cysticercosis
Echinococcus multilocularis Hydatid disease
Spirometra mansoni Hydatid disease
Sparganosis
Table 2.45 Diseases caused by the filarial worms
Organism Adult worm Microfilariae Major vector Clinical signs Distribution
Wuchereria bancmfti Lymphatics Blood Culex species Fever Tropics
Lymphangitis
Elephantiasis
Brugia timori/malayi Lymphatics Blood Mansonia species Fever East and South
Lymphangitis East Asia,
Elephantiasis South India,
Sri Lanka
Loa loa Subcutaneous Blood Chrysops species 'Calabar' swellings West and
Urticaria Central Africa
Onchocerca Subcutaneous Skin, eye Simulium species Subcutaneous Africa, South
nodules America
Eye disease
Mansonella perstans Retroperitoneal Blood Culicoides species Allergic eosinophilia Sub-Saharan
Africa, South
America
pattern of C. fatigans. Non-periodic forms of W. bancmfti, Clinical features
transmitted by day-biting species of mosquito, are found Following the bite of an infected mosquito, the larvae
in the South Pacific. Brugia malayi (and the closely related enter the lymphatics and are carried to regional lymph
B. timori) are very similar to W. bancmfti, exhibiting the nodes. Here they grow and mature for 6-18 months.
same nocturnal periodicity. The usual vectors are Adult worms produce allergic lymphangitis. The
mosquitoes of the genus Mansonia, although other clinical picture depends on the individual immune
mosquitoes have been implicated. response, which in turn may depend on factors such as
107
Infectit ind sexually transmitted diseases
age at first exposure. In endemic areas many people have Loiasis '
asymptomatic infection. Sometimes early infection is Loiasis, seen in humid forest areas of West and Central
marked by bouts of fever accompanied by pain, tender- Africa and affects 3-13 million people - in some areas, up
ness and erythema along the course of affected lymphatics. to 40% of the population. It is caused by infection with
Involvement of the spermatic cord and epididymis are Loa loa. This is a small (3-7 cm) filarial worm which is
common in Bancroftian filariasis. These acute attacks found in the subcutaneous tissues. The microfilariae
subside spontaneously in a few days, but usually recur. circulate in the blood during the day, but cause no direct
Recurrent episodes cause intermittent lymphatic obstruc- symptoms. The vectors are day-biting flies of the genus
tion, which in time can become fibrotic and irreversible. Chrysops, known as the tabanid fly (horse or deer fly).
Obstructed lymphatics may rupture, causing cellulitis Adult worms migrate around the body in sub-
and further fibrosis; there may also be chylous pleural cutaneous tissue planes. Worms do not replicate in
effusions and ascites. Over time there is progressive humans and may be present for years, frequently without
enlargement, coarsening, and fissuring of the skin, causing symptoms. From time to time localized, tender,
leading to the classical appearances of elephantiasis. The hot, soft tissue swellings occur due to hypersensitivity
limbs or scrotum may become hugely swollen. Eventually (Calabar swellings) often near to a joint. These are pro-
the adult worms will die, but the lymphatic obstruction duced in response to the passage of a worm and usually
remains and tissue damage continues. Elephantiasis takes subside over a few days or weeks. There may also be
many years to develop, and is only seen in association more generalized urticaria and pruritus. Occasionally a
with recurrent infection in endemic areas. worm may be seen crossing the eye under the conjunctiva;
Occasionally the predominant features of filarial they may also enter retro-orbital tissue, causing severe
infection are pulmonary. Microfilariae become trapped in pain. Short-term residents of endemic areas often have
the pulmonary capillaries, generating intense local allergic more severe manifestations of the disease.
response. The resulting pneumonitis causes cough, fever, Microfilariae may be seen on stained blood films,
weight loss, and shifting radiological changes, associated although these are often negative. Serological tests are
with a high peripheral eosinophil count. This is known as relatively insensitive, and cross-react with other micro-
tropical pulmonary eosinophilia (see p. 940). filariae. There is usually massive eosinophilia. DEC may
cause severe allergic reactions (including fever, urticaria,
myalgia, and occasionally encephalitis) associated with
Diagnosis parasite killing and is being replaced by newer agents.
The diagnosis of filariasis is usually made on clinical Ivermectin in single doses of 200^00 ug/kg is effective: it
grounds, supported by a high eosinophil count. Sero- may occasionally cause severe reactions. Albendazole,
logical tests are sensitive, especially in the earlier stages, which causes a more gradual reduction in microfilarial
but can cross-react with other nematodes: they become load, may be preferable in heavily-infected patients. Drug
negative 1-2 years after effective treatment. PCR assays reactions are more likely if there is a high microfilarial
are being developed. Microfilariae start to appear in the load, or if there is co-infection with Onchocerca volvulus.
peripheral blood about a year after infection, and may be Mass treatment with either DEC or ivermectin can
detected on a stained nocturnal blood film. Parasitological decrease the transmission of infection, but the mainstay
diagnosis is difficult in established elephantiasis. The of prevention is vector avoidance and control.
clinical picture is usually diagnostic, but similar lymphatic
damage may occasionally be caused by silicates absorbed Onchocerciasis
through the feet from volcanic soil. Onchocerciasis (river blindness) affects 18 million people
world-wide, mostly in West and Central Africa. It also
occurs in the Yemen, and parts of Central and South
Treatment America. It is the result of infection with Onchocerca
Diethylcarbamazine (DEC) kills both adult worms and volvulus. Infection is transmitted by day-biting flies of the
microfilariae. Serious allergic responses may occur as the genus Simulium: principally S. damnosum in West Africa, S.
parasites are killed, and particular care is needed when neavei in East Africa, and S. metallicum in America.
using DEC in areas endemic for loiasis. Old multi-dose
regimens are now being replaced by single-dose treat-
ment often in combination with albendazole. Associated Pathogenesis
bacterial infections should be treated promptly, and recon- Infection occurs when larvae are inoculated by the bite of
structive surgery may be needed to remove excess tissue. an infected fly. The worms mature in 2-4 months, and can
Mass chemotherapy can decrease the prevalence and live for more than 15 years. Adult worms, which can
severity of infection in endemic areas and 80 million reach lengths of 50 cm (although less than 0.5 mm in
people have already been treated under the WHO diameter), live in the subcutaneous tissues. They may
eradication programme. Early diagnosis and treatment form fibrotic nodules, especially over bony prominences
prevent the development of elephantiasis. These and sites of trauma. Huge numbers of microfilariae are
approaches must be combined with vector control to distributed in the skin, and may invade the eyes. Live
achieve permanent results, while individual protection microfilariae cause relatively little harm, but dead
depends on avoidance of mosquito bites. parasites may cause severe allergic reactions, with
108
Helminthic infections
hyaline necrosis and loss of tissue collagen and elastin. In do not cause serious disease there may be minor allergic
the eye a similar process causes conjunctivitis, sclerosing reactions and an eosinophilia.
keratin's, uveitis, and secondary glaucoma. Choroidoretinitis
is also occasionally seen. Dracunculiasis
Infection with the Guinea worm, Dracunculus medinensis,
Clinical features occurs when water fleas containing the parasite larvae are
Symptoms usually start about a year after infection. swallowed in contaminated drinking water. Ingested
Initially there is generalized pruritus, with urticaria and larvae mature, penetrate the intestinal wall, and mate,
fleeting oedema. Subcutaneous nodules (which can be after which the male usually dies. The female worm,
detected by ultrasound) start to appear, and in dark- which can reach over a metre in length, migrates through
skinned individuals, hypo- and hyperpigmentation from connective and subcutaneous tissue for 9-18 months
excoriation and inflammatory changes. Over time more before surfacing, usually on the skin of the leg. An allergic
chronic inflammatory changes appear, with roughened, blister forms, and then bursts, exposing the anterior end
inelastic skin. Superficial lymph nodes become enlarged, of the worm. The uterus of the worm ruptures, releasing
and in the groin may hang down in loose folds of larvae: the worm is attracted to the surface by cooling,
skin ('hanging groin'). Eye disease, which is associated and so the larvae are likely to be deposited in water. They
with chronic heavy infection, usually first manifests as are ingested by the small crustacean water fleas, and the
itching and conjunctival irritation. This gradually cycle is completed. The disease is found in sub-Saharan
progresses to more extensive eye disease and eventually Africa, Egypt, the Arabian peninsula, and parts of Central
to blindness. Short-term travellers are unlikely to become Asia (India is now Guinea worm free). It is usually
infected as the black flies are not efficient vectors of the acquired by people collecting water at water holes.
disease. A persistent skin ulcer may develop at the site of
rupture: bacterial infection is common, and tetanus can
Diagnosis occur. If the worm is broken there may be a systemic
In endemic areas the diagnosis can often be made allergic reaction.
clinically, especially if supported by finding eosinophilia The diagnosis is usually clinical.
on a blood film. In order to identify parasites, skin snips The traditional treatment, extracting the worm over
taken from the iliac crest or shoulder are placed in saline several days by winding it round a stick, is probably still
under a cover slip. After 4 hours, microscopy will show the most effective. The worm should not be damaged.
microfilariae wriggling free on the slide. If this is Antibiotics may be needed to control secondary infection.
negative, DEC can be applied topically under an Anthelminthic drugs are of little value.
occlusive dressing: this will provoke an allergic rash in Water fleas (and thus infective larvae) can be removed
the majority of infected people (modified Mazzotti from drinking water by chemical treatment or by simple
reaction) but this is not routinely performed as it is filtration. Large-scale eradication programmes have been
unpleasant. Slit-lamp examination of the eyes may reveal in place for several years and the incidence oi infecticm
the microfilariae. Serological tests are frequently positive has fallen dramatically, with only 75 000 cases reported in
in endemic areas, but this does not imply current the year 2000: 75% of these were from the Sudan. Man is
infection. ELISA and Western blots have been used. Tests the only host of D. medinensis, and it should therefore be
may be negative in expatriates with a low worm load. possible to completely eradicate this parasite.

Management and prevention Human intestinal nematodes


Ivermectin, in a single dose of 150 jj.g/kg, kills micro-
filariae and prevents their return for 6-12 months. There Adult intestinal nematodes (also sometimes referred to as
is little effect on adult worms, so annual (or more soil-transmitted helminths, or geohelminths) live in the
frequent) retreatment is needed. In patients co-infected human gut. There are two main types of life cycle, both
with Loa loa, ivermectin may occasionally induce severe including a soil-based stage. In some cases infection is
allergic reactions, including a toxic encephalopathy. spread by ingestion of eggs (which often require a period
Since 1974 the WHO Onchocerciasis Control Programme of maturation in the environment), while in others the
has had a considerable impact on onchocerciasis in West eggs hatch in the soil and larvae penetrate directly through
Africa. A combination of vector control measures and, the skin of a new host (Fig. 2.34). Ascaris lumbricoides
more recently, mass treatment with ivermectin, has led to deviates from the simplified life cycle shown in that the
a decrease in both infection rates and progression to larvae invade the duodenum and enter the venous system,
serious disease. Humans are the only host but measures via which they reach the lungs. They are eventually
are required over a long period because of the longevity expectorated and swallowed, entering the intestine where
of the worm (10-15 years). they complete their maturation. Strongyloides is also
unusual, in that it is the only nematode that is able to
Mansonellosis complete its life cycle in humans. Larvae may hatch
Mansonella perstans is a filarial worm transmitted by before leaving the colon, and so are able to reinfect the
biting midges of the genus Culicoides. Small numbers of host by penetrating the intestinal wall and entering the
microfilariae are found in the blood, and although they venous system.
109
ally transmitted diseases
Passive (oral) Percutaneous
e.g. Trichuris trichiura e.g. Ancyclostoma duodenale
Enterobius vermicularis Necator americanus
Ascaris lumbricoides Strongyloides stercoralis
via circulation

Mouth
Ingested by into lungs, into
humans trachea Filariform larvae
Oesophagus (infective form)
Eggs
(infective form)

Adult worms T
Larva
Rhabditiform larvae

develop in Hatched larvae Hatch in soil

from gut

Fertilized eggs in

faeces Intestine Eggs


Fig. 2.34 A schematic life cycle of intestinal nematodes.
Ascariasis (roundworm infection) infection causes a significant burden of disease, especially
A. lumbricoides is a pale yellow worm, 20-35 cm in length in children.
(Fig. 2.35). It is found world-wide but is particularly com- Ascaris eggs can be identified in the stool, and
mon in poor rural communities, where there is heavy occasionally adult worms emerge from the mouth or the
faecal contamination of the immediate environment. anus. They may also be seen on barium enema studies.
Larvae migrate through the tissues to the lungs before Appropriate drug treatments are shown in Box 2.15. Very
being expectorated and swallowed; adult worms are rarely, surgical or endoscopic intervention may be
found in the small intestine. Ova are deposited in faeces, required for intestinal or biliary obstruction.
and require a 2- to 4-month maturation in the soil before
they are infective. Threadworm (Enterobius vermicularis)
Infection is usually asymptomatic, although heavy E. vermicularis is a small (2-12 mm) worm, which is
infections are associated with nausea, vomiting, abdom- common throughout the world. Larval development
inal discomfort and anorexia. Worms can sometimes takes place mainly in the small intestine, and adult
obstruct the small intestine, the most common site being worms are normally found in the colon. The gravid
at the ileocaecal valve. They may also occasionally invade female deposits eggs around the anus causing intense
the appendix, causing acute appendicitis, or the bile duct, itching, especially at night. Unlike A. lumbricoides, the
resulting in biliary obstruction and suppurative cholangitis. eggs do not require a maturation period in soil, and
Larvae in the lung may produce pulmonary eosinophilia. infection is often directly transmitted from anus to mouth
Heavy infection in children, especially those who are via the hands. Eggs may also be deposited on clothing
already malnourished, may have significant effects on and bed linen, and are subsequently either ingested or
nutrition and development. Serious morbidity and inhaled. Apart from discomfort and local excoriation,
mortality are rare in ascariasis, but the huge number of infection is usually harmless.
people infected means that on a global basis roundworm Ova can be collected either using a moistened perianal
swab, or by applying adhesive cellophane tape to the
perianal skin. They can then be identified by microscopy.
The most commonly used drugs in the UK are
mebendazole and piperazine (Box 2.15). However,
isolated treatment of an affected person is often in-
effective. Other family members (especially small
children) may also need to be treated, and the whole
family should be given advice about personal hygiene.
Two courses of treatment 2 weeks apart may break the
cycle of autoinfection. , "s ' ■'■'■■ "

Whipworm (Trichuris trichiura)


Fig. Ascaris lumbricoides, approximately 20 cm Infections with whipworm are common world-wide,
2.35 especially in poor communities with inadequate sanitation.
110
Helminthic infections

Box 2.15 Drugs used for treating human intestinal nematodes (single dose unless otherwise stated)
Ascaris Hookworm Enterobius Trichuris Strongyloides
Piperazine 75 mg/kg
Pyrantal pamoate 10 mg/kg
Oxantel pamoate 10 mg/kg n/a
Albendazole 400 mg*
Mebendazole 500 mgf 25
Tiabendazole mg/kg* 5 n/a n/a n/a n/
Levamisole mg/kg n/a a
Ivermectin 200 |jg/kg* n/a n/a n/a n/a
n/a
++, highly effective; +, moderately effective; -, ineffective; n/a, drug not used for this indication/no data available
* Twice daily for 3 days in strongyloidiasis
t WHO recommended dose for developing countries; in UK commonly given as 100 mg single dose for threadworm, or 100 mg twice daily for 3
days for whipworm
* Once daily for 2 days
Adult worms, which are 3-5 cm long, inhabit the terminal associated with epigastric pain and nausea, resembling
ileum and caecum, although in heavy infection they are peptic ulcer disease. Chronic heavy infection, particularly
found throughout the large bowel. The head of the worm on a background of malnourishment, may cause iron
is embedded in the intestinal mucosa. Ova are deposited deficiency anaemia. Blood loss has been estimated at
in the faeces, and require a maturation period of 3-4 weeks about 0.15 mL/worm/day for A. duodenale, and 0.03 mL/
in the soil before becoming infective. worm/day for N. americanus; other factors may also be
Infection is usually asymptomatic, but mucosal involved in the development of anaemia, which may be
damage can occasionally be so severe that there is colonic accompanied by hypoproteinaemia. Heavy infection in
ulceration, dysentery, or rectal prolapse. children is associated with delays in physical and mental
Diagnosis is made by finding ova on stool microscopy, development.
or occasionally by seeing adult worms on sigmoidoscopy.
Drug treatment is shown in Box 2.15. Diagnosis and treatment
The diagnosis is made by finding eggs on faecal micro-
Hookworm infection scopy. In infections heavy enough to cause anaemia these
Hookworm infections, caused by the human hookworms will be present in large numbers. The aim of treatment in
Ancylostoma duodenale and Necator americanus, are found endemic areas is reduction of worm burden rather than
world-wide. They are relatively rare in developed complete eradication: albendazole or mebendazole,
countries, but very common in areas with poor sanitation which can both be given as a single dose, are the best
and hygiene: overall about 25% of the world's population drugs (Box 2.15). The WHO is promoting mass treatment
are affected. Hookworm infection is a major contributing programmes for schoolchildren in many parts of the
factor to anaemia in the tropics. A. duodenale is found world, together with treatment for schistosomiasis where
mainly in East Asia, North Africa and the Mediterranean, appropriate.
while N. americanus is the predominant species in South
and Central America, South East Asia and sub-Saharan Strongyloidiasis
Africa. Strongyloides stercoralis is a small (2 mm long) worm
Adult worms (which are about 1 cm long) live in the which lives in the small intestine. It is found in many
duodenum and upper jejunum, where they are often parts of the tropics and subtropics, and is especially
found in large numbers. They attach firmly to the mucosa common in Asia. Eggs hatch in the bowel, and larvae are
using the buccal plate, feeding on blood. Eggs passed in found in the stool. Usually these are non-infective
the faeces develop in warm moist soil, producing rhabditiform larvae, which require a further period of
infective filariform larvae. These penetrate directly maturation in the soil before they can infect a new host,
through the skin of a new host, and are carried in the but sometimes this maturation can occur in the large
bloodstream to the lungs. Having crossed into the alveoli, bowel. Infective filariform larvae can therefore penetrate
the parasites are expectorated and then swallowed, thus directly through the perianal skin, reinfecting the host. In
arriving at their definitive home. . this way autoinfection may continue for years or even
decades. Some war veterans who were imprisoned in the
Clinical features Far East during the Second World War have been found
Local irritation as the larvae penetrate the skin ('ground to have active strongyloidiasis over 50 years later. After
itch') may be followed by transient pulmonary signs and skin penetration the life cycle is similar to that of the
symptoms, often accompanied by eosinophilia. Light hookworm, except that the adult worms may burrow into
infections, especially in a well-nourished person, are the intestinal mucosa, causing a local inflammatory
often asymptomatic. Heavier worm loads may be response.
111
Infectious diseases, tropical medicine and sexually transmitted diseases
Clinical features a granulomatous response, but some may migrate into
Skin penetration by S. stercoralis causes a similar local other tissues including lungs, striated muscle, heart,
dermatitis to hookworm. In autoinfection this manifests brain, and eye. In most cases infection is asymptomatic,
as a migratory linear weal around the buttocks and lower and the larvae die without causing serious problems. In
abdomen (cutaneous larva currens). In heavy infections heavy infections there may be generalized symptoms
damage to the small intestinal mucosa can cause (fever and urticaria) and eosinophilia, as well as focal
malabsorption, diarrhoea and even perforation. There is signs related to the migration of the parasites. Pulmonary
usually a persistent eosinophilia. In patients who are involvement may cause bronchospasm and chest X-ray
immunosuppressed (e.g. by corticosteroid therapy or changes. Ocular infection may produce a granulomatous
intercurrent illness) filariform larvae may penetrate swelling mimicking a retinoblastoma, while cardiac or
directly through the bowel wall in huge numbers, causing neurological involvement may occasionally be fatal.
an overwhelming and usually fatal generalized infection Rarely, larvae survive in the tissues for many years,
(the strongyloidiasis hyperinfestation syndrome). This causing symptoms long after infection.
condition is often complicated by septicaemia due to Isolation of the larvae is difficult, and the diagnosis is
bowel organisms. usually made serologically. Albendazole 400 mg daily for
a week is the most effective treatment.
Diagnosis and treatment
Motile larvae may be seen on stool microscopy, especially Cutaneous larva migrans (CLM)
after a period of incubation. Serological tests are also CLM is caused by the larvae of the non-human hookworms
useful. The best drug for treating strongyloidiasis is Ancylostoma braziliense and A. caninum. Like human
ivermectin (200 Hg/kg daily for 2 days); albendazole and hookworms, these hatch in warm moist soil, and then
tiabendazole are also used. penetrate the skin. In man they are unable to complete a
normal life cycle, and instead migrate under the skin for
days or weeks until they eventually die. The wandering of
Zoonotic nematodes the larva is accompanied by a clearly-defined, serpiginous,
A number of nematodes which are principally parasites itchy rash ('creeping eruption'), which progresses at the rate
of animals may also affect man. The most common are of about 1 cm per day. There are usually no systemic
described below. symptoms. The diagnosis is purely clinical. Single larvae
may be treated with a 10% solution of topical tiabendazole;
Trichinosis multiple lesions may require systemic therapy with
The normal hosts of Trichinella spiralis, the cause of tiabendazole or albendazole or ivermectin.
trichinosis, include pigs, bears and warthogs. Man is
infected by eating undercooked meat from these animals. FURTHER READING
Ingested larvae mature in the small intestine, where Bundy DAP, de Silva NR (1998) Can we deworm this
adults release new larvae which penetrate the bowel wall wormy world? British Medical Bulletin 54: 421^32.
and migrate through the tissues. Eventually these larvae Hoerauf A, Buttner D, Adjei O, Pearlman E (2003)
encyst in striated muscle. Onchocerciasis. British Medical journal 326: 207-210.
Light infections are usually asymptomatic. Heavier Hotez DJ et al. (2004) Hookworm infections. New
loads of worms produce gastrointestinal symptoms as the England journal of Medicine 353: 799-807.
adults establish themselves in the small intestine,
followed by systemic symptoms as the larvae invade. The
latter include fever, oedema, and myalgia. Massive infec-
TREMATODES
tion may occasionally be fatal, but usually the symptoms
subside once the larvae encyst. Trematodes (flukes) are flat leaf-shaped worms. They
The diagnosis can usually be made from the clinical have complex life cycles, often involving fresh water
picture, associated eosinophilia, and serological tests. If snails and intermediate mammalian hosts. Disease is
necessary it can be confirmed by muscle biopsy a few caused by the inflammatory response to eggs or to the
weeks after infection. Albendazole (20 mg/kg for 7 days) adult worms.
given early in the course of the illness will kill the adult
worms and decrease the load of larvae reaching the
tissues. Analgesia and steroids may be needed for Water-borne flukes
symptomatic relief. Schistosomiasis
Schistosomiasis affects over 200 million people in the
Toxocariasis (visceral larva migrans) tropics and subtropics, most of whom live in sub-Saharan
Eggs of the dog roundworm, Toxocara canis, are occasion- Africa. Chronic infection causes significant morbidity,
ally ingested by humans, especially children. The eggs and after malaria it has the most socio-economic impact
hatch and the larvae penetrate the small intestinal wall of any parasitic disease. Schistosomiasis is largely a
and enter the mesenteric circulation, but are then unable disease of the rural poor, but has also been associated
to complete their life cycle in a 'foreign' host. Many are with major development projects such as dams and
held up in the capillaries of the liver, where they generate irrigation schemes.
112
Helminthic infections
2
Parasitology and pathogenesis Snail
There are three main species of schistosome which com-
monly cause disease in man: Schistosoma mansoni, S. Cercariae
haematobium, and S. japonicum. S. intercalatum and S. (infective form
for humans)
mekongi are less important. The geographical distribution
is shown in Figure 2.36. Eggs are passed in the urine or
faeces of an infected person, and hatch in fresh water to
release the miracidia (Fig. 2.37). These ciliated organisms Miracidia
(larvae)
penetrate the tissue of the intermediate host, a species of
water snail specific to each species of schistosome. After
Hatch in
multiplying in the snail, large numbers of fork-tailed water
cercariae are released back into the water, where they can
survive for 2-3 days. During this time the cercariae can Mature
schistosome
penetrate the skin or mucous membranes of the definitive
pair in
host, man. Transforming into schistosomulae, they pass mesenteric
through the lungs before reaching the portal vein, where venules
they mature into adult worms (the male is about 20 mm
Portal
long, and the female a little larger). Worms pair in the vein Ova
portal vein before migrating to their final destination:
mesenteric veins in the case of S. mansoni and S. japonicum,
and the vesicular plexus for S. haematobium. Here they may
remain for many years, producing vast numbers of eggs.
Liver
The majority of these are released in urine or faeces, but a „. .. [ and fibrosis
small number become embedded in the bladder or bowel Bladder J

wall, and a few are carried in the circulation to the liver or


other distant sites. I Inflammation

The pathology of schistosome infection varies with Fig. 2.37 A schematic life cycle of Schistosoma.
species and stage of infection. In the early stages there
may be local and systemic allergic reactions to the
migrating parasites. As eggs start to be deposited there
may be a local inflammatory response in the bowel or
bladder, while ectopic eggs may produce granulomatous
lesions anywhere in the body. Chronic heavy infection, in
I I S. haematobium

[...'.'.1 S. mansoni |

S. japonicum
Fi
g.
2.
36
Sc
his
to
so
mi
asi
s-
ge
og
ra
ph
ica
l
dis
tri
bu
tio
n.
Infectious diseases, tropical medicine and sexually transmitted diseases
which large numbers of eggs accumulate in the tissues, tion, the best specimen for examination is a filtered mid-
leads to fibrosis, calcification, and in some cases, dysplasia day urine sample. Parasites may also be found in semen,
and malignant change. Morbidity and mortality are related and in rectal snip preparations. S. mansoni and S. japonicum
to duration of infection and worm load, as well as to the eggs can usually be found in faeces or in a rectal snip.
species of parasite. Children in endemic areas tend to have Serological tests are available, and may be useful in the
the heaviest worm load, because of both increased diagnosis of travellers returning from endemic areas,
exposure to infection, and differences in the immune although the test may not become positive for 12 weeks
response between adults and children. after infection: a parasitological diagnosis should always
be made if possible. X-rays, ultrasound examinations,
Clinical features and endoscopy may show abnormalities of the bowel or
Cercarial penetration of the skin may cause local urinary tract in chronic disease, although these are non-
dermatitis ('swimmer's itch'). After a symptom-free specific. Liver biopsy may show the characteristic
period of 3-i weeks, systemic allergic features may periportal fibrosis.
develop, including fever, rash, myalgia, and pneumonitis
(Katayama fever). These allergic phenomena are common Management
in non-immune travellers, but are rarely seen in local The aim of treatment in endemic areas is to decrease the
populations, who are usually exposed to infection from worm load and therefore minimize the chronic effects of
early childhood onwards. If infection is sufficiently egg deposition. It may not always be possible (or even
heavy, symptoms from egg deposition may start to desirable) to eradicate adult worms completely, and
appear 2-3 months after infection. reinfection is common. However, a 90% reduction in egg
output has been achieved in mass treatment programmes,
S. haematobium infection (bilharzia). The earliest symp- and in light infections where there is no risk of re-
tom is usually painless terminal haematuria. As bladder exposure the drugs are usually curative. The most widely
inflammation progresses there is increased urinary used is praziquantel (40 mg/kg as a single dose), which is
frequency and groin pain. Obstructive uropathy effective against all species of schistosome, well-tolerated,
develops, leading to hydronephrosis, renal failure, and and reasonably cheap.
recurrent urinary infection. There is a strong association
between chronic urinary schistosomiasis and squamous Prevention
cell bladder carcinoma. The genitalia may also be Prevention of schistosomiasis is difficult, and relies on a
affected, and ectopic eggs may cause pulmonary or combination of approaches. Mass treatment of the
neurological disease. population (especially children) will decrease the egg
load in the community. Health education programmes,
S. mansoni usually affects the large bowel. Early disease the provision of latrines, and access to a safe water supply
produces superficial mucosal changes, accompanied by should decrease the contact with infected water. Attempts
blood-stained diarrhoea. Later the mucosal damage to eradicate the snail host have generally been
becomes more marked, with the formation of rectal unsuccessful, although man-made bodies of water can
polyps, deeper ulceration, and eventually fibrosis and often be made less 'snail-friendly'. Travellers should be
stricture formation. Ectopic eggs are carried to the liver, advised to avoid potentially infected water. Oral artemether
where they cause an intense granulomatous response. is safe and shows a prophylactic effect against S. mansoni.
Hepatitis is followed by progressive periportal fibrosis,
leading to portal hypertension, oesophageal varices and
splenomegaly (p. 392). Hepatocellular function is usually FURTHER READING
well preserved. Magnusson P (2003) Treatment and re-treatment
strategies for schistosomiasis control in different
settings: a review of 10 years' experiences. Acta
S. japonicum, unlike the other species, infects numerous Tropica 86: 243-254.
other mammals apart from man. It is similar to S. mansoni, Partners for parasite control:
but infects both large and small bowel, and produces a http://who.int/wormcontrol.
greater number of eggs. Disease therefore tends to be Utzinger J et al. (2003) Sustainable schistosomiasis
more severe, and rapidly progressive. Hepatic involve- control. Lancet 362:1932-1934.
ment is more common, and neurological involvement is
seen in about 5% of cases.
Food-borne flukes
Diagnosis
Many flukes infect man via ingestion of an intermediate
Schistosomiasis is suggested by relevant symptoms host, often fresh water fish.
following fresh water exposure in an endemic area. In the
early allergic stages the diagnosis can only be made Paragonimiasis
clinically. When egg deposition has started, the charac-
Over 20 million people are infected with lung flukes of
teristic eggs (with a terminal spine in the case of
the genus Paragonimus. The adult worms (of which the
S. haematobium, and a lateral spine in the other species)
major species is P. westermani) live in the lungs, producing
can be detected on microscopy. In S. haematobium infec-
eggs which are expectorated or swallowed and passed in
114
Helminthic infections
the faeces. Miracidia emerging from the eggs penetrate Adult worms live in the human intestine, where they
the first intermediate host, a fresh water snail. Larvae attach to the epithelium using suckers on the anterior
released from the snail seek out the second intermediate portion (scolex). From the scolex arises a series of
host, fresh water Crustacea, in which they encyst as progressively developing segments, called proglottids.
metacercariae. Humans and other mammalian hosts The mature distal segments contain eggs, which may
become infected after consuming uncooked shellfish. either be released directly into the faeces, or are carried
Cercariae penetrate the small intestinal wall, and migrate out with an intact detached proglottid. The eggs are
directly from the peritoneum to the lungs across the consumed by intermediate hosts, after which they hatch
diaphragm. Having established themselves in the lung, into larvae (oncospheres). These penetrate the intestinal
the adult worms may survive for 20 years. wall of the host (pig or cattle) and encyst in the tissues.
The common clinical features are fever, cough and Man ingests the cysts in undercooked meat or fish, and
mild haemoptysis. In heavy infections the disease may the cycle is completed when the parasites excyst in the
progress, sometimes mimicking pneumonia or pulmon- stomach and develop into adult worms in the small
ary tuberculosis. Ectopic worms may cause signs in the intestine. Infections are usually solitary, but several adult
abdomen or the brain. tapeworms may coexist. The exceptions to this life cycle
The diagnosis is made by detection of ova on sputum are the dwarf tapeworm, Hymenolepis nana, which has
or stool microscopy. Serological tests are also available. no intermediate host and is transmitted from person to
Radiological appearances are variable and non-specific. person by the faeco-oral route and Taenia solium which
Treatment is with praziquantel 25 mg/kg three times daily produces cysticercosis (see below).
for 3 days. Prevention involves avoidance of inadequately
cooked shellfish.
Taenia saginata
T. saginata, the beef tapeworm, may reach a length of
Liver flukes several metres. It is common in all countries where
The human liver flukes, Clonorchis sinensis, Opisthorchis undercooked beef is eaten. The adult worm causes few
felineus, and O. viverrini, are almost entirely confined to if any symptoms. Infection is usually discovered when
East and South East Asia, where they infect more than proglottids are found in faeces or on underclothing, often
20 million people. Adults live in the bile ducts, releasing causing considerable anxiety. Ova may also be seen on
eggs into the faeces. The parasite requires two inter- stool microscopy. Infection can be cleared with a single
mediate hosts, a fresh water snail and a fish, and humans dose of praziquantel (10 mg/kg). It can be prevented
are infected by consumption of raw fish. The cycle is by careful meat inspection, or by thorough cooking
completed when excysted worms migrate from the small of beef.
intestine into the bile ducts.
Infection is often asymptomatic, but may be associated Taenia solium and cysticercosis
with cholangitis and biliary carcinoma. The diagnosis is
T. solium, the pork tapeworm, is generally smaller than
made by identifying eggs on stool microscopy. Treatment
T. saginata, although it can still reach 6 metres in length. It
is with a single dose of praziquantel (40 mg/kg), and
is particularly common in South America, South Africa,
infection can be avoided by cooking fish adequately.
China, and parts of South East Asia. As with T. saginata
infection is usually asymptomatic. The ova of the two
Other fluke infections species are identical, but the proglottids can be dis -
tinguished on inspection.
Man can also be infected with a variety of animal flukes, Tapeworms are mainly acquired by eating uncooked
notably the liver fluke Fasciola hepatica, and the intestinal pork while cysticercosis follows the ingestion of eggs
fluke Fasciolopsis bush. Both require a water snail as an from contaminated food and water. Faeco-oral auto-
intermediate host; cercariae encyst on aquatic vegetation, infection can occur but is rare. Patients with tapeworms
and then are consumed by animals or man. After do not usually develop cysticercosis and patients with
ingestion, F. hepatica penetrates the intestinal wall before cysticercosis do not usually harbour tapeworms. Follow-
migrating to the liver: during this stage it causes systemic ing the ingestion of eggs, the larvae are liberated, penetrate
allergic symptoms. After reaching the bile ducts, it causes the intestinal wall, and are carried to various parts of
similar problems to those of the other liver flukes. F. buski the body where they develop into cysticerci (Fig. 2.38).
does not migrate after it excysts, and causes mainly bowel These are cysts, 0.5-1 cm diameter, containing the scolex
symptoms. of a new adult worm. Common sites for cysticerci include
The best treatment for F. buski is praziquantel subcutaneous tissue, skeletal muscle and brain.
25 mg/kg, three doses in 24 hours, and for F. hepatica, Superficial cysts may be felt under the skin, but usually
triclabendazole 10 mg/kg as a single dose (which may cause no significant symptoms. Cysts in the brain can
need repeating). cause a variety of problems including epilepsy, personality
change, hydrocephalus and focal neurological signs
CESTODES (p. 1241). These may only appear many years after infection.
Muscle cysts tend to calcify, and are often visible on
Cestodes (tapeworms) are ribbon-shaped worms which X-rays. Cutaneous cysts can be excised and examined.
vary from a few millimetres to several metres in length. Brain cysts are less prone to calcification, and are often
115
Infectious diseases, tropical medicine and sexually transmitted diseases
Pig Human

'Scolex Scolex
evaginates
in human
stomach
Raw or
undercooked
pork ingested

n
by human
Cysticercus
Body tissues, Liver Human
e.g. muscle

Dead
end
-
Hydatidcyst

Cysticercus

Gravid terminal
Embryo leaves segments
embryophore (proglottid)
in proximal
small intestine
Ruptures (before/after
excretion in faeces)
Faeces
ingested by pig

Egg
Wall---------__

Hexacanth
-embryo
fig. 2.38 A schematic life cycle of Taenia solium. Fig. 2.39 A schematic life cycle of Echinococcus
granulosus.
^iiSl only seen on CT or MRI scan. Serological tests may
support the diagnosis.
utilization of B12 by the parasite) may occur. Diagnosis
and treatment are the same as for Taenia species.
Treatment is again with praziquantel: niclosamide
1 g repeated after 2 hours is also effective. There is no Hydatid disease
evidence that drug treatment should be accompanied by Hydatid disease occurs when humans become an inter-
a purgative, as was previously believed. mediate host of the dog tapeworm, Echinococcus granulosus
(Fig. 2.39). The adult worm lives in the gut of domestic
Treatment of cerebral cysticercosis (p. 1241) and wild canines, and the larval stages are usually found
The role of anthelminthics in cysticercosis remains in sheep, cattle and camels. Man may become infected
controversial. Even in neurocysticercosis there is little either from direct contact with dogs, or from food or
evidence of benefit, although symptomatic patients with water contaminated with dog faeces. After ingestion the
viable neurocysts should probably be treated. Albendazole parasites excyst, penetrate the small intestine wall, and are
15 mg/kg daily for 8-20 days is the drug of choice; the carried to the liver and other organs in the bloodstream. A
alternative is praziquantel 50 mg/kg daily (in divided slow-growing, thick-walled cyst is formed, inside which
doses) for 15 days. further larval stages of the parasite develop. The life cycle
Successful treatment is accompanied by increased cannot be completed unless the cyst is eaten by a dog.
local inflammation, and corticosteroids should be given Hydatid disease is prevalent in areas where dogs are used
during and after the course of anthelminthic. Anti- in the control of livestock, especially sheep. It is common in
convulsants should be given for epilepsy, and surgery Australia, Argentina, the Middle East, and parts of East
may be indicated if there is hydrocephalus. Prevention of Africa; small foci of infection are still found in North Wales
cysticercosis depends on good hygiene, as well as on the and rural Scotland.
eradication of human T. solium infection. Symptoms depend mainly on the site of the cyst. The
liver is the most common organ affected (60%), followed
Diphyllobothrium latum by the lung (20%), kidneys (3%), brain (1%) and bone
Infection with the fish tapeworm, D. latum, is common in (1 %). The symptoms are those of a slowly growing benign
northern Europe and Japan, owing to the consumption of tumour. Pressure on the bile ducts may cause jaundice.
raw fish. The adult worm reaches a length of several Rupture into the abdominal cavity, pleural cavity or
metres, but like the other tapeworms usually causes no biliary tree may occur. In the latter situation, intermittent
symptoms. A megaloblastic anaemia (due to competitive jaundice, abdominal pain and fever associated with
Sexually transmitted infections

eosinophilia result. A cyst rupturing into a bronchus may laundry and linen, burrow into the skin to form boil-like
result in its expectoration and spontaneous cure, but if lesions: a central breathing orifice may be visible. Again,
secondary infection supervenes a chronic pulmonary the main risk is secondary infection. It is not always easy
abscess will form. Focal seizures can occur if cysts are to extract the larva: covering it with petroleum jelly may
present in the brain. Renal involvement produces lumbar bring it up in search of air.
pain and haematuria. Calcification of the cyst occurs in
about 40% of cases. Systemic envenoming
A related parasite of foxes, E. multilocularis, causes a
similar but more severe infection, alveolar hydatid Many arthropods can cause local or systemic illness
disease. These cysts are invasive and metastases may through envenoming, i.e. injection of venom.
occur.
The diagnosis and treatment of hydatid liver disease The main role of arthropods in causing human disease is
are described on page 392. as vectors of parasitic and viral infections. Some of these
infections are shown in Table 2.4, and discussed in detail
elsewhere.

ARTHROPOD ECTOPARASITES FURTHER READING


Garcia HH (2003) Taenia solium cysticercosis. Lancet 362:
Arthropods, which include the arachnid ticks and mites 547-556. Heukelbach J, Feldmeier H (2004)
as well as insects, may be responsible for human disease Ectoparasites - the
in several ways. underestimated realm. Lancet 363: 889-891. McManus
DP et al. (2003) Echinococcosis. Lancet 362:
1295-1304. Moss PJ, Beeching NJ (2003) Ectoparasites in
Local hypersensitivity reactions Infectious
Diseases, 2nd edn. London: Mosby.
Local lesions may be caused by hypersensitivity to
allergens in arthropod saliva. This common reaction,
known as papular urticaria, is non-specific and is seen in
the majority of people in response to the bite of a variety
of blood-sucking arthropods including mosquitoes, bugs,
SEXUALLY TRANSMITTED
ticks, lice, and mites. Occasionally tick bites may cause a INFECTIONS
more severe systemic allergic response, especially in
previously sensitized individuals. Sexually transmitted infections (STIs) are among the most
Most of these parasites alight on man only to feed, but common causes of illness in the world and remain
some species of lice live in very close proximity to the epidemic in all societies. The public health, social and
skin: body lice in clothing, and head and pubic lice on economic consequences are extensive, both of the acute
human hairs (p. 1325). infections and their longer-term sequelae. There has been
a recent sharp increase in the incidence of STIs in the
UK (as in the rest of the world). New presentations at
Resident ectoparasite infections genitourinary medicine (GUM) clinics in the UK rose by
37% from 1 546 812 in 2002 to 2 125 243 in 2003.
Other ectoparasites are actually resident within the skin,
Between 1997 and 2002 there has been an increase in
causing more specific local lesions.
both gonorrhoea (97%) and syphilis (716%) infections.
There has been a steady rise in the incidence of Chlamydia
Scabies (p. 1325)
trachomatis with a 103% increase over the same time
period. Viral conditions, particularly herpes simplex
Jiggers
virus (HSV) and human papillomavirus, have also
Jiggers is due to infection with the jigger flea, Tunga increased substantially. Increased numbers may also
penetrans, and is common throughout South America and reflect recent public health campaigns promoting STI
Africa. The pregnant female flea burrows into the sole of screening and the use of increasingly sensitive diagnostic
the foot, often between the toes. The egg sac grows to tests. Substantial rises in human immunodeficiency virus
about 0.5 cm in size, before the eggs are discharged onto (HIV) infection in the UK have further heightened aware-
the ground. The main danger is bacterial infection or ness of STIs. In 2002 over 49 000 adults were estimated to
tetanus. The flea should be removed with a needle or have HIV, with up to one-third being unaware of their
scalpel, and the area kept clean until it heals. infection. Many people attend GUM clinics to seek infor-
mation, advice and checks of their sexual health, but have
Myiasis no active STI.
Myiasis is caused by invasion of human tissue by the Those most likely to acquire STIs are young people,
larva of certain flies, principally the Tumbu fly, Cordylobia homo- and bisexual men and black and ethnic minority
anthropophaga (found in sub-Saharan Africa), and the populations. Changes in incidence reflect high-risk sexual
human botfly, Dermatobia hominis (Central and South behaviour and inconsistent use of condoms. Increased
America). The larvae, which hatch from eggs laid on
Infectious diseases, tropical medicine and sexually transmitted diseases
travel both within and between countries, recreational Table 2.46 Causes of vaginal discharge
drug use, alcohol and more frequent partner change are Infective Non-infective
also implicated. Multiple infections frequently coexist,
some of which may be asymptomatic and facilitate Candida albicans Cervical polyps
spread. Trichomonas vaginalis
Bacterial vaginosis
Neisseria gonorrhoeae
Approach to the patient Chlamydia trachomatis
Herpes simplex
Patients presenting with possible STIs are frequently Neoplasms
anxious, embarrassed and concerned about confidentiality.
Staff must be alert to these issues and respond sensitively. Non-infective
The clinical setting must ensure privacy and reinforce Physical or chemical trauma
confidentiality. Urethral stricture Non-
specific (aetiology unknown)
History
The history of the presenting complaint frequently
focuses on genital symptoms, the three most common Retained products (e.g. tampons)
being vaginal discharge (Table 2.46), urethral discharge Chemical irritation
(Table 2.47), and genital ulceration (Table 2.48). Details
should be obtained of any associated fever, pain, itch,
Table 2.47 Causes of urethral discharge
malodour, genital swelling, skin rash, joint pains and eye
symptoms. All patients should be asked about dysuria, Infective
haematuria and loin pain. A full general medical, family Infective
and drug history, particularly of any recent antibacterial
or antiviral treatment, allergies and use of oral contra- Behget's syndrome Toxic
ceptives, must be obtained. In women, menstrual, contra- epidermal necrolysis
Stevens-Johnson
ception and obstetric history should be obtained. Any past
syndrome
or current history of drug misuse should be explored. Carcinoma
A detailed sexual history should be taken and include Trauma
the number and types of sexual contacts (genital/genital,
oral/genital, anal/genital, oral/anal) with dates, partner's Neisseria gonorrhoeae Chlamydia
sex, whether regular or casual partner, use of condoms trachomatis Mycoplasma genitilium
and other forms of contraception, previous history of STIs Ureaplasma urealyticum Trichomonas
including dates and treatment received, HIV testing and vaginalis Herpes simplex virus Human
results and hepatitis B vaccination status. papillomavirus (meatal warts) Urinary tract
Enquires should be made concerning travel abroad to infection (rare) Treponema pallidum
(meatal chancre)
areas where antibiotic resistance is known or where
particular pathogens are endemic.
Table 2.48 Causes of genital ulceration
Examination
General examination must include the mouth, throat, Non-infective
skin and lymph nodes in all patients. Signs of HIV infec- Syphilis:
tion are covered on page 144. The inguinal, genital and Primary chancre
perianal areas should be examined with a good light Secondary mucous patches
source. The groins should be palpated for lymph- Tertiary gumma
adenopathy and hernias. The pubic hair must be Chancroid
examined for nits and lice. The external genitalia must be Lymphogranuloma venereum
examined for signs of erythema, fissures, ulcers, chancres, Donovanosis Herpes simplex:
pigmented or hypopigmented areas and warts. Signs of Primary
Recurrent
trauma may be seen.
Herpes zoster
In men, the penile skin should be examined and the
foreskin retracted to look for balanitis, ulceration, warts
or tumours. The urethral meatus is located and the
presence of discharge noted. Scrotal contents are palpated In women, Bartholin's glands must be identified and
and the consistency of the testes and epididymis noted. A examined. The cervix should be inspected for ulceration,
rectal examination/proctoscopy should be performed in discharge, bleeding and ectopy and the walls of the
patients with rectal symptoms, those who practise vagina for warts. A bimanual pelvic examination is per-
anoreceptive intercourse and patients with prostatic formed to elicit adnexal tenderness or masses, cervical
symptoms. A search for rectal warts is indicated in patients tenderness, and to assess the position, size and mobility
with perianal lesions. of the uterus. Rectal examination and proctoscopy are
performed if the patient has symptoms or practises
anoreceptive intercourse.

Investigations
Although the history and examination will guide investi-
gation, it must be remembered that multiple infections
may coexist, some being asymptomatic. Full screening is
indicated in any patient who may have been in contact
with an STL
In men ■ Urethral swabs for gonococcal culture and Chlamydia
■ Urethral smears for Gram staining testing
118
Sexually transmitted infections
■ Two-glass urine test and urinalysis groups at particular risk are being implemented at a
■ Rectal swabs for Gram staining and culture for national level. Appropriate and accessible services must
N. gonorrhoeae and C. trachomatis be well advertised. Avoiding multiple partners, correct
m Throat swab for culture for N. gonorrhoeae and consistent use of condoms and avoiding sex with
m Blood for syphilis and HIV serology (with counselling). people who have symptoms of infection may reduce the
risks of acquiring an STI. For those who change their
In women sexual partners frequently, regular check-ups (approxi-
m Smears from the lateral vaginal wall for Gram staining mately 3-monthly) are advisable. Once people develop
■ Vaginal swab for culture of Candida and Trichomonas symptoms they should be encouraged to seek medical
m A wet preparation is made from the posterior fornix advice as soon as possible to reduce complications and
for Trichomonas and for the potassium hydroxide test spread to others.
for bacterial vaginosis
■ The pH of vaginal secretions using narrow-range
indicator paper Sexual assault
■ Endocervical smears and swabs for Gram staining, The medical and psychological management of people
gonococcal culture and Chlamydia tests who have been sexually assaulted requires particular
■ Urethral smears and swabs for Gram staining and sensitivity and should be undertaken by an experienced
gonococcal culture clinician in ways that reduce the risks of further trauma.
■ Rectal and throat swabs for N. gonorrhoeae and Post-traumatic stress disorder is common. Although most
C. trachomatis, if indicated frequently reported by women, both women and men may
■ Urinalysis suffer sexual assault. Investigations for and treatment of
■ Cervical cytology sexually transmitted infections in people who have been
■ Blood for syphilis and HIV serology (with counselling). raped can be carried out in GUM departments. Collection
of material for use as evidence, however, should be
Additional investigations when indicated carried out within 7 days of the assault by a physician
m Urine sample for nucleic acid amplification tests if trained in forensic medicine and must take place before
available locally any other medical examinations are performed.
■ Blood for hepatitis B and C serology
■ Swabs for HSV and Haemophilus ducreyi from clinically History
suspicious lesions into special media In addition to the general medical, gynaecological and
■ Smears and swabs from the subpreputial area in men contraceptive history, full details of the assault, including
with balanoposthitis (inflammation of glans penis and the exact sites of penetration, ejaculation by the assailant
prepuce) for candidiasis and condom use should be obtained, together with
■ Scrapings from lesions suspicious of early syphilis for details of the sexual history both before and after the
immediate dark-ground microscopy event. ■. ' :'
■ Pregnancy testing
■ Cervical cytology Examination
■ Stools for Giardia, Shigella or Salmonella from those Any injuries requiring immediate attention must be dealt
practising oral/anal sex. with prior to any other examination or investigations.
Accurate documentation of any trauma is necessary.
Forced oral penetration may result in small palatal
Treatment, prevention and control haemorrhages. In cases of forced anal penetration, anal
The treatment of specific conditions is considered in the examination including proctoscopy should be carried
appropriate section. Many GUM clinics keep basic stocks out, noting any trauma.
of medication and dispense directly to the patient.
Tracing the sexual partners of patients is crucial in Investigations
controlling spread of STIs. The aims are to prevent the A full STI screen at presentation with a second exam-
spread of infection within the community and to ensure ination 2 weeks later is recommended. Cultures for
that people with asymptomatic infection are properly Neisseria gonorrhoeae and tests for Chlamydia trachomatis
treated. Appropriate antibiotic therapy may be offered to should be obtained from all sites of actual or attempted
those who have had recent intercourse with someone penetration. C. trachomatis culture is the only test
known to have an active infection (epidemiological treat- currently accepted as evidence. Gram-stained slides of
ment). Interviewing people about their sexual partners urethral, cervical and rectal specimens for microscopy for
requires considerable tact and sensitivity, and specialist gonococci should be performed. Bacterial vaginosis,
health advisors are available in GUM climes. yeasts and Trichomonas vaginalis (TV) tests should be
Prevention starts with education and information. carried out on vaginal material. Syphilis serology
People begin sexual activity at ever-younger ages and should be requested and a serum saved. Hepatitis B, HIV
education programmes need to include school pupils as and hepatitis C testing should be offered. Specimens
well as young adults. Education of health professionals is
should be identified as having potential medicolegal
also crucial. Public health campaigns aimed at informing
implications.
119
Infectious diseases, tropical medicine and sexually transmitted diseases
Management
Preventative therapy for gonorrhoea and chlamydia
may be advised using a single dose combination of
ciprofloxacin 500 mg and azithromycin 1 g. Hep B vaccine
should be offered and may be of value up to 3 weeks after
the event. HIV prophylaxis may be offered within
72 hours of the assault, based upon a specific risk assess-
ment. Post-coital oral contraception may be given within
72 hours of assault. Psychological care provision and
appropriate referral to support agencies should be
arranged. Sexual partners should be screened and treated
if necessary.
Initial follow-up at 2 weeks should be arranged to
review the patient's needs and the prophylaxis regimens
that are in place, with further follow-up as needed. Fig. 2.40 Neisseria gonorrhoeae - Gram-negative
intracellular diplococci. Courtesy of Dr B Goh.
CLINICAL SYNDROMES

HIV and AIDS


These are discussed in the section starting on page 129.

Gonorrhoea (GC)
Neisseria gonorrhoeae is a Gram-negative intracellular
diplococcus (Fig. 2.40), which infects epithelium parti-
cularly of the urogenital tract, rectum, pharynx and
conjunctivae. Humans are the only host and the organism
is spread by intimate physical contact. It is very intolerant
to drying and although occasional reports of spread by
fomites exist, this route of infection is extremely rare.

Clinical features
Up to 50% of women and 10% of men are asymptomatic.
The incubation period is 2-14 days with most symptoms
occurring between days 2 and 5. In men the most com-
Fig. 2.41 Neisseria gonorrhoeae - purulent urethral
mon syndrome is one of anterior urethritis causing discharge. Courtesy of Dr B Goh.
dysuria and/or urethral discharge (Fig. 2.41). Compli-
cations include ascending infection involving the epi-
didymis or prostate leading to acute or chronic infection. Diagnosis
In homosexual men rectal infection may produce proctitis N. gonorrhoeae can be identified from infected areas by
with pain, discharge and itch. culture on selective media with a sensitivity of at least
In women the primary site of infection is usually the 95%. Microscopy of Gram-stained secretions may demon-
endocervical canal. Symptoms include an increased or strate intracellular, Gram-negative diplococci, allowing
altered vaginal discharge, pelvic pain due to ascending rapid diagnosis. The sensitivity ranges from 90% in
infection, dysuria, and intermenstrual bleeding. Compli- urethral specimens from symptomatic men to 50% in
cations include Bartholin's abscesses and in rare cases a endocervical specimens. Nucleic acid amplification tests
perihepatitis (Fitzhugh-Curtis syndrome) can develop. (NAATs) using urine specimens are non-invasive and
On a global basis GC is one of the most common causes highly sensitive, although may give false positive results.
of female infertility. Rectal infection, due to local spread, Microscopy should not be used for pharyngeal specimens.
occurs in women and is usually asymptomatic, as is Blood culture and synovial fluid investigations should be
pharyngeal infection. Conjunctival infection is seen in performed in cases of disseminated GC. Coexisting
neonates born to infected mothers and is one cause of pathogens such as Chlamydia, Trichomonas and syphilis
ophthalmia neonatorum. must be sought.
Disseminated GC leads to arthritis (usually mono-
articular or pauciarticular) (see p. 572) and characteristic Treatment
papular or pustular rash with an erythematous base in Treatment is indicated in those patients who have a
association with fever and malaise. It is more common in positive culture for GC, positive microscopy or a positive
NAAT. Epidemiological treatment is given to patients
120
Sexually transmitted infections |
who have had recent infections. In men 40% of nucleic acid (NGU). NGU occurring
sexual intercourse with non-gonococcal and post- amplification techniques shortly after infection
someone with confirmed gonococcal urethritis is such as PCR or ligase with gonorrhoea is
GC infection. Although N. due to Chlamydia. As CT chain reaction (LCR): known as postgonococcal
gonorrhoeae is sensitive is often asymptomatic none is diagnostic. urethritis (PGU).
to a wide range of much infection goes In men first-voided Gonococcal urethritis and
antimicrobial agents, unrecognized and urine samples are tested, chlamydial urethritis (a
antibiotic-resistant strains untreated, which sustains or urethral swabs major cause of NGU) are
have shown a recent the infectious pool in the obtained. In women discussed above.
significant increase in the population. The long-term endocervical swabs are Trichomonas vaginalis,
UK. Up to 10% of strains complications associated the best specimens, and Mycoplasma genitilium,
show resistance to with Chlamydia infection, up to 20% additional Ureaplasma urealyticum
penicillins and especially infertility, positives will be detected and Bacteroides spp. are
ciprofloxacin and over impose significant if urethral swabs are also responsible for a
40% resistance to morbidity in the UK. The taken. Urine specimens proportion of cases. HSV
tetracyclines. Immediate organism has a world- are much less reliable than can cause urethritis in
therapy based on Gram- wide distribution. endocervical swabs in about 30% of cases of
stained slides is usually women and are not primary infection,
initiated in the clinic, Clinical features recommended. Specimen considerably fewer in
prior to culture and In men CT gives rise to an quality is critical and it recurrent episodes. Other
sensitivity results. anterior urethritis with must contain cellular causes include syphilitic
Antibiotic choice is dysuria and discharge; material. chancres and warts within
influenced by travel infection is asymptomatic the urethra. Non-sexually
history or details known in up to 50% and Treatment transmitted NGU may be
from contacts. detected by contact Tetracyclines or macrolide due to urinary tract
Single-dose oral tracing. Ascending antibiotics are most infections, prostatic
therapy with either infection leads to commonly used to treat infection, foreign bodies
cefixime (400 mg), epididymitis. Rectal Chlamydia. Doxycycline and strictures.
ceftriaxone i.m. (250 infection leading to 100 mg 12-hourly for 7
mg) or spectinomycin 2 proctitis occurs in men days or azithromycin 1 g Clinical features
g i.m. (not generally practising anoreceptive as a single dose are both The urethral discharge is
available in the UK) intercourse. In women the effective for often mucoid and worse
successfully treats most common site of uncomplicated infection. in the mornings. Crusting
uncomplicated anogenital infection is the endo- Tetracyclines are at the meatus or stains on
infection. Single-dose cervix where it may go contraindicated in underwear occur. Dysuria
amoxicillin 3 g with unnoticed; up to 80% of pregnancy. Other is common but not
probenecid 1 g, infection in women is effective regimens universal. Discomfort or
ciprofloxacin (500 mg) or asymptomatic. Symptoms include erythromycin 500 itch within the penis may
ofloxacin (400 mg) are include vaginal mg four times daily. be present. The
recommended for use in discharge, post-coital or Routine test of cure is incubation period is 1—5
areas with low prevalence intermenstrual bleeding not necessary after weeks with a mean of 2—3
of antibiotic resistance. and lower abdominal treatment with weeks. Asymptomatic
Longer courses of pain. Ascending infection doxycycline or urethritis is a major
antibiotics are required for causes acute salpingitis. azithromycin, although reservoir of infection.
complicated infections. Reiter's disease (see p. if symptoms persist or Reiter's disease causing
There should be at least 568) has been related to reinfection is suspected conjunctivitis and/or
one follow-up infection with C. then further tests should arthritis occurs,
assessment, and culture trachomatis. Neonatal be taken. Sexual contacts particularly in HLA B27-
tests should be repeated infection, acquired from must be traced and positive individuals.
at least 72 hours after the birth canal, can treated, particularly as so
treatment is complete. All result in mucopurulent many infections are Diagnosis
sexual contacts should be conjunctivitis and clinically silent.
Smears should be taken
examined and treated as pneumonia.
from the urethra when
necessary.
Diagnosis Urethritis the patient has not
voided urine for at least
CT is an obligate Urethritis is usually
Chlamydia intracellular bacterium,
4 hours and should be
characterized in men by a
trachomatis (CT)______________________
which complicates discharge from the
Gram stained and
Genital infection with CT examined under a high-
diagnosis. Cell culture urethra, dysuria and
is common, with up to power (xlOOO) oil-
techniques provide the varying degrees of dis-
5% of sexually active 'gold standard' but are immersion lens. The
comfort within the penis.
women in the UK expensive and require presence of five or
In 10-15% of cases there
infected. It is regularly considerable expertise. are no symptoms. A wide
found in association with Indirect diagnostic tests array of aetiologies can
other pathogens: 20% of include direct fluorescent give rise to the clinical
men and 40% of women antibody (DIF) tests, picture which are divided
with gonorrhoea have enzyme immunoassays into two broad bands:
been found to have (EIA) and gonococcal or non-
coexisting chlamydial gonococcal urethritis
Infectious diseases, tropical medicine and sexually transmitted diseases
more polymorphonuclear leucocytes per high-power anorectal Crohn's disease. The destruction of local lymph
field is diagnostic. Men who are symptomatic but have no nodes can lead to lymphoedema of the genitalia.
objective evidence of urethritis should be re-examined
and tested after holding urine overnight. Cultures for Diagnosis
gonorrhoea must be taken together with specimens for The diagnosis is often made on the basis of the charac-
Chlamydia testing. teristic clinical picture after other causes of genital
ulceration or inguinal lymphadenopathy have been
Treatment excluded. Syphilis and genital herpes must be excluded.
Therapy for NGU is with either doxycycline 100 mg 12-
■ Isolation of C. tradiomatis in tissue culture. The
hourly or azithromycin 1 g orally as a single dose.
sensitivity is 75-85%.
Sexual intercourse should be avoided. The vast majority
■ Antigen-detection methods with material from bubo
of patients will show partial or total response. Sexual
aspirates or ulcer scrapes:
partners must be traced and treated; C. tmchomatis can be
isolated from the cervix in 50-60% of the female partners - direct immunofluorescence using monoclonal
antibodies
of men with PGU or NGU, many of whom are asymp-
- enzyme immunoassay (ElA).
tomatic. This causes long-term morbidity in such women,
acts as a reservoir of infection for the community, and ■ Sensitivity 70-80%.
may lead to reinfection in the index case if not treated. ■ Positive C. tradiomatis serology (complement fixation
tests, L-type immunofluorescence or micro-immuno-
fluorescence test, IF). A fourfold rise in antibody titre
Recurrent/persistent NGU
in the course of the illness is diagnostic. NB: Micro-IF
This is a common and difficult clinical problem, and can
is the only serological means of distinguishing
occur in 20-60% of men treated for acute NGU. The usual
different serotypes of CT.
time for patients to re-present is 2-3 weeks following
treatment. Tests for organisms, e.g. Mycoplasma, Chlamydia Treatment
and Ureaplasma are usually negative. It is necessary to
document objective evidence of urethritis, check adherence Early treatment is critical to prevent the chronic phase.
to treatment and establish any possible contact with Doxycycline (100 mg twice daily for 21 days) or
untreated sexual partners. Investigations should include erythromycin (500 mg four times daily for 21 days) is
wet preparation and culture of urethral material for efficacious. Follow-up should continue until signs and
Trichomonas vaginalis. Cultures should be taken for HSV. A symptoms have resolved, usually 3-6 weeks. Chronic
mid-stream urine sample should be examined and infection may result in extensive scarring and abscess and
cultured. A further 1 week's treatment with erythromycin sinus formation. Surgical drainage or reconstructive
500 mg four times a day for 2 weeks plus metronidazole surgery is sometimes required. Sexual partners in the 30
400 mg twice daily for 5 days may be given, and any days prior to onset should be examined and treated if
specific additional infection treated appropriately. If necessary.
symptoms are mild and all partners have been treated,
patients should be reassured and further antibiotic
therapy avoided. In cases of frequent recurrence and/ or Syphilis_____________________________
florid unresponsive urethritis, the prostate should be Syphilis is a chronic systemic disease, which is acquired
investigated and urethroscopy or cystoscopy performed or congenital. In its early stages diagnosis and treatment
to investigate possible strictures, periurethral fistulae or are straightforward but untreated it can cause complex
foreign bodies. sequelae in many organs and eventually lead to death.
The causative organism, Treponema pallidum (TP), is a
motile spirochaete that is acquired either by close sexual
Lymphogranuloma venereum (LGV) contact or can be transmitted transplacentally. The organ-
Chlamydia tradiomatis types LGV 1, 2 and 3 are respon- ism enters the new host through breaches in squamous or
sible for this sexually transmitted infection. It is endemic columnar epithelium. Primary infection of non-genital
in the tropics, with the highest incidences in Africa, India sites may occasionally occur but is rare.
and South East Asia. Both acquired and congenital syphilis have early and
late stages, each of which has classic clinical features
Clinical features (Table 2.49).
The primary lesion is a painless ulcerating papule on the
genitalia occurring 7-21 days following exposure. It is Primary
frequently unnoticed. A few days to weeks after this Between 10-90 days (mean 21 days) after exposure to the
heals, regional lymphadenopathy develops. The lymph pathogen a papule develops at the site of inoculation.
nodes are painful and fixed and the overlying skin This ulcerates to become a painless, firm chancre. There is
develops a dusky erythematous appearance. Finally, usually painless regional lymphadenopathy in associ-
nodes may become fluctuant (buboes) and can rupture. ation. The primary lesion may go unnoticed, especially if
Acute LGV also presents as proctitis with perirectal it is on the cervix or within the rectum. Healing occurs
abscesses, the appearances sometimes resembling spontaneously within 2-3 weeks.
122
Sexually transmitted infections

Table 2.49 Classification and clinical features of


Clinical features
syphilis
Acquired Hard
Early stages chancre
Primary
Painless, regional lymphadenopathy
Secondary General: Fever, malaise, arthralgia, sore
throat and generalized lymphadenopathy
Skin: Red/brown maculopapular non-itchy,
sometimes scaly rash; condylomata lata
Mucous membranes: Mucous patches,
'snail-track' ulcers in oropharynx and
on genitalia
Late
stages Late benign: Gummas (bone and viscera) Fig. 2.42 Rash of secondary syphilis on the palms.
Tertiary Cardiovascular: Aortitis and aortic Courtesy of Dr B Goh.
regurgitation
Neurosyphilis: Meningovascular
involvement, general paralysis of the during a period known as early latency, a 2-year period in
insane (GPI) and tabes dorsalis
the UK (1 year in USA). Late latency is based on reactive
Congenital Stillbirth or failure to thrive Early stages syphilis serology with no clinical manifestations for at
'Snuffles' (nasal infection with discharge) Skin and mucous least 2 years. This can continue for many years before the
membrane lesions as in late stages of syphilis become apparent.
secondary syphilis Late stages
'Stigmata': Hutchinson's teeth, 'sabre'
Tertiary
tibia and abnormalities of long bones
Keratitis, uveitis, facial gummas and Late benign syphilis, so called because of its response to
CNS disease therapy rather than its clinical manifestations, generally
involves the skin and the bones. The characteristic lesion,
the gumma (granulomatous, sometimes ulcerating,
Secondary lesions), can occur anywhere in the skin, frequently at
Between 4-10 weeks after the appearance of the primary sites of trauma. Gummas are commonly found in the
lesion constitutional symptoms with fever, sore throat, skull, tibia, fibula and clavicle, although any bone may be
malaise and arthralgia appear. Any organ may be affected involved. Visceral gummas occur mainly in the liver
- leading, for example, to hepatitis, nephritis, arthritis (hepar lobatum) and the testes.
and meningitis. In a minority of cases the primary chancre Cardiovascular and neurosyphilis are discussed on
may still be present and should be sought. Signs include: pages 810 and 1240.

■ Generalized lymphadenopathy (50%) Congenital syphilis


■ Generalized skin rashes involving the whole body Congenital syphilis usually becomes apparent between
including the palms and soles but excluding the face the second and sixth week after birth, early signs being
(75%) - the rash, which rarely itches, may take many nasal discharge, skin and mucous membrane lesions, and
different forms, ranging from pink macules, through failure to thrive. Signs of late syphilis generally do not
coppery papules, to frank pustules (Fig. 2.42) appear until after 2 years of age and take the form of
■ Condylomata lata - warty, plaque-like lesions found in 'stigmata' relating to early damage to developing struc-
the perianal area and other moist body sites tures, particularly teeth and long bones. Other late
■ Superficial confluent ulceration of mucosal surfaces - manifestations parallel those of adult tertiary syphilis.
found in the mouth and on the genitalia, described as
'snail track ulcers' Investigations for diagnosis
■ Acute neurological signs in less than 10% of cases (e.g. Treponema pallidum is not amenable to in vitro culture
aseptic meningitis). -the most sensitive and specific method is identification by
Untreated early syphilis in pregnant women leads to fetal dark-ground microscopy. Organisms may be found in
infection in at least 70% of cases and may result in variable numbers, from primary chancres and the
stillbirth in up to 30%. mucous patches of secondary lesions. Individuals with
either primary or secondary disease are highly infectious.
Latent Serological tests used in diagnosis are either treponemal-
Without treatment, symptoms and signs abate over specific or non-specific (cardiolipin test) (Table 2.50):
3-12 weeks, but in up to 20% of individuals may recur ■ Treponemal specific. The T. pallidum enzyme
immunoassay (EIA). T. pallidum haemagglutination or
particle agglutination assay (TPHA/TPPA) and
fluorescent treponemal antibodies absorbed (FTA-abs)
Infectious diseases, tropical medicine and sexually transmitted diseases
HSS5HBH

Table 2.50 Syphilis serology


Stage of infection Results
EIA FTA-abs TPHA/TPPA VDRL/RPR
Very early
primary +
Early primary
Primary
Secondary or
latent
Late latent
Treated
Biological
false-positive
EIA, enzyme immunoassay; FTA-abs, fluorescent Treponema antibodies absorbed; TPHA/TPPA, Treponema pallidum haemagglutination/particle
agglutination assay; VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin
test are both highly specific for treponemal disease but doxycycline 200 mg daily or erythromycin 500 mg four
will not differentiate between syphilis and other times daily is given orally for 2-4 weeks depending on
treponemal infection such as yaws. These tests usually the stage of the infection. Non-compliant patients can be
remain positive for life, even after treatment. ■ treated with a single dose of benzathine penicillin G 2.4 g
Treponemal non-specific. The Venereal Disease intramuscularly. These long-acting penicillins are not
Research Laboratory (VDRL) and rapid plasma reagin generally available in the UK but are imported directly by
(RPR) tests are non-specific, becoming positive within 3- GUM clinics.
4 weeks of the primary infection. They are quantifiable tests The Jarisch-Herxheimer reaction, which is due to release
which can be used to monitor treatment efficacy and are of TNF-oc, IL-6 and IL-8, is seen in 50% of patients with
helpful in assessing disease activity. They generally primary syphilis and up to 90% of patients with
become negative by 6 months after treatment in early secondary syphilis. It occurs about 8 hours after the first
syphilis. The VDRL may also become negative in injection and usually consists of mild fever, malaise and
untreated patients (50% of patients with late-stage headache lasting several hours. In cardiovascular or
syphilis) or remain positive after treatment in late stage. neurosyphilis the reaction, although rare, may be severe
False-positive results may occur in other conditions - and exacerbate the clinical manifestations. Prednisolone
particularly infectious mononucleosis, hepatitis, given for 24 hours prior to therapy may ameliorate the
Mycoplasma infections, some protozoal infections, reaction but there is little evidence to support its use.
cirrhosis, malignancy, autoimmune disease and chronic Penicillin should not be withheld because of the Jarisch-
infections. Herxheimer reaction; since it is not a dose-related
phenomenon, there is no value in giving a smaller dose.
The EIA is the screening test of choice and can detect both
The prognosis depends on the stage at which the
IgM and IgG antibodies. A positive test is then confirmed
infection is treated. Early and early latent syphilis have an
with the TPHA/TPPA and VDRL/RPR tests. All serological
excellent outlook but once extensive tissue damage has
investigations may be negative in early primary syphilis;
occurred in the later stages the damage will not be
the EIA IgM and the FTA-abs being the earliest tests to be
reversed although the process may be halted. Symptoms
positive. The diagnosis will then hinge on positive dark-
in cardiovascular and neurosyphilis may therefore persist.
ground microscopy, and treatment should not be delayed
All patients treated for early syphilis must be followed
if serological tests are negative in such situations.
up at regular intervals for the first year following
In certain cases, examination of the CSF for evidence of
treatment. Serological markers should be followed and a
neurosyphilis and a chest X-ray to determine the extent of
fall in titre of the VDRL/RPR of at least fourfold is
cardiovascular disease will be indicated.
consistent with adequate treatment for early syphilis. The
sexual partners of all patients with syphilis and the
Treatment parents and siblings of patients with congenital syphilis
Treponemocidal levels of antibiotic must be maintained must be contacted and screened. Babies born to mothers
in serum for at least 7 days in early syphilis to cover the who have been treated for syphilis in pregnancy are
slow division time of the organism (30 hours). In late retreated at birth.
syphilis treponemes may divide even more slowly
requiring longer therapy.
Early syphilis (primary or secondary) should be treated
with long-acting penicillin such as procaine benzyl-
Chancroid
penicillin (procaine penicillin) (e.g. Jenacillin A which Chancroid or soft chancre is an acute STI caused by
also contains benzylpenicillin) 600 mg intramuscularly Haemophilus ducreyi. It is probably the commonest cause
daily for 10 days. For late-stage syphilis, particularly of genital ulceration world-wide, and is prevalent in parts
when there is cardiovascular or neurological involve- of Africa and Asia. Epidemiological studies in Africa have
ment, the treatment course should be extended for a shown an association between genital ulcer disease,
further week. For patients sensitive to penicillin, either frequently chancroid, and the acquisition of HIV infec-
124
Sexually transmitted infections

tion. A new urgency to control chancroid has resulted painful. Almost any cutaneous or mucous membrane site
from these observations. can be involved, including the mouth and anorectal
regions. Extension of the primary infection from the
Clinical features external genitalia to the inguinal regions produces the
The incubation period is 3-10 days. At the site of characteristic lesion, the 'pseudo-bubo'.
inoculation an erythematous papular lesion forms which
then breaks down into an ulcer. The ulcer frequently has Diagnosis and treatment
a necrotic base, a ragged edge, bleeds easily and is pain- The clinical appearance usually strongly suggests the
ful. Several ulcers may merge to form giant serpiginous diagnosis but K. granulomatis (Donovan bodies) can be
lesions. Ulcers appear most commonly on the prepuce identified intracellularly in scrapings or biopsies of an
and frenulum in men and can erode through tissues. In ulcer. Successful culture has only recently been reported
women the most commonly affected site is the vaginal and PCR techniques and serological methods of diagnosis
entrance and the perineum. The lesions in women some- are being developed, but none is routinely available.
times go unnoticed. Antibiotic treatment should be given until the lesions
At the same time, inguinal lymphadenopathy develops have healed. A minimum of 3 weeks' treatment is rec-
(usually unilateral) and can progress to form large buboes ommended. Regimens include doxycycline 100 mg twice
which suppurate. daily, co-trimoxazole 960 mg twice daily, azithromycin
500 mg daily or 1 g weekly, or ceftriaxone 1 g daily.
Diagnosis and treatment Sexual partners should be examined and treated if
Chancroid must be differentiated from other genital ulcer necessary.
diseases (see Table 2.48). Co-infection with syphilis and
herpes simplex is common. Isolation of H. ducreyi in Herpes simplex (p. 43)
specialized culture media is definitive but difficult. Swabs
should be taken from the ulcer and material aspirated Genital herpes is one of the most common STIs world-
from the local lymph nodes for culture. Polymerase chain wide. Between 1997 and 2002 there has been a 17%
reaction (PCR) techniques are available. Gram stains of increase in diagnoses of genital herpes in the UK. The
clinical material may show characteristic coccobacilli. peak incidence is in 16- to 24-year-olds of both sexes.
Single-dose regimens include azithromycin 1 g orally Infection may be either primary or recurrent. Trans-
or ceftriaxone 250 mg i.m. Other regimens include mission occurs during close contact with a person who is
ciprofloxacin 500 mg twice daily for 3 days, erythromycin shedding virus. Most genital herpes is due to type 2.
500 mg four times daily for 7 days. Clinically significant Genital contact with oral lesions caused by HSV-1 can
plasmid-mediated antibiotic resistance in H. ducreyi is also produce genital infection.
developing. Susceptible mucous membranes include the genital
Patients should be followed up at 3-7 days, when if tract, rectum, mouth and oropharynx. The virus has the
treatment is successful ulcers will be responding. ability to establish latency in the dorsal root ganglia by
Sexual partners should be examined and treated epi- ascending peripheral sensory nerves from the area of
demiologically, as asymptomatic carriage has been inoculation. It is this ability which allows for recurrent
reported. attacks.
HIV-infected patients should be closely monitored, as
healing may be slower. Multiple-dose regimens are Clinical features
needed in HIV patients since treatment failures have been Asymptomatic infection has been reported but is rare.
reported with single-dose therapy. Primary genital herpes is usually accompanied by
systemic symptoms of varying severity including fever,
myalgia and headache. Multiple painful shallow ulcers
Donovanosis develop which may coalesce (Fig. 2.43). Atypical lesions
Donovanosis is the least common of all STIs in North are common. Tender inguinal lymphadenopathy is usual.
America and Europe, but is endemic in the tropics and Over a period of 10-14 days the lesions develop crusts
subtropics, particularly the Caribbean, South East Asia and dry. In women with vulval lesions the cervix is
and South India. Infection is caused by Klebsiella almost always involved. Rectal infection may lead to a
gmnulomatis, a short, encapsulated Gram-negative bacillus. florid proctitis. Neurological complications can include
The infection was also known as granuloma inguinale. aseptic encephalitis and/or involvement of the sacral
Although sexual contact appears to be the most usual autonomic plexus leading to retention of urine.
mode of transmission, the infection rates are low, even Recurrent attacks occur in a significant proportion of
between sexual partners of many years' standing. people following the initial episode. Precipitating factors
vary, as does the frequency of recurrence. A symptom
Clinical features prodrome is present in some people prior to the appear-
In the vast majority of patients, the characteristic, heaped- ance of lesions. Systemic symptoms are rare in recurrent
up ulcerating lesion with prolific red granulation tissue attacks.
appears on the external genitalia, perianal skin or the The clinical manifestations in immunosuppressed
inguinal region within 1-4 weeks of exposure. It is rarely patients (including those with HIV) may be more severe,
Infectious diseases, tropical medicine and sexually transmitted diseases
Fig. HSV in pregnancy
2.43 The potential risk of infection to the neonate needs to be
considered in addition to the health of the mother. Infec-
tion occurs either transplacentally or via the birth canal. If
HSV is acquired for the first time during pregnancy,
transplacental infection of the fetus may, rarely, occur.
Management of primary HSV in the first or second
trimester will depend on the woman's clinical condition
and aciclovir can be prescribed in standard doses.
Aciclovir therapy during the last 4 weeks of pregnancy
may prevent recurrence at term.
Primary acquisition in the third trimester or at term
with high levels of viral shedding usually leads to
Herpes simplex rash on the penis. Courtesy of delivery by caesarean section.
For women with previous infection, concern focuses
on the baby acquiring HSV from the birth canal. The risk
asymptomatic shedding increased, and recurrences occur is very low in recurrent attacks. For women with recur-
with greater frequency. Systemic spread has been rent episodes, only those with genital lesions at the onset
documented (see p. 139). of labour are delivered by caesarean section. Sequential
cultures during the last weeks of pregnancy to predict
Diagnosis viral shedding at term are no longer indicated.
Although the history and examination can be highly
suggestive of HSV infection, a firm diagnosis can be made Prevention and control
only on the basis of isolation of virus from lesions. Swabs Patients must be advised that they are infectious when
should be taken from the base of lesions and placed in lesions are present; sexual intercourse should be avoided
viral transport medium. Virus is most easily isolated from during this time or during prodromal stages. Condoms
new lesions. Type-specific immune responses can be may not be effective as lesions may occur outside the
found 8-12 weeks following primary infection and may areas covered. Sexual partners should be examined and
form the basis for newer serological assays, although may need information on avoiding infection.
these are not yet available in routine clinical practice.

Management Warts
Primary Anogenital warts are amongst the most common sexually
Saltwater bathing or sitting in a warm bath is soothing acquired infections. The causative agent is human papillo-
and may allow the patient to pass urine with some degree mavirus (HPV) especially types 6 and 11 (p. 48). HPV is
of comfort. Aciclovir 200 mg five times daily, famciclovir acquired by direct sexual contact with a person with either
250 mg three times daily or valaciclovir 500 mg twice clinical or subclinical infection. Genital HPV infection is
daily, all for 5 days, are useful if patients are seen whilst common, with only a small proportion of those infected
new lesions are still forming. If lesions are already crust- being symptomatic. Neonates may acquire HPV from an
ing, antiviral therapy will do little to change the clinical infected birth canal, which may result either in anogenital
course. Secondary bacterial infection occasionally occurs warts or in laryngeal papillomas. The incubation period
and should be treated. Rest, analgesia and antipyretics ranges from 2 weeks to 8 months or even longer.
should be advised. In rare instances patients may need to
be admitted to hospital and aciclovir given intravenously, Clinical features
particularly if HSV encephalitis is suspected. Warts develop around the external genitalia in women,
usually starting at the fourchette, and involve the
Recurrence perianal region. The vagina may be infected. Flat warts
Recurrent attacks tend to be less severe and can be may develop on the cervix and are not easily visible on
managed with simple measures such as saltwater bath- routine examination. Such lesions are associated with
ing. Psychological morbidity is associated with recurrent cervical intraepithelial neoplasia. In men the penile shaft
genital herpes and frequent recurrences impose strains on and subpreputial space are the most common sites,
relationships; patients need considerable support. Long- although warts involve the urethra and meatus. Perianal
term suppressive therapy is given in patients with lesions are more common in men who practise ano-
frequent recurrences. An initial course of aciclovir 400 mg receptive intercourse but can be found in any patient. The
twice daily or valaciclovir 250 mg twice daily for rectum may become involved. Warts become more florid
6-12 months significantly reduces the frequency of during pregnancy or in immunosuppressed patients.
attacks, although there may still be some breakthrough.
Therapy should be discontinued after 12 months and the Diagnosis
frequency of recurrent attacks reassessed. The diagnosis is essentially clinical. It is critical to
differentiate condylomata lata of secondary syphilis.
126
Sexually transmitted infections
2
Unusual lesions should be biopsied if the diagnosis is in cytes are also seen. Culture techniques are good and
doubt. Up to 30% of patients have coexisting infections confirm the diagnosis. Trichomonas is sometimes observed
with other STIs and a full screen must be performed. on cervical cytology with a 60-80% accuracy in diagnosis.
New, highly sensitive and specific tests based on poly-
Treatment merase chain reactions are in development.
Significant failure and relapse rates are seen with current Metronidazole is the treatment of choice, either 2 g
treatment modalities. Choice of treatment will depend on orally as a single dose or 400 mg twice-daily for 7 days.
the number and distribution of lesions. Local agents, There is some evidence of metronidazole resistance and
including podophyllin extract (15-25% solution, once or nimorazole may be effective in these cases. Topical
twice weekly), podophyllotoxin (0.5% solution or 1.5% therapy with intravaginal tinidazole can be effective, but
cream in cycles), and trichloroacetic acid, are useful for if extravaginal infection exists this may not be eradicated
non-keratinized lesions. Those that are keratinized and vaginal infection reoccurs. Male partners should be
respond better to physical therapy, e.g. cryotherapy, treated, especially as they are likely to be asymptomatic
electrocautery or laser ablation. Imiquimod (5% cream and more difficult to detect. i ■■->■■:
used three times a week) is indicated in both types.
Podophyllin, podophyllotoxin and imiquimod are not
advised in pregnancy.
Candidiasis_____________________ ^ _ ^
Sexual contacts should be examined and treated if Vulvovaginal infection with Candida albicans is extremely
necessary. In view of the difficulties of diagnosing common. The organism is also responsible for balanitis in
subclinical HPV, condoms should be used for up to men. Candida can be isolated from the vagina in a high
8 months after treatment. Because of the association of proportion of women of childbearing age, many of whom
HPV with cervical intraepithelial neoplasia, women with will have no symptoms.
warts and female partners of men with warts are advised The role of Candida as pathogen or commensal is
to have regular cervical screening, i.e. every 3 years. difficult to disentangle and it may be changes in host
Colposcopy may be useful in women with vaginal and environment which allow the organism to produce
cervical warts. pathological effects. Predisposing factors include preg-
nancy, diabetes, and the use of broad-spectrum antibiotics
and corticosteroids. Immunosuppression can result in
Hepatitis B more florid infection.
____________________________________
This is discussed in Chapter 7. Sexual contacts should be Clinical features
screened and given vaccine if they are not immune (see In women, pruritus vulvae is the dominant symptom.
p. 366). • - ■ , . ■ ■ Vaginal discharge is present in varying degree. Many
women have only one or occasional isolated episodes.
Recurrent candidiasis (four or more symptomatic
Trichomoniasis episodes annually) occurs in up to 5% of healthy women
Trichomonas vaginalis (TV) is a flagellated protozoon of reproductive age. Examination reveals erythema and
which is predominantly sexually transmitted. It is able to swelling of the vulva with broken skin in severe cases.
attach to squamous epithelium and can infect the vagina The vagina may contain adherent curdy discharge. Men
and urethra. Trichomonas may be acquired perinatally in may have a florid balanoposthitis. More commonly, self-
babies born to infected mothers. limiting burning penile irritation immediately after
Infected women may, unusually, be asymptomatic. sexual intercourse with an infected partner is described.
Commonly the major complaints are of vaginal discharge Diabetes must be excluded in men with balanoposthitis.
which is offensive and of local irritation. Men usually
present as the asymptomatic sexual partners of infected Diagnosis
women, although they may complain of urethral dis- Microscopic examination of a smear from the vaginal wall
charge, irritation or urinary frequency. reveals the presence of spores and mycelia. Culture of
Examination often reveals a frothy yellowish vaginal swabs should be undertaken but may be positive in
discharge and erythematous vaginal walls. The cervix women with no symptoms. Trichomonas and bacterial
may have multiple small haemorrhagic areas which lead vaginosis must be considered in women with itch and
to the description 'strawberry cervix'. Trichomonas infec- discharge.
tion in pregnancy has been associated with preterm
delivery and low birth-weight. Treatment
Topical. Pessaries or creams containing one of the
imidazole antifungals such as clotrimazole 500 mg single
Diagnosis and treatment dose used intravaginally are usually effective. Nystatin is
Phase-contrast, dark-ground microscopy of a drop of also useful.
vaginal discharge shows TV swimming with a charac-
teristic motion in 40-80% of female patients. Similar Oral. The triazole drugs such as fluconazole 150 mg as
preparations from the male urethra will only be positive a single dose or itraconazole 200 mg twice in 1 day are
in about 30% of cases. Many polymorphonuclear leuco-
127
Infectious diseases, tropical medicine and sexually transmitted diseases
used systemically where topical therapy has failed or is tomatic women who fulfil the diagnostic criteria for BV.
inappropriate. Recurrent candidiasis may be treated with The diagnosis should be fully discussed and treatment
fluconazole 100 mg weekly for 6 months, or clotrimazole offered if the woman wishes. Until the relevance of BV to
pessary 500 mg weekly for 6 months. other pelvic infections is elucidated, the treatment of
The evidence for sexual transmission of Candida is asymptomatic women with BV is not to be recommended.
slight and there is no evidence that treatment of male There is no convincing evidence that simultaneous treat-
partners reduces recurrences in women. ment of the male partner influences the rate of recurrence
of BV, and routine treatment of male partners is not
Bacterial vaginosis___________________ indicated.

Bacterial vaginosis (BV) is a disorder characterized by an


offensive vaginal discharge. The aetiology and patho- INFESTATIONS (see also p. 1326)
genesis are unclear but a mixed flora of Gardnerella
vaginalis, anaerobes including Bacteroides, Mobiluncus spp. Pediculosis pubis
and Mycoplasma hominis, replaces the normal lactobacilli The pubic louse (Phthirus pubis) is a blood-sucking insect
of the vagina. Amines and their breakdown products which attaches tightly to the pubic hair. They may also
from the abnormal vaginal flora are thought to be respon- attach to eyelashes and eyebrows. It is relatively host-
sible for the characteristic odour associated with the con- specific and is transferred only by close bodily contact.
dition. As vaginal inflammation is not part of the syndrome Eggs (nits) are laid at hair bases and usually hatch within
the term vaginosis is used rather than vaginitis. The a week. Although infestation may be asymptomatic the
condition has been shown to more common in black most common complaint is of itch.
women than in white. It is not regarded as a sexually
transmitted disease. Diagnosis
Lice may be seen on the skin at the base of pubic and
Clinical features other body hairs. They resemble small scabs or freckles
Vaginal discharge and odour are the most common but if they are picked up with forceps and placed on a
complaints although a proportion of women are asymp- microscope slide will move and walk away. Blue macules
tomatic. A homogeneous, greyish white, adherent dis- may be seen at the feeding sites. Nits are usually closely
charge is present in the vagina, the pH of which is raised adherent to hairs. Both are highly characteristic under the
(greater than 5). Associated complications are ill-defined low-power microscope.
but may include chorioamnionitis and an increased As with all sexually transmitted infections, the patient
incidence of premature labour in pregnant women. must be screened for coexisting pathogens.
Whether BV disposes non-pregnant women to upper
genital tract infection is unclear. Treatment
Both lice and eggs must be killed with 0.5% malathion,
Diagnosis 1% permethrin or 0.5% carbaryl. The preparation should
Different authors have differing criteria for making the be applied to all areas of the body from the neck down
diagnosis of BV. In general it is accepted that three of the and washed off after 12 hours. In a few cases a further
following should be present for the diagnosis to be made: application after 1 week may be necessary. For severe
■ characteristic vaginal discharge infestations, antipruritics may be indicated for the first
■ the amine test: raised vaginal pH using narrow-range 48 hours. All sexual partners should be seen and screened.
indicator paper (> 4.7)
■ a fishy odour on mixing a drop of discharge with 10% Scabies
potassium hydroxide
This is discussed on page 1325.
■ the presence of clue cells on microscopic examination
of the vaginal fluid.
Clue cells are squamous epithelial cells from the vagina FURTHER READING
Adler M (2004) The ABC of Sexually Transmitted Diseases,
which have bacteria adherent to their surface, giving a
5th edn. London: BMA Books.
granular appearance to the cell. A Gram stain gives a British Association of Sexual Health and HIV. Clinical
typical reaction of partial stain uptake. effectiveness guidelines: http://www.bashh.org/
guidelines/ceguidelines.htm August 2004.
Treatment Brown AE, Sadler KE, Tomkins SE et al. (2004) Recent
Metronidazole given orally in doses of 400 mg twice daily trends in HIV and other STIs in the United Kingdom:
for 5-7 days is usually recommended. A single dose of data to the end of 2002. Sexually Transmitted Infections
2 g metronidazole is less effective. Topical 2% clindamycin 80(3): 159-166.
cream 5 g intravaginally once daily for 7 days is effective. Centers for Disease Control and Prevention (2002)
Recurrence is high, with some studies giving a rate of Sexual assault and STDs. Sexually transmitted
diseases treatment guidelines. MMWR
80% within 9 months of completing metronidazole
Recommendations and Reports 51(RR-6): 69-74.
therapy. There is debate over the treatment of asymp-
128
Human immune deficiency virus (HIV) and AIDS
Donovan B (2004) Sexually transmissible infections other Sexual intercourse (vaginal and anal)
than HIV. Lancet 363(9408): 545-556. Globally, heterosexual intercourse accounts for the vast
Health Protection Agency (2003). Renewing the Focus: HIV majority of infections, and coexistent STIs, especially
and Other Sexually Transmitted Infections in the United those causing genital ulceration, enhance transmission.
Kingdom in 2002. London: HPA.
Passage of HIV appears to be more efficient from men to
Klausner JD, Kent CK (2004) HIV and sexually
transmitted diseases. Latest views on synergy, women, and to the passive partner in anal intercourse,
treatment, and screening. Postgraduate Medicine 115(4): than vice versa.
79-84. In the UK, sex between men still accounts for over half
Lacey, H (2001) National Guidelines on the Management of the infections reported, but there is an increasing rate of
Adult Victims of Sexual Assault. Online. Available: heterosexual transmission. Between 2000 and 2003 53% of
http://www.bashh.org/guidelines/ceguidelines. htm new diagnoses were a result of heterosexual exposure,
(accessed August 2004). frequently in high-endemicity countries. Of these infec-
tions, 67% were in women compared to 5% in the late
1980s. In central and sub-Saharan Africa the epidemic has
always been heterosexual and more than half the infected
adults in these regions are women. South East Asia and
the Indian subcontinent are experiencing an explosive
HUMAN IMMUNE DEFICIENCY epidemic, driven by heterosexual intercourse and a high
incidence of other sexually transmitted diseases.
VIRUS (HIV) AND AIDS
Mother to child (parentally, perinatally, breast-
Epidemiology
feeding)
HIV, the cause of the acquired immune deficiency Vertical transmission is the most common route of HIV
syndrome (AIDS), continues to spread, being described infection in children. European studies suggest that,
as a global health emergency by the World Health without intervention, 15% of babies born to HIV-infected
Organization (WHO) in 2003. UNAIDS estimates for 2002 mothers are likely to be infected, although rates of up to
are that 41 million people are infected with HIV world - 40% have been reported from Africa and the USA.
wide, over 70% of whom are in sub-Saharan Africa. Increased vertical transmission is associated with
Approximately 16 000 new infections occur daily, the advanced disease in the mother, maternal viral load,
majority in young adults. HIV is now the leading single prolonged and premature rupture of membranes, and
cause of death in adults, causing 5 million deaths in 2003. chorioamnionitis. Transmission can occur in utero
In sub-Saharan Africa 5000 men and women and 1000 although the majority of infections take place perinatally.
children die of HIV every 24 hours. Dramatic rises in Breast-feeding has been shown to increase the risk of
infection have been seen in SE Asia with eastern Europe vertical transmission by up to 20%. In the developed
and Russia having the most rapidly expanding epidemic world interventions to reduce vertical transmission,
in 2003. including the use of antiretroviral agents, delivery by
The human and economic costs are huge - 33% of 15- caesarean section and the avoidance of breast-feeding
year-olds in high-prevalence countries in Africa will die have led to a dramatic fall in the numbers of infected
of HIV, life expectancy in African countries is falling with children. The lack of access to these interventions in
an inevitable impact on the fabric of society and on resource-poor countries in which 90% of infections occur
economic growth and stability. The advent of more is a major issue.
effective therapy for HIV has brought geographical
differences in the impact of the epidemic into stark relief, Contaminated blood, blood products and organ
with falling mortality and morbidity in resource-rich donations
settings that are unmatched in poorer parts of the world. Screening of blood and blood products was introduced in
Although in the UK and other wealthy countries deaths 1985 in Europe and North America. Prior to this, HIV
from HIV have fallen, new diagnoses are rising sharply. infection was associated with the use of clotting factors
At least 5000 new diagnoses were recorded in the UK in (for haemophilia) and with blood transfusions. In some
2003, a 20% increase over the preceding year, and the developing countries where blood is not screened or
highest annual number since surveillance began, with the treated, and in areas where the rate of new HIV infections
result that prevalence is rising. Demographics have is very high, transfusion-associated transmission remains
varied greatly within different regions influenced by significant.
social, behavioural, cultural and political factors. Despite
the fact that HIV can be isolated from a wide range of Contaminated needles (intravenous drug misuse,
body fluids and tissues, the majority of infections are
injections, needle-stick injuries)
transmitted via semen, cervical secretions and blood. The
The practice of sharing needles and syringes for intra-
character of the epidemic in different regions of the world
venous drug use continues to be a major route of trans-
has been influenced by the relative frequency of each of
mission of HIV in both developed countries and parts of
the routes of transmission.
South East Asia, Latin America and the states of the
former Soviet Union. In some areas, including the UK,
129
Infectious diseases, tropical medicine and sexually transmitted diseases
successful education and needle exchange schemes have central and sub-Saharan Africa have multiple M
reduced the rate of transmission by this route. Iatrogenic subtypes.
transmission from needles and syringes used in develop- ■ Group O (outlier) subtypes. These are highly divergent
ing countries is reported. Healthcare workers have a risk from group M and are confined to small numbers
of approximately 0.3% following a single needle-stick centred on the Cameroons.
injury with known HIV infected blood.
There is no evidence that HIV is spread by social or Recombination of viral material generates an array of
household contact or by blood-sucking insects such as circulating recombinant forms (CRFs), which increases
mosquitoes and bed bugs. the genetic diversity that may be encountered.
Connections between genetic diversity and biological
effects, in particular pathogenicity, rates of transmission
The virus and response to therapy, are being sought.
HIV belongs to the lentivirus group of the retrovirus
family. There are at least two types, HIV-1 and HIV-2. Pathogenesis
HIV-2 is almost entirely confined to West Africa although The interrelationship between HIV and the host immune
there is evidence of some spread to the Indian sub - system is the basis of the pathogenesis of HIV disease.
continent. HIV-2 is associated with an AIDS-type illness The host cellular receptor that is recognized by HIV
although it may be more indolent in nature. The structure surface glycoprotein is the CD4 molecule, which defines
of the virus is shown in Figure 2.44. the cell populations that are susceptible to infection (Fig.
Retroviruses are characterized by the possession of the 2.45). The interaction between CD4 and HIV surface
enzyme reverse transcriptase, which allows viral RNA to glycoprotein together with chemokine co-receptors CCR5
be transcribed into DNA, and thence incorporated into and CXCR4 is responsible for HIV entry into cells.
the host cell genome. Reverse transcription is an error- Mutations in the gene expressing the receptor for
prone process with a significant rate of misincorporation chemokine CCR5 may impair entry of HIV into cells and
of bases. This, combined with a high rate of viral turn - therefore confer some resistance to this infection.
over, leads to considerable genetic variation and a Auxiliary viral proteins such as those coded by the Nef
diversity of viral subtypes or clades. On the basis of DNA gene have a role in influencing host cell membrane
sequencing, HIV-1 is divided into two subtypes: proteins and signal transduction pathways. CD4 receptors
and HIV surface glycoprotein interactions mediate the
■ Group M (major) subtypes. There are at least 10, which
process of syncytium formation, which is a cytopathic
are denoted A-J. There is a predominance of subtype B
effect of HIV infection.
in Europe, North America and Australia, but areas of
Studies of viral turnover in HIV-infected individuals
have demonstrated a virus half-life in the circulation of
Reverse p17,
about 6 hours. To maintain observed levels of plasma
matrix viraemia, 108-109 virus particles need to be released and
transcriptase cleared daily. Virus production by infected cells lasts for
about 2 days and is probably limited by the death of the
cell, owing to direct HIV effects, linking HIV replication
Lipid layer to the process of CD4 destruction and depletion. Studies
suggest that immunopathogenesis is a result of defective
T cell homeostasis in HIV infection. The progressive and
severe depletion of CD4 helper lymphocytes has pro-
found repercussions for the functioning of the immune
RNA system (see p. 1218). Cell-mediated immunodeficiency,
which is the major consequence, leaves the host open to
infections with intracellular pathogens, whilst the co-
Protease existing antibody abnormalities predispose to infections
with capsulated bacteria. HIV also has a direct effect on
certain tissues, notably the nervous system.

gp160 Diagnosis and natural history (Fig 2 46)


p24, core HIV infection is diagnosed either by the detection of
virus-specific antibodies (anti-HIV) or by direct identifi-
Fig. 2.44 Structure of HIV. Two molecules of single- cation of viral material.
stranded RNA are shown within the nucleus. The reverse
transcriptase polymerase converts viral RNA into DNA (a
characteristic of retroviruses). The protease includes integrase
Detection of IgG antibody to envelope components
(p32 and p10). The p24 (core protein) levels can be used to (gp!20 and its subunits). This is the most commonly
monitor HIV disease. p17 is the matrix protein. gp120 is the used marker of infection. The routine tests used for
outer envelope glycoprotein which binds to cell surface CD4 screening are based on ELISA techniques, which may be
molecules. gp41, a transmembrane protein, influences confirmed with Western blot assays. Up to 3 months
infectivity and cell fusion capacity.
130
Human immune deficiency virus (HIV) and AIDS
LYMPHOCYTE

of virally encoded
DNA into host genome

\\ Structural proteins
^ , p 2 4 , p 1 7

Fig. 2.45 HIV entry and replication in CD4 T lymphocytes. The human immune deficiency virus binds to the host
CD4 inoculate via the envelope giycoprotein gp120. gp41 binds to the cell chemokine causing receptor fusion and uncoating
of RNA. DNA copies are made from both RNA templates (reverse transcriptase). The enzyme polymerase from the host cell
leads to formation of dsDNA. In the nucleus the virally encoded DNA is inserted into the host genome (integration).
Regulatory proteins control transcription (a process in which an RNA molecule is synthesized from a DNA template). The
virus is reassembled in the cytoplasm and budded out from the host cell.
6weeks-10years a reliable marker of active infection, and in uninfected
(average) babies will be gradually lost over the first 18 months
of life.
Other than in exceptional circumstances, HIV anti-
body testing should be carried out only after full dis-
cussion of the implications with the patient and with the
patient's express consent.
Simple and rapid HIV antibody assays are increasingly
available, giving results within hours. Such assays are
easy to perform and require little or no additional equip-
ment. They are designed for use with individual or a
limited number of samples, Assays that can utilize alter-
i i i i r
12 years |" 612 native body fluids to serum/plasma such as saliva, whole
12 3 4 5 6
Weeks (average) M Weeks blood and urine are becoming accessible.
A serologic testing algorithm for recent HIV sero-
Antiretroviral conversions (STARHS) can be used to identify recently
therapy
acquired infection. A highly sensitive ELISA that is able to
Fig. 2.46 The immune response to HIV (seroconversion). detect HIV antibodies 6-8 weeks after infection is paired
with a less sensitive (detuned) test that identifies later
may elapse from initial infection to antibody detection HIV antibodies within 130 days. A positive result on the
(serological latency, or window period). These antibodies to sensitive test and a negative 'detuned' test are indicative
HIV have no protective function and persist for life. As with of recent infection, whilst positive results on both tests
all IgG antibodies, anti-HIV will cross the placenta. All point to an infection that is more than 130 days old. The
babies born to HIV-infected women will thus have the major application of this is in epidemic surveillance and
antibody at birth. In this situation, anti-HIV antibody is not monitoring.
131
Infectious diseases, tropical medicine and sexually transmitted diseases
IgG antibody to p24 (anti-p24). This can be detected Box2.17 AIDS-defining conditions
from the earliest weeks of infection and through the
asymptomatic phase. It is frequently lost as disease Candidiasis of bronchi, trachea or lungs
Candidiasis, oesophageal
progresses.
Cervical carcinoma, invasive
Coccidioidomycosis, disseminated or extrapulmonary
Antigen assays. Nucleic acid-based assays are avail- Cryptococcosis, extrapulmonary
able which amplify and test for components of the HIV Cryptosporidiosis, chronic intestinal (1-month
genome. These assays are used to aid diagnosis of HIV in duration)
the babies of HIV-infected mothers or in situations where Cytomegalovirus (CMV) disease (other than liver,
serological tests may be inadequate, such as subtyping spleen or nodes)
HIV variants for medicolegal reasons. (See the discussion CMV retinitis (with loss of vision) |
of viral load monitoring, p. 143.) Encephalopathy, HIV-related
Herpes simplex, chronic ulcers (1-month duration); or
bronchitis, pneumonitis or oesophagitis
Viral p24 antigen (p24ag). This is detectable shortly Histoplasmosis, disseminated or extrapulmonary
after infection but has usually disappeared by 8-10 weeks Isosporiasis; chronic intestinal (1-month duration)
after exposure. It can be a useful marker in individuals Kaposi's sarcoma
who have been infected recently but have not had time to Lymphoma, Burkitt's
mount an antibody response. Lymphoma, immunoblastic (or equivalent term)
Lymphoma (primary) of brain
Isolation of Virus in culture. This is a specialized tech- Mycobacterium avium-intracellulare complex or
nique available in some laboratories to aid diagnosis and M. kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis, any site
as a research tool.
Mycobacterium, other species or unidentified species,
disseminated or extrapulmonary |
CLINICAL FEATURES OF HIV INFECTION Pneumocystis carinii pneumonia 1
Pneumonia, recurrent
The spectrum of illnesses associated with HIV infection is Progressive multifocal leucoencephalopathy
broad and is the result of both direct HIV effects and the Salmonella septicaemia, recurrent
associated immune dysfunction. Several classification Toxoplasmosis of brain
systems exist, the most widely used being the 1993 Wasting syndrome, due to HIV
Centers for Disease Control (CDC) classification (Box
2.16). This classification depends to a large extent on
definitive diagnoses of infection, which makes it more
difficult to use in those areas of the world without Incubation
sophisticated laboratory support. As immunosuppression The 2-4 weeks immediately following infection are
progresses the patient is susceptible to an increasing usually silent both clinically and serologically.
range of opportunistic infections and tumours, certain of
which meet the criteria for the diagnosis of AIDS Seroconversion/primary illness
(Box 2.17). The majority of HIV seroconversions are also clinically
Since 1993 the definition of AIDS has differed between silent. In a proportion, a self-limiting non-specific illness
the USA and Europe. The USA definition includes indivi- occurs 6-8 weeks after exposure. Symptoms include fever,
duals with CD4 counts below 200 in addition to the arthralgia, myalgia, lethargy, lymphadenopathy, sore
clinical classification based on the presence of specific throat, mucosal ulcers and occasionally a transient faint
indicator diagnoses shown in Box 2.17. In Europe the pink maculopapular rash. Neurological symptoms are
definition remains based on the diagnosis of specific common, including headache, photophobia, myelopathy,
clinical conditions with no inclusion of CD4 lymphocyte neuropathy and in rare cases encephalopathy. The illness
counts. lasts up to 3 weeks and recovery is usually complete.
132 Sox 2.16 Summary of CDC classification of HIV infection
Absolute CD4 count A: Asymptomatic OR persistent B: HIV-related conditions,* C: Clinical conditions
(/mm3) generalized lymphadenopathy not A or C listed in AIDS
OR acute seroconversion surveillance case
illness definition (see Box 2.17)
>500 A1 B1 C1
200-499 A2 B2 C2
<200 A3 B3 C4
* Examples of category B conditions include: bacillary angiomatosis, candidiasis (oropharyngeal), constitutional symptoms, oral hairy
leucoplakia, herpes zoster invoiving more than one dermatome, idiopathic thrombocytopenic purpura, listeriosis, pelvic inflammatory disease
especially if complicated by tubo-ovarian abscess, peripheral neuropathy
Human immune deficiency virus (HIV) and AIDS
Laboratory abnormalities include lymphopenia with < 100/mm3) disseminated infections with organisms
atypical reactive lymphocytes noted on blood film, of very low virulence such as M. avium-intracellulare
thrombocytopenia and raised liver enzymes. CD4 (MAI) and Cryptosporidium are able to establish them-
lymphocytes may be markedly depleted and the CD4 : selves. These infections are very resistant to treatment,
CD8 ratio reversed. Antibodies to HIV may be absent mainly because there is no functioning immune
during this early stage of infection, although the level of response to clear organisms. This hierarchy of infection
circulating viral RNA is high and p24 core protein may be allows for appropriate intervention with prophylactic
detectable. Patients experiencing a seroconversion illness drugs.
may have a more rapidly progressive course of infection.
EFFECTS OF HIV INFECTION
Clinical latency am

The majority of people with HIV infection are asymp- Neurological disease
tomatic for a substantial but variable length of time. Infection of the nervous tissue occurs at an early stage but
However, the virus continues to replicate and the person clinical neurological involvement increases as HIV
is infectious. Studies suggest a median time of 10 years advances. This includes AIDS dementia complex (ADC),
from infection to development of AIDS, although some sensory polyneuropathy and aseptic meningitis
patients progress much more rapidly and others have (see p. 1241). These conditions are much less common
remained symptom-free for up to 15 years. Older age is since the introduction of HAART (highly active anti-
associated with more rapid progression, and the retroviral therapy). The pathogenesis is thought to be
influence of putative protective genetic factors is under due both to the release of neurotoxic products by HIV
scrutiny. Gender and pregnancy per se do not appear to itself and to cytokine abnormalities secondary to immune
influence the rate of progression, although women may dysregulation.
fare less well for a variety of reasons. A subgroup of ADC has varying degrees of severity, ranging from
patients with asymptomatic infection have persistent mild memory impairment and poor concentration
generalized lymphadenopathy (PGL), defined as lymph- through to severe cognitive deficit, personality change
adenopathy (> 1 cm) at two or more extrainguinal sites and psychomotor slowing. Changes in affect are common
for more than 3 months in the absence of causes other and depressive or psychotic features may be present. The
than HIV infection. The nodes are usually symmetrical, spinal cord may show vacuolar myelopathy histologically.
firm, mobile and non-tender. There may be associated In severe cases brain CT scan shows atrophic change of
splenomegaly. The architecture of the nodes shows varying degrees. MRI changes consist of white matter
hyperplasia of the follicles and proliferation of the lesions of increased density on T2-weighted sections. EEG
capillary endothelium. Biopsy is rarely indicated. Similar may show non-specific changes consistent with encepha-
disease progression has been noted in asymptomatic lopathy. The CSF is usually normal, although the protein
patients with or without PGL. Nodes may disappear with concentration may be raised. Patients with mild neuro-
disease progression. logical dysfunction may be unduly sensitive to the effects
of other insults such as fever, metabolic disturbance
Symptomatic HIV infection or psychotropic medication, any of which may lead to a
marked deterioration in cognitive functioning.
As HIV infection progresses the viral load rises, the CD4
Sensory polyneuropathy is seen frequently in HIV
count falls, and the patient develops an array of symp-
infection, most commonly in the legs and feet, although
toms and signs. The clinical picture is the result of direct
hands may be affected in advanced disease. In its most
HIV effects and of the associated immunosuppression.
severe form it causes intense pain, usually in the feet,
In an individual patient the clinical consequences of
which may disrupt sleep, impair mobility and generally
HIV-related immune dysfunction will depend on at least
reduce the quality of life.
three factors:
Autonomic neuropathy may also occur with postural
■ The microbial exposure of the patient throughout life. Many hypotension and diarrhoea. Autonomic nerve damage is
clinical episodes represent reactivation of previously found in the small bowel. Zalcitabine, didanosine and
acquired infection, which has been latent. Geographical stavudine produce a similar neuropathy as a major toxic
factors determine the microbial repertoire of an side-effect and must be used with caution in patients with
individual patient. Those organisms requiring intact HIV neuropathy.
cell-mediated immunity for their control are most HAART has a beneficial effect on HIV neurological
likely to cause clinical problems. disease, with startling improvement in cognitive function
■ The pathogenicity of organisms encountered. High-grade in many patients with ADC. It may also have a neuro-
pathogens such as Mycobacterium tuberculosis, Candida protective role.
and the herpesviruses are clinically relevant even
when immunosuppression is mild, and will thus occur Eye disease
earlier in the course of the disease. Less virulent organ Eye pathology is a regular finding in HIV infection,
isms occur at later stages of immunodeficiency. usually in the later stages. The most serious is cyto-
■ The degree of immunosuppression of the host. When megalovirus retinitis (see p. 138), which is sight-
patients are severely immunocompromised (CD4 count threatening. Retinal cotton wool spots due to HIV per se
133
Infectious diseases, tropical medicine and sexually transmitted diseases
are rarely troublesome but they may be confused with ■ Other complications. Myelotoxic drugs include
CMV retinitis. Anterior uveitis can present as acute red zidovudine (megaloblastic anaemia, red cell aplasia,
eye associated with rifabutin therapy for mycobacterial neutropenia), lamivudine (anaemia, neutropenia),
infections in HIV. Steroids used topically are usually ganciclovir (neutropenia), systemic chemotherapy
effective but modification of the dose of rifabutin is (pancytopenia) and co-trimoxazole (agranulocytosis).
required to prevent relapse. Pneumocystis, toxoplasmosis,
syphilis and lymphoma can all affect the retina and the Gastrointestinal effects (see p. 335)
eye may be the site of first presentation. Weight loss and diarrhoea are extremely common in HIV-
infected patients. Wasting is a common feature of
Mucocutaneous manifestations (see Table 2.52) advanced HIV infection, which although originally
The skin is a common site for HIV-related pathology as attributed to direct HIV effects on metabolism, is usually
the function of dendritic and Langerhans' cells, both a consequence of anorexia. There is a small increase in
target cells for HIV, is disrupted. Delayed-type hyper- resting energy expenditure in all stages of HIV, but
sensitivity (p. 226), a good indicator of cell-mediated weight and lean body mass usually remain normal
immunity, is frequently reduced or absent even before during periods of clinical latency when the patient is
clinical signs of immunosuppression appear. Pruritus is a eating normally.
common complaint at all stages of HIV. Generalized dry, HIV enteropathy is a term that has been used to
itchy, flaky skin is typical and the hair may become thin describe a syndrome of diarrhoea, malabsorption and
and dry. An intensely pruritic papular eruption favouring weight loss for which no other pathology has been found.
the extremities may be found, particularly in patients HIV infection of the lymphocytes (in the lamina propria)
from sub-Saharan Africa. Eosinophilic folliculitis presents which are distributed throughout both the large and
with urticarial lesions particularly on the face, arms small bowel, with disturbance of cytokine production,
and legs. may be responsible. Villous atrophy is a common histo-
Drug reactions with cutaneous manifestations are logical finding in the small bowel.
extremely frequent, with rashes developing notably to Hypochlorhydria is reported in patients with advanced
sulphur-containing drugs amongst others (see Fig. 23.39, HIV disease and may have consequences for drug
p. 1359). Recurrent aphthous ulceration, which is severe absorption and bacterial overgrowth in the gut.
and slow to heal is common and can impair the patient's Rectal lymphoid tissue cells are the targets for HIV
ability to eat. Biopsy may be indicated to exclude other infection during penetrative anal sex and may be a
causes of ulceration. Topical steroids are useful and reservoir for infection to spread through the body.
resistant cases may respond to thalidomide.
In addition to the above the skin is a common site of Renal complications
opportunistic infections (see below). HIV-associated nephropathy (HIVAN) (see p. 635),
although rare, can cause significant renal impairment,
particularly in more advanced disease. It is most fre-
Haematological complications quently seen in black male patients and can be exacer-
Anaemia, neutropenia and thrombocytopenia are all bated by heroin use.
common in advanced HIV infection. Nephrotic syndrome subsequent to focal glomerulosderosis
■ Lymphopenia - this progresses as the CD4 count falls. is the usual pathology, which may be a consequence of
■ Anaemia of chronic HIV infection is usually mild, HIV cytopathic effects on renal tubular epithelium. The
normochromic and normocytic. course is usually relentlessly progressive and dialysis
■ Neutropenia is common and usually mild. may be required.
■ Isolated thrombocytopenia may occur early in infection Many nephrotoxic drugs are used in the management
and be the only manifestation of HIV for some time. of HIV-associated pathology, particularly foscarnet,
Platelet counts are often moderately reduced but can amphotericin B, pentamidine, sulfadiazine and indinavir.
fall dramatically to 10-20 x 109/L producing easy
bleeding and bruising. Circulating antiplatelet anti Respiratory complications
bodies lead to peripheral destruction. Megakaryocytes The upper airway and lungs serve as a physical barrier to
are increased in the bone marrow but their function is airborne pathogens and any damage will decrease the
impaired. Effective antiretroviral therapy usually efficiency of protection, leading to an increase in upper
produces a rise in platelet count. Thrombocytopenic and lower respiratory tract infections. The sinus mucosa
patients undergoing dental, medical or surgical may also function abnormally in HIV infection and is
procedures may need therapy with human immuno- frequently the site of chronic inflammation. Response to
globulin, which gives a transient rise in platelet count, antibacterial therapy and topical steroids is usual but
or be given platelet transfusion. Steroids are best some patients require surgical intervention. A similar
avoided. process is seen in the middle ear, which can lead to
■ Pancytopenia occurs because of underlying oppor chronic otitis media.
tunistic infection or malignancies, in particular Lymphoid interstitial pneumonitis (LIP) is well described
Mycobacterium avium-intracellulare, disseminated in paediatric HIV infection but is uncommon in adults.
cytomegalovirus and lymphoma. There is an infiltration of lymphocytes, plasma cells and
134
Human immune deficiency virus (HIV) and AIDS
lymphoblasts in alveolar tissue. Epstein-Barr virus may infection. Patients with CD4 counts above 200 are at low
be present. The patient presents with dyspnoea, and a dry risk for the majority of AIDS-defining OIs. A hierarchy of
cough, which may be confused with pneumocystis thresholds for specific infectious risks can be constructed.
infection (see p. 136). Reticular nodular shadowing is Mechanisms include defective T cell function against
seen on chest X-ray. Therapy with steroids may produce protozoa, fungi and viruses, impaired macrophage func-
clinical and histological benefit in some patients. tion against intracellular bacteria such as mycobacteria
and salmonella and defective B cell immunity against
Endocrine complications capsulated bacteria such as Strep, pneumoniae and
Various endocrine abnormalities have been reported, Haemophilus. Many of the organisms causing clinical
including reduced levels of testosterone and abnormal disease are ubiquitous in the environment or are already
adrenal function. The latter assumes clinical significance carried by the patient.
in more advanced disease when intercurrent infection Diagnosis in an immunosuppressed patient may be
superimposed upon borderline adrenal function precipi- complicated by a lack of typical signs, as the inflam-
tates clear adrenal insufficiency requiring replacement matory response is impaired. Examples are lack of neck
doses of gluco- and mineralocorticoid. CMV is also impli- stiffness in cryptococcal meningitis or minimal clinical
cated in adrenal-deficient states. findings in early Pneumocystis carinii pneumonia (PCP).
Multiple pathogens may coexist. Indirect serological tests
Cardiac complications are frequently unreliable. Specimens must be obtained
Cardiomyopathy, although rare associated with HIV, may from the appropriate site for examination and culture in
lead to congestive cardiac failure. Lymphocytic and order to make a diagnosis.
necrotic myocarditis have been described. Ventricular
biopsy should be performed to ensure other treatable Opportunistic infections in the HAART
causes of myocarditis are excluded. Antiretrovirals era_________________________________
therapy may be helpful.
In many developed countries the mortality and morbidity
associated with HIV infection have declined dramatically
since the introduction of potent antiretroviral therapy. In
CONDITIONS ASSOCIATED WITH the USA the age-adjusted death rate from AIDS fell 48%
IMMUNODEFICIENCY between 1996 and 1997 and death rates across Europe fell
fivefold between 1995 and 1998. European data showed a
Immunodeficiency allows the development of oppor-
fall in AIDS defining illnesses (ADI) from 30.7 per
tunistic infections (OI) (Table 2.51). These are diseases 100 patient years of observation to 2.5 per 100 patient
caused by organisms that are not usually considered years between 1994 and 1998, with patients on HAART
pathogenic, unusual presentations of known pathogens, having a lower rate of ADIs than patients not on HAART.
and the occurrence of tumours that may have an oncogenic This trend has continued - recent data from Europe
viral aetiology. Susceptibility increases as the patient demonstrate a 50% lower incidence of AIDS in 1998-2001
becomes more immunosuppressed. CD4 T lymphocyte than in 1996-1998, irrespective of CD4 count. Potential
numbers are used as markers to predict the risk of long-term adverse effects associated with HAART have
not altered its effectiveness in treating AIDS. However the
decline has been steeper for some OIs than others,
Table 2.51 Major HIV-associated pathogens suggesting that the immune reconstitution due to
Protozoa Bacteria HAART may not be functionally equal against all HIV-
Salmonella spp. associated complications. Importantly not all patients
Mycobacterium tuberculosis have adequate responses to these medications, even if
M. avium-intracellulare they are available and tolerable. Immune reconstitution
Streptococcus pneumoniae with HAART may produce unusual responses to oppor-
Staphylococcus aureus
tunistic pathogens and confuse the clinical picture. Thus
Haemophilus influenzae
Moraxella catarrhalis
prevention and treatment of OIs remains an integral part
Rhodococcus equii of the management of HIV infection.
Bartonella quintana
Nocardia Prevention of opportunistic infection in
Toxoplasma gondii HIV-infected patients
Cryptosporidium parvum Avoid infection
Microsporidia spp. Exposure to certain organisms can be avoided in those
Leishmania donovani known to be HIV infected. Attention to food hygiene
Isospora belli will reduce exposure to salmonella, toxoplasmosis and
Viruses Cryptosporidium, and protected sexual intercourse will
Cytomegalovirus Herpes reduce exposure to herpes simplex virus (HSV), hepatitis
simplex Varicella zoster B and papillomaviruses. Cytomegalovirus (CMV)-negative
Human papillomavirus patients should be given CMV-negative blood products.
Papovavirus
Fungi and yeasts
Pneumocystis carinii
Cryptococcus neoformans
Candida spp.
Dermatophytes {Trichophyton)
Aspergillus fumigatus
Histoplasma capsulatum
Coccidioides immitis
135
Infectious diseases, tropical medicine and sexually transmitted
Immunization strategies gress to confluent alveolar shadows throughout the
Immunization may not be as effective in HIV-infected lungs. High-resolution CT scans of the chest demonstrate
individuals. Live virus vaccines should not be used (e.g. a characteristic ground-glass appearance even when there
yellow fever, live polio). is little to see on the chest X-ray. The patient is usually
Hepatitis A and B vaccines should be given for those hypoxic and desaturates on exercise. Definitive diagnosis
without natural immunity who are at risk, particularly if rests on demonstrating the organisms in the lungs via
there is coexisting liver pathology, e.g. hepatitis C. bronchoalveolar lavage. As the organism cannot be
cultured in vitro it must be directly observed either with
Chemoprophylaxis silver staining or immunofluorescent techniques.
In the absence of a normal immune response, many OIs
are hard to eradicate using antimicrobials, and the Treatment should be instituted as early as possible. First-
recurrence rate is high. Primary and secondary chemo- line therapy is with intravenous co-trimoxazole (100 mg/
prophylaxis has reduced the incidence of many OIs. kg per day sulfamethoxazole and 20mg/kg per day
Advantages must be balanced against the potential for trimethoprim in divided doses) for 21 days. Up to 40% of
toxicity, drug interactions and cost, with each medication patients receiving this regimen will develop some
added to what are often complex drug regimens. adverse drug reaction, including a typical allergic rash.
Primary prophylaxis has been shown to be effective in Mutations in the gene for dihydropteroate synthetase in
reducing the risk of Pneumocystis carinii, toxoplasmosis P. carinii, which may theoretically lead to co-trimoxazole
and Mycobacterium avium-intracellulare. resistance, have been reported. There is, however, no
Primary prophylaxis is not normally recommended evidence that co-trimoxazole is becoming less efficacious
against cytomegalovirus, herpesviruses or fungi. clinically. If the patient is sensitive to co-trimoxazole,
With the introduction of HAART and immune intravenous pentamidine (4 mg/kg per day) or dapsone
reconstitution, ongoing chemoprophylaxis for previously and trimethoprim are given for the same duration.
life-threatening conditions (e.g. Pneumocystis carinii, Atovaquone or a combination of clindamycin and
cytomegalovirus retinitis, cryptococcus, toxoplasmosis, primaquine is also used. In severe cases (P ao2 less than
MAI) can be discontinued in those patients with CD4 9.5 kPa), systemic corticosteroids have been shown to
counts that remain consistently above 200 and who have reduce mortality and should be added. Continuous
a low viral load. American guidelines for stopping and positive airways pressure (CPAP) or mechanical venti-
restarting prophylaxis have been published. It is neces- lation (see p. 982) may be required if the patient remains
sary to review such decisions as clinical and laboratory severely hypoxic or becomes too tired. Pneumothorax not
parameters change. In developing countries unable to uncommonly complicates the clinical course in an already
obtain HAART, long-term secondary prophylaxis is severely hypoxic patient.
advocated. Other less severe but recurrent infections Long-term secondary prophylaxis is required in
may also warrant prophylaxis (e.g. herpes simplex, developing countries without HAART in patients whose
candidiasis). CD4 count remains below 200, and to prevent relapse, the
usual regimen being co-trimoxazole 960 mg three times a
week. Patients sensitive to sulphonamide are given either
dapsone or pyrimethamine or nebulized pentamidine.
SPECIFIC CONDITIONS ASSOCIATED WITH The latter only protects the lungs and does not penetrate
HIV INFECTION the upper lobes particularly efficiently; hence if relapses
occur on this regimen they may be either atypical or
Fungal infections extrapulmonary.
Pneumocystis carinii (see p. 95) This organism most
commonly causes pneumonia (PCP) but can cause Cryptococcus (see p. 93)
disseminated infection. It is not usually seen until The most common presentation of cryptococcus in the
patients are severely immunocompromised with a CD4 context of HIV is meningitis, although pulmonary and
count below 200. The infection remains common disseminated infections can also occur. The organism,
although the use of primary prophylaxis in patients with C. neoformans, is widely distributed - often in bird
CD4 < 200 has reduced the incidence. The organism droppings - and is usually acquired by inhalation. The
damages alveolar epithelium, which impedes gas onset may be insidious with non-specific fever, nausea
exchange and reduces lung compliance. and headache. As the infection progresses the conscious
The onset is often insidious over a period of weeks, level is impaired and changes in affect may be noted. Fits
with a prolonged period of increasing shortness of breath or focal neurological presentations are uncommon. Neck
(usually on exertion), non-productive cough, fever and stiffness and photophobia may be absent as these signs
malaise. Clinical examination reveals tachypnoea, depend on the inflammatory response of the host, which
tachycardia, cyanosis and signs of hypoxia. Fine crackles in this setting is abnormal.
are heard on auscultation, although in mild cases there The diagnosis is made on examination of the CSF (a
may be no auscultatory abnormality. In early infection the CT scan must be carried out before lumbar puncture to
chest X-ray is normal but the typical appearances are of exclude space-occupying pathology). Indian ink staining
bilateral perihilar interstitial infiltrates, which can pro- shows the organisms directly and CSF cryptococcal
136
Human immune deficiency virus (HIV) and AIDS

antigen is positive at variable titre. It is unusual for the Table 2.52 Some mucocutaneous manifestations of
cryptococcal antigen to become negative after treatment, HIV infection (see also Ch. 23)
although the levels should fall substantially. Cryptococci Skin Mucous membranes
can also be cultured from CSF and/or blood.
Factors associated with a poor prognosis include a Dry skin and scalp Candidiasis:
high organism count in the CSF, a low white cell count Onychomycosis oral
in the CSF, and an impaired consciousness level at Seborrhoeic dermatitis vulvovaginal
presentation. Tinea: Oral hairy leucoplakia
cruris Aphthous ulcers
pedis Herpes simplex:
Treatment. Initial treatment is usually with intravenous
Pityriasis: genital
amphotericin B (0.7 mg/kg per day), although intravenous
versicolor oral
fluconazole (400 mg daily) is useful if renal function is rosea labial
impaired or if amphotericin side-effects are troublesome. Folliculitis Periodontal disease
Oral fluconazole can be substituted if the organism is Acne Warts:
shown to be fully sensitive and the patient is responding. Molluscum contagiosum oral
The mortality from a first episode of cryptococcal Warts genital
meningitis is up to 20%. Relapse is very common, poss- Herpes zoster:
ibly from a prostatic reservoir in men. Lifelong secondary mutidermatomal
prophylaxis is required in the absence of HAART. disseminated
Papular pruritic eruption
Candida (see p. 91) Scabies
Icthyosis
Mucosal infection with Candida is very common in HIV-
Kaposi's sarcoma
infected patients. Oral Candida is one of the most common
conditions. C. albicans is the usual organism, although
C. krusei and C. glabrata occur. Pseudomembranous
candidiasis consisting of creamy plaques in the mouth unless the neutrophil count can be sustained, and neutro-
and pharynx is the best recognized. Erythematous Candida
penic patients should be supported with granulocyte
is more subtle and appears as reddened areas on the hard
colony-stimulating factors.
palate or as atypical areas on the tongue. Angular cheilitis
can occur in association with either form or more rarely
Histoplasmosis (see p. 92)
alone. Vulvovaginal Candida is often problematic.
This infection is a well-recognized complication of HIV in
Oesophageal Candida infection produces dysphagia
the USA where it is endemic in soil. The most common
with retrosternal discomfort (see p. 279). Barium swallow
manifestation is with pneumonia, which may be confused
or endoscopy shows multiple areas of ulceration through-
with Pneumocystis carinii in its presentation (see above).
out the length of the oesophagus. Fluconazole or
itraconazole are the agents of choice. With prolonged
exposure to these agents in HIV-infected patients, azole- Superficial dermatophyte infections
resistant C. albicans is becoming an increasing problem. These are common. Nail infection with Tricophyton
Switching azoles may produce a response. Symptom rubrum causes onychomycosis (see p. 1323 and
relief may require intravenous amphotericin. Disseminated Table 2.52).
Candida is uncommon in the context of HIV infection.
C. krusei may colonize patients who have been treated Protozoal infections
with fluconazole, as it is fluconazole-resistant. Amphotericin
is useful in the treatment of this infection and an attempt Toxoplasmosis (see p. 103)
to type Candida from clinically azole-resistant patients Toxoplasma gondii most commonly causes encephalitis and
should be made. cerebral abscess in the context of AIDS, usually as a result
of reactivation of previously acquired infection. The
Aspergillus (see p. 93) incidence depends on the rate of seropositivity to toxo -
Infection with Aspergillus fumigatus occurs in advanced plasmosis in the particular population. High levels are
HIV disease. Aspergillus is controlled by functioning found in France where up to 90% of the adult population
neutrophils, and patients with long-standing neutropenia is seropositive. About 25% of the adult UK population is
(often due to chemotherapy) and those on ganciclovir toxoplasmosis seropositive. AIDS patients who have these
therapy for CMV and myelotoxic antiretrovirals, are antibodies may develop cerebral toxoplasmosis.
prone to this infection. Spores are airborne and The clinical presentation is of a focal neurological
ubiquitous. Following inhalation, lung infection proceeds lesion with convulsions, fever, headache and possible
to haematogenous spread to other organs. Sinus infection confusion. Examination reveals focal neurological signs
occurs. in more than 50% of cases. Eye involvement with
The prognosis is very poor, with amphotericin B being chorioretinitis may also be present. In most but not all
the mainstay of therapy. Itraconazole is also effective. It is cases toxoplasmosis serology is positive. Typically CT
almost impossible to deal effectively with Aspergillus scan of the brain shows multiple ring-enhancing lesions.
A single lesion on CT may be found to be one of several
Infectious diseases, tropical medicine and sexually transmitted diseases
on MRI. A solitary lesion on MRI, however, makes a
Viral infections
diagnosis of toxoplasmosis unlikely.
The definitive method of diagnosis is brain biopsy, but Hepatitis virus B and C (see pp. 364 and 367)
in most cases an empirical trial of anti-toxoplasmosis Because of the comparable routes of transmission of
therapy is instituted and if this leads to radiological hepatitis viruses and HIV, co-infection is common,
improvement within 3 weeks this is considered diag- particularly in drug users and those infected by blood
nostic. The differential diagnosis includes cerebral products. A higher prevalence of hepatitis viruses is
lymphoma, tuberculoma or focal cryptococcal infection. found in those with HIV infection than in the general
population. With the striking improvement in prognosis
Treatment is with pyrimethamine for at least 6 weeks in HIV since the introduction of HAART, morbidity and
(loading dose 200 mg, then 50 mg daily) combined with mortality of hepatitis co-infection has become increasingly
sulfadiazine and folinic acid. Clindamycin and pyri- significant and may limit life expectancy in HIV. In co-
methamine may be used in patients allergic to sulphona- infected patients the hepatotoxicity associated with
mide. Anticonvulsants should be given. Lifelong main- certain antiretroviral agents may be potentiated.
tenance is required to prevent relapse unless the CD4 Hepatitis B infection does not appear to influence the
count can be restored by HAART. There is some evidence natural history of HIV; however, in HIV co-infected
to suggest that co-trimoxazole as PCP prophylaxis has patients there is a significantly reduced rate of hepatitis B
some ability to reduce the incidence of toxoplasmosis. e antigen (HBeAg) clearance, and the risk of developing
chronic infection is increased. HBV reactivation and
Cryptosporidiosis (see p. 105) reinfection is also seen. Liver disease occurs most
Ciyptosporidium parvum can cause a self-limiting acute commonly in those with high HBV DNA levels indicative
diarrhoea in an immunocompetent individual. In HIV of continuing replication.
infection it can cause severe and progressive watery It has been suggested that hepatitis C is associated
diarrhoea which may be associated with anorexia, with more rapid progression of HIV infection, and the
abdominal pain, nausea and vomiting. Cysts attach to the CD4 responses to HAART in co-infected patients may be
epithelium of the small bowel wall, causing secretion of blunted. Hepatitis C progression is both more likely and
fluid into the gut lumen and failure of fluid absorption. It more rapid in the presence of HIV infection, and the
is associated with sclerosing cholangitis (see p. 404). The levels of hepatitis C viral activity tend to be elevated. The
cysts are seen on stool specimen microscopy using Kinyoun hepatotoxicity associated with HAART is worse in those
acid-fast stain. The organism is readily identified in small with HCV co-infection.
bowel biopsy specimens. Assessment of co-infected patients requires full
Treatment is largely supportive, as there are no effec- clinical and laboratory evaluation and staging of both
tive antimicrobial agents available other than a non- infections. For HCV both viral load and genotype will
absorbable aminogylycoside, paromamycin, which may influence therapeutic decision-making. In HBV infection,
have a limited effect on diarrhoea. detection and quantification of HBV DNA acts as a
marker of viral activity, whilst the significance of viral
Microsporidiosis genotype is still uncertain. Liver biopsy is useful to obtain
Enterocytozoon bieneusi and Septata intestinalis are
a histological staging of disease.
associated with diarrhoeal illness in HIV infection. Spores There are limited treatment options for HBV. The ideal
can be detected in stools using a trichrome or fluorescent time to start treatment is not clear; however, response
stain that attaches to the chitin of the spore surface. rates for co-infected patients may be better at higher CD4
Albendazole eradicates the infection with amelioration of counts. Treatments for HBV include some agents with
symptoms. concomitant anti-HIV activity, including lamivudine and
tenofovir. These must be used within an effective anti-
Leishmaniasis (see p. 101) HIV regimen.
In HCV co-infection, criteria for treatment are similar
This is a cause of illness in immunosuppressed HIV-
for those infected with HCV alone, depending on stage of
infected individuals who have been in endemic areas,
disease and HCV genotype. Pegylated interferon has
which include South America, tropical Africa and much
greater efficacy than standard interferon in this situation
of the Mediterranean. Symptoms are frequently non- and is combined with ribavirin. In HIV/HCV co-infected
specific with fever, malaise, diarrhoea and weight loss. patients those with a CD4 count above 200 have a better
Splenomegaly, anaemia and thrombocytopenia are chance of success. In general it is preferable to treat HCV
significant findings. Amastigotes may be seen on bone first if HIV infection is stable, as this minimizes
marrow biopsy or from splenic aspirates. Serological tests hepatotoxicity associated with HAART. However, if the
exist for Leishmania but they are not reliable in this setting. CD4 count is low or the patient is at risk of HIV pro-
gression, HIV therapy should be instituted first.
Treatment is based on sodium stibogluconate (pentavalent
antimony) but in HIV infection the response may be better Cytomegalovirus (see p. 46)
to liposomal amphotericin. Relapse without HAART is CMV can be a cause of considerable morbidity in HIV-
common unless long-term secondary prophylaxis is infected individuals, especially in the later stages of
given.
138
Human immune deficiency virus (HIV) and AIDS
2
disease. The major problems encountered are retinitis, intravenous ganciclovir. Ganciclovir can be given directly
colitis, oesophageal ulceration, encephalitis and pneumo- into the vitreous cavity but regular injections are
nitis. CMV infection is associated with an arteritis, which required. A sustained-release implant of ganciclovir can
may be the major pathogenic mechanism. CMV also be surgically inserted into the affected eye. Cidofovir is
causes polyradiculopathy and adrenalitis. available for use when the above drugs are contra-
indicated. It has renal toxicity.
CMV retinitis
This tends to occur once the CD4 count is below 100 and CMV colitis
is found in up to 30% of AIDS cases. It is the most com- The usual presenting features include abdominal pain,
mon cause of eye disease and blindness. Although often generalized or left iliac, diarrhoea which may be
usually unilateral to begin with, the infection frequently bloody, generalized abdominal tenderness with rebound
progresses to involve both eyes. Presenting features in some cases, and a low-grade fever. Loops of dilated
depend on the area of retina involved (loss of vision being large bowel may be seen on abdominal X-ray. Sigmoid-
most common with macular involvement) and include oscopy shows a friable or ulcerated mucosa, which
floaters, loss of visual acuity, field loss and scotomata, should be biopsied. The diagnosis is made on the
orbital pain and headache. histological appearances with characteristic 'owls eye'
Examination of the fundus (Fig. 2.47) reveals haemor- cytoplasmic inclusion bodies (see Fig. 2.16).
rhages and exudates, which follow the vasculature of the
retina (so called 'pizza pie' appearances). The features are Treatment with either intravenous ganciclovir or
highly characteristic and the diagnosis is made clinically. foscarnet for 3 weeks improves symptoms and the
Retinal detachment and papillitis may occasionally occur. histological changes are reversed. However, relapse is
If untreated, retinitis spreads within the eye, destroying common once therapy is stopped, unless HAART is
the retina within its path. Routine fundoscopy should be available. The issue of long-term maintenance therapy in
carried out on all HIV-infected patients to look for this situation is controversial since, unlike CMV retinitis,
evidence of early infection. Any patient with symptoms repeated attacks of colitis do not necessarily have
of visual disturbance should have a thorough examin- significant long-term sequelae of the sort associated with
ation with pupils dilated, and if no evident pathology retinitis. Given the complications associated with main-
is seen a specialist ophthalmologic opinion should be tenance anti-CMV therapy there may be no overall
sought. benefit.
Other sites along the gastrointestinal tract also are
TrBatment for CMV should be started as soon as possible prone to CMV infection. Solitary ulceration of the
with either ganciclovir (lOmg/kg daily) or foscarnet oesophagus, usually in the lower third, causes painful
(60mg/kg 8-hourly) given intravenously for at least dysphagia. CMV can also cause hepatitis.
3 weeks, or until retinitis is quiescent. Reactivation is
common, leading to blindness. The major side-effect CMV neurological conditions
of ganciclovir is myelosuppression, and foscarnet is CMV polyradiculopathy usually affects the lumbosacral
nephrotoxic. Maintenance therapy requires long-term roots, leading to paraparesis and sphincter disturbance.
vascular access through either a Hickman line or sub- The CSF has an increase in white cells, which surprisingly
cutaneous reservoir device. An oral form of ganciclovir is are almost all neutrophils. Although progression may be
available which has some long-term benefit when used as arrested by anti-CMV medication, functional recovery
maintenance therapy, but has a lower efficacy than may not occur. The encephalopathy of CMV has clinical
similarities to that caused by HIV itself. It tends to
respond poorly to therapy.

Herpesviruses (see pp. 43 and 1321) Herpes simplex


infection occurs with greater frequency and severity,
presenting in an ulcerative rather than vesicle form in
profoundly immunosuppressed individuals. Genital,
oral and occasionally disseminated infection is seen.
Viral shedding may be prolonged in comparison with
immunocompetent patients.
Varicella zoster can occur at any stage of HIV but tends
to be more aggressive and longer-lasting in the more
immunosuppressed patient. Multidermatomal zoster
may occur.
Therapy with aciclovir is usually effective. Frequent
recurrences need suppressive therapy. Aciclovir-resistant
strains (usually due to thymidine kinase-deficient
mutants) in HIV-infected patients have become more
Fig. 2.47 Untreated CMV retinitis. common. Such strains may respond to foscarnet.
139
Infectious diseases, tropical medicine and sexually transmitted diseases
Herpesvirus 8 (HHV-8) is associated with Kaposi's histological and viral examination of brain tissue obtained
sarcoma (see p. 48). at biopsy. There is no specific therapy. HAART which
enhances the immune response has, however, produced
Epstein-Barr virus (see p. 47) both clinical and radiological remission in a number of
Patients with HIV have been shown to have high levels of cases. Addition of cidofovir to HAART may improve
EBV colonization. There are increased EBV titres in outcome in some patients.
oropharyngeal secretions and high levels of EBV-infected
B cells. The normal T cell response to EBV is depressed in
HIV. EBV is strongly associated with primary cerebral Bacterial infections
lymphoma and non-Hodgkin's lymphoma (see below). Bacterial infection in HIV is common and frequently
Oral hairy leucoplakia caused by EBV is a sign of disseminated. Cell-mediated immune responses normally
immunosuppression first noted in HIV but now also control infection against intracellular bacteria, e.g.
recognized in other conditions. It appears intermittently Mycobacterium. The abnormalities of B cell function
on the lateral borders of the tongue or the buccal mucosa associated with HIV lead to infections with encapsulated
as a pale ridged lesion. Although usually asymptomatic, bacteria, as reduced production of IgG2 cannot protect
patients may find it unsightly and occasionally painful. against the polysaccharide coat of such organisms. These
The virus can be identified histologically and on electron- functional abnormalities may be present well before there
microscopy. There is a variable response to aciclovir. is a significant decline in CD4 numbers and so bacterial
sepsis may be seen at early stages of HIV infection.
Human papillomavirus (see p. 48) HPV produces Streptococcus pneumoniae, Haemophilus influenzae and
genital, plantar and occasionally oral warts, which Moraxella catarrhalis infections are examples. Bacterial
may be slow to respond to therapy and recur infection is often disseminated and, although usually
repeatedly. HPV is associated with the more rapid amenable to standard antibiotic therapy, may reoccur.
development of cervical and anal intraepithelial Long-term prophylaxis is required if recurrent infection is
neoplasia, which in time may progress to squamous cell frequent.
carcinoma of the cervix or rectum in HIV-infected Skin conditions such as folliculitis, abscesses and
individuals. cellulitis are common and are usually caused by Staph.
aureus. Periodontal disease, which may be necrotizing,
Papovavirus (see p. 48) causes pain and damage to the gums. It is more common
JC virus, a member of the papovavirus family, which in smokers, but no specific causative agent has been
infects oligodendrocytes, causes progressive multifocal identified. Therapy is with local debridement and
leucoencephalopathy (PML). This leads to demyelination systemic antibiotics.
particularly within the white matter of the brain. The Salmonella (non-typhoidal) (see p. 68) is a frequent
features are of progressive neurological and/ or intel- pathogen in HIV infection. Salmonellas are able to
lectual impairment, often including hemiparesis or survive within macrophages, this being a major factor in
aphasia. The course is usually inexorably progressive but their pathogenicity. Organisms are usually acquired
a stuttering course may be seen. Radiologically the orally and frequently result in disseminated infection.
lesions are usually multiple and confined to the white Gastrointestinal disturbance may be disproportionate to
matter. They do not enhance with contrast and do not the degree of dissemination, and once the pathogen is in
produce a mass effect. MRI (Fig. 2.48) is more sensitive the bloodstream any organ may be infected. Salmonella
than CT and reveals enhanced signal on T2-weighted osteomyelitis and cystitis have been reported. Diagnosis
images of the lesions. Definitive diagnosis is made on is from blood and stool cultures.
Response to standard antibiotic therapy, depending on
laboratory sensitivities, is usually good. Recurrent infec-
tion is, however, common and long-term prophylaxis
may be required.
Education on food hygiene should be provided.

Mycobacteria
Mycobacterium tuberculosis (see p. 86) The
interaction between HIV and TB has several
particular characteristics. Many parts of the world with a
high prevalence of TB also have high rates of HIV
infection. The respiratory transmission of TB means both
HIV-positive and negative people are being infected.
Although more common in immunosuppressed patients,
TB can cause disease when there is only minimal
immunosuppression and thus often appears early in the
Fig, 2.48 MRI scans showing progressive multifocal course of HIV infection. In many countries where HIV is
leucoencephalopathy. spreading and TB is endemic there has been a substantial
140
Human immune deficiency virus (HIV) and AIDS
increase in the incidence of tuberculosis. HIV-related TB Treatment of mycobacteria in the age of
frequently represents reactivation of latent TB, but there HAART (see pp. 144 and 149)
is also clear evidence of newly acquired infection and Treatment of TB in HIV co-infected patients presents
nosocomial spread in HIV-infected populations. specific challenges and requires input from a specialist
The pattern of disease differs with immuno- physician. Treatment is similar to that for HIV-negative
suppression. Patients with relatively well preserved CD4 patients, although intermittent and short-course regimens
counts have a clinical picture similar to that seen in HIV- are not advised. Therapy should be initiated with four
negative patients with pulmonary infection. drugs, isoniazid, rifampicin, pyrazinamide and etham-
In more advanced HIV disease, atypical pulmonary butol for 2 months. Once sensitivities are confirmed,
presentations without cavitation and prominent hilar pyrazinamide and ethambutol may be withdrawn and
lymphadenopathy, or extrapulmonary TB affecting the other two drugs continued for 4 months, although
lymph nodes, bone marrow or liver occur. Bacteraemia this may be extended in some circumstances. The drug-
may be present. drug interactions between antiretroviral and anti-
The diagnosis depends on demonstrating the organisms tuberculous medications are complex and are a con-
in appropriate tissue specimens. The response to sequence of enzyme induction or inhibition. Rifampicin is
tuberculin testing is blunted in HIV-positive individuals a potent inducer of cytochrome P450, which is also the
and is unreliable. Sputum microscopy may be negative route for metabolism of HIV protease inhibitors. Using
even in pulmonary infection and culture techniques are both drugs together results in a reduction in circulating
the best diagnostic tool. protease inhibitor with reduced efficacy and increased
M. tuberculosis infection usually responds well to potential for drug resistance. Some protease inhibitors
standard treatment regimens, although the duration of themselves block cytochrome P450, which leads to
therapy may be extended, especially in extrapulmonary potentially toxic levels of rifampicin and problems such
infection. Multidrug resistance is becoming a problem, as uveitis and hepatotoxicity. The non-nucleoside reverse
particularly in the USA where it is becoming a nosocomial transcriptase class also interacts variably with rif amycins,
danger. Cases from HIV units in the UK have been requiring dose alterations. Additionally, there are over-
reported. Compliance with antituberculous therapy lapping toxicities between HAART regimens and anti-
needs to be emphasized. Treatment of TB in the HIV- tuberculous drugs, in particular hepatotoxicity, peripheral
infected individual is not curative and long-term neuropathy and gastrointestinal side-effects. Rifabutin
isoniazid prophylaxis may be given. In patients from TB has a weaker effect on cytochrome P450 and may be
endemic areas, primary prophylaxis may prevent emerg- substituted for rifampicin. Dose adjustments must be
ence of infection. Immune reconstitution phenomenon as made for drugs used in this situation to take account of
a result of HAART occurs (p. 149). these interactions.
Paradoxical inflammatory reactions (immune reconsti
Mycobacterium avium-intracellulare tution inflammatory syndrome, IRIS) which can include
Atypical mycobacteria, particularly M. avium-intracelluhre exacerbation of symptoms, new or worsening clinical
(MAI), generally appear only in the later stages of HIV signs and deteriorating radiological appearances have
infection when patients are profoundly immuno- been associated with the improvement of immune
suppressed. It is a saprophytic organism of low patho- function seen in HIV-infected patients starting HAART in
genicity that is ubiquitous in soil and water. Entry may be the face of M. tuberculosis infection. They are most
via the gastrointestinal tract or lungs with dissemination commonly seen in the first few weeks after initiation of
via infected macrophages. HAART in patients recovering from TB and can last
The major clinical features are fevers, malaise, weight several weeks or months. The syndrome does not reflect
loss, anorexia and sweats. Dissemination to the bone inadequate TB therapy and is not confined to any parti
marrow causes anaemia. Gastrointestinal symptoms may cular combination of antiretroviral agents. It is vital to
be prominent with diarrhoea and malabsorption. At this exclude new pathology in this situation. Given these
stage of disease patients frequently have other concurrent complexities, in certain circumstances it may be prefer
infections, so differentiating MAI is difficult on clinical able to delay the initiation of HAART until TB is under
grounds. Direct examination and culture of blood, lymph control. .,
node, bone marrow or liver give the diagnosis most
reliably.
MAI is typically resistant to standard antituberculous Infections due to other organisms
therapies, although ethambutol may be useful. Drugs Strongyloides (see p. Ill), a nematode found in tropical
such as rifabutin in combination with clarithromycin or areas, may produce a hyperinfection syndrome in HIV-
azithromycin reduce the burden of organisms and in infected patients. Larvae are produced which invade
some ameliorate symptoms. A common combination is through the bowel wall and migrate to the lung and
ethambutol, rifabutin and clarithromycin. Addition of occasionally to the brain. Albendazole or ivermectin may
amikacin to a drug regimen may produce a good symp- be used to control infection. Gram-negative septicaemia
tomatic response. Primary prophylaxis with rifabutin or can develop (see p. 967).
azithromycin may delay the appearance of MAI, but no Scabies (see p. 1325) may be much more severe in HIV
corresponding increase in survival has been shown. infection. It may be widely disseminated over the body
141
Infectious diseases, tropical medicine and sexually transmitted diseases
and appear as atypical, crusted papular lesions known as prevent new ones emerging. For patients with aggressive
'Norwegian scabies', from which mites are readily disease, systemic chemotherapy is indicated using
demonstrated. Superadded staphylococcal infection may combinations of vincristine and bleomycin or the newer
occur. Treatment with conventional agents such as liposomal preparations of doxorubicin. Response is often
lindane may fail, and ivermectin has been used to good very good although of uncertain duration. Alpha-
effect in some patients. interferon is also effective.

Lymphoma
Neoplasms
A significant proportion of patients with HIV develop
The mortality and morbidity associated with neoplasia in lymphoma, mostly of the non-Hodgkin's, large B cell
HIV is substantial, non-Hodgkin's lymphoma being the type. These are frequently extranodal, often affecting the
most significant tumour now, ahead of Kaposi's sarcoma. brain, lung and gastrointestinal tract. Many of these
tumours are strongly associated with Epstein- Barr virus
Kaposi's sarcoma (see p. 1353) (EBV), with evidence of expression of latent gene nuclear
Kaposi's sarcoma (KS) in association with HIV (epidemic antigens such as EBNA 1-6, some of which are involved
KS) behaves more aggressively than that associated with in the immortalization of B cells and drive a neoplastic
HIV-negative populations (endemic KS). The incidence pathway.
has fallen significantly since the introduction of HAART. HIV-associated lymphomas are frequently very
The tumour is most common in homosexual men and aggressive. Patients often present with systemic 'B'
others who have acquired HIV sexually, particularly from syndromes and progress rapidly despite chemotherapy.
a partner who has KS, implicating a sexually transmitted Primary cerebral lymphoma is variably responsive to
cofactor in the pathogenesis. Human herpesvirus 8 radiotherapy but overall carries a poor prognosis.
(HHV-8) is involved in pathogenesis. KS skin lesions are Lymphomas occurring early in the course of HIV infec-
characteristically pigmented, well circumscribed and tion tend to respond better to therapy and carry a better
occur in multiple sites. It is a multicentric tumour consist- prognosis, occasionally going into complete remission.
ing of spindle cells and vascular endothelial cells, which
together form slit-like spaces in which red blood cells Squamous cell carcinoma
become trapped. This process is responsible for the Squamous cell carcinoma, especially of the cervix and
characteristic purple hue of the tumour. In addition to the anus, is associated with HIV. Human papillomavirus may
skin lesions, KS affects lymphatics and lymph nodes, the have a role in the pathogenesis of these malignancies.
lung and gastrointestinal tract, giving rise to a wide range Women with HIV infection should have yearly cervical
of symptoms and signs. Most patients with visceral cytology for detection of premalignant change.
involvement also have skin or mucous membrane lesions.
Visceral KS carries a worse prognosis than that confined
to the skin. Kaposi's sarcoma is seen around the eye INVESTIGATIONS AND MONITORING
(Fig. 2.49), particularly in the conjunctivae, which can
lead to periorbital oedema. Initial assessment
A full history should be taken, followed by examination.
Treatment with local radiotherapy gives good results in Baseline investigations will depend on the clinical setting,
skin lesions and is helpful in lymph node disease. but those for an asymptomatic person in the UK are
Initiation of HAART may cause regression of lesions and shown in Box 2.18.

Monitoring
Patients are regularly monitored to assess the progression
of the infection. Clinical examination will identify signs of
immunosuppression (such as oral hairy leucoplakia) and
detect early evidence of major opportunistic events.
Decisions about appropriate intervention can be made.

Immunological monitoring
CD4 lymphocytes. The absolute CD4 count and the
percentage of total lymphocytes that this represents falls
as HIV progresses. These figures bear a relationship to the
risk of the occurrence of HIV-related pathology, with
patients with counts below 200 cells at greatest risk.
Rapidly falling CD4 counts and those below 350 are an
indication to consider HAART. Routine assays measure
numbers of circulating CD4 lymphocytes but are unable
to assess cellular function, which may be abnormal, even
Fig. 2.49 Kaposi's sarcoma of the eyelid. when numbers are relatively well preserved. Factors
142
Human immune deficiency virus (HIV) and AIDS
Box 2.18 Baseline investigations in a newly a correlation between HIV RNA levels and long-term
diagnosed asymptomatic patient with HIV prognosis, independent of the CD4 count. Those patients
infection with a viral load consistently greater than 10 000 copies/
Haematology mL have a 10 times higher risk of progression to AIDS
Full blood count, differential count and film over the ensuing 5 years than those consistently below
Erythrocyte sedimentation rate 10 000 copies/mL. Although a correlation exists between
Biochemistry
viral load and CD4 cell numbers, the viral load appears to
Serum, liver and renal function be the best predictor of the long-term prognosis, whilst
Serum lipid profile Blood the CD4 count will give warning of the risks of immediate
glucose or shorter-term problems.
HIV RNA is the standard marker of treatment efficacy,
Immunology
with levels falling in response to the introduction of effec-
Lymphocyte subsets
Virology
tive antiretroviral medication (see below). Both duration
HIV antibody (confirmatory) and magnitude of virus suppression are pointers to clinical
HIV viral load outcome. None of the currently available therapies is able
Hepatitis serology (A, B and C) to suppress viral replication indefinitely, and a rising viral
Cytomegalovirus antibody load indicates drug failure.
Various guidelines exist for viral load monitoring in
Microbiology
Toxoplasmosis serology clinical practice. Baseline measurements are followed by
Syphilis serology repeat estimations at intervals of 3-4 months, ideally in
Screen for other sexually transmitted infections conjunction with CD4 counts to allow both pieces of
evidence to be used together in decision-making. Follow-
Other
ing initiation of antiretroviral therapy or changes in
Cervical cytology
therapy, effects on viral load should be seen by 4 weeks,
reaching a maximum at 10-12 weeks, when repeat viral
load testing should be carried out (see Fig. 2.46).
other than HIV (e.g. smoking, exercise, intercurrent infec
tions and diurnal variation) also affect CD4 numbers. Phenotype determination
CD4 counts are performed at approximately 3-monthly Two phenotypes of HIV, syncytium-inducing (SI) and
intervals unless values are approaching critical levels for non-syncytium-inducing (NSI), exist and appear to
intervention, in which case they are performed more correlate with disease progression. This is a specialized
frequently. : technique that is currently available only as a research
tool.
Virological monitoring
Viral load (HIV RNA) Genotype determination
The replication of HIV continues at a high rate through - Clear genotype variations exist within HIV and there are
out the course of infection, with many billion new virus increasing numbers of well-identified point mutations
particles being produced daily. The rate of viral clearance associated with antiretroviral drugs. Viral genotype has
is relatively constant in any individual and thus the level now entered routine practice to guide therapy, parti -
of viraemia is a reflection of the rate of virus replication. cularly in treatment-experienced patients and women
This has both prognostic and therapeutic value. who are pregnant.
The commonly used term 'viral load' has been coined
to encompass viraemia and HIV RNA levels. Three HIV
RNA assays for viral load are in current use:
MANAGEMENT OF THE HIV-INFECTED
:
■ branched-chain DNA (bDNA) . ' PATIENT (Box 2.19)
■ reverse transcription polymerase chain reaction (RT-
PCR) The possibility of understanding HIV as a chronic
■ nucleic acid sequence-based amplification (NASBA). controllable condition came with the advent of highly
active antiretroviral therapy (HAART). Since then
Results are given in copies of viral RNA per millilitre of management in the resource-rich world has moved away
plasma, or converted to a logarithmic scale, and there is from treating opportunistic conditions in immuno-
good correlation between tests. The most sensitive test is suppressed patients towards delivering long-term, effec-
able to detect as few as 20 copies of viral RNA per tive suppressive therapy. The emphasis on using treatments
millilitre. Transient increases in viral load are seen follow- to sustain life has shifted in favour of managing life with
ing immunizations (e.g. for influenza and Pneumococcus) the current therapies.
or during episodes of acute intercurrent infection (e.g. Nonetheless there is still no cure for HIV and patients
tuberculosis); and viral load measurements should not be must live with a chronic, infectious and unpredictable
carried out within a month of these events. condition. Limitations to efficacy include the inability of
By about 6 months after seroconversion to HIV, the current drugs to clear HIV from certain intracellular pools,
viral set-point for an individual is established and there is the occurrence of serious side-effects, strict adherence
143
Infectious diseases, tropical medicine and sexually transmitted diseases
Box 2.19 An approach to sick HIV-positive patients
Potential problems include Examine:
Adverse drug reactions Acute opportunistic infections - the genitalia, e.g. herpes simplex, syphilis,
Presentation or complication of malignancy Immune gonorrhoea
reconstitution phenomenon Infection in an - the fundi, e.g. CMV retinitis
immunocompromised host Organic or functional brain - the mouth
disorders Non-HIV-related pathology must not be *• Lymphadenopathy.
forgotten
Immediate investigations
Full medical history Full blood count and differential count
Remember: Liver and renal function tests
Antiretroviral drugs, prophylaxis, travel, previous HIV- Plasma glucose
related pathology, potential source of infectious agents Blood gases including acid-base balance
(food hygiene, pets, contacts with acute infections, Blood cultures, including specimens for mycobacterial
contact with TB, sexually transmitted infections) Secure culture Microscopy and culture of
confidentiality. Check with patient who is aware of HIV available/appropriate
diagnosis. specimens: stool, sputum, urine, CSF Malaria screen
in recent travellers from malaria areas Serological tests for
Full physical examination
cryptococcal antigen, toxoplasmosis:
Remember:
save serum for viral studies Chest X-ray CT/MR
Signs of adverse drug reactions, e.g. skin rashes, oral
scan of brain if focal neurological signs, and
ulceration
ALWAYS before lumbar puncture
Signs of disseminated sepsis
Clinical evidence of immunosuppression, e.g. oral
A/6: Lymphocyte subsets and HIV viral load assays may
Candida, oral hairy leucoplakia
yield misleading results during intercurrent illness.
Focal neurological signs and/or meningism
Evidence of altered mental state - organic or functional
requirements, complex drug-drug interactions, and the protease are so far the most developed. Newer agents of
ongoing emergence of resistant viral strains. these classes with improved pharmacokinetic, side-effect
The aims of management in HIV infection are to main- and resistance profiles are coming into production.
tain physical and mental health, to avoid transmission of
the virus, and to provide appropriate palliative support Reverse transcriptase inhibitors are of three types:
as needed. The complexity of HIV infection means that it nucleoside analogues (nucleoside reverse transcription
is best managed via a multidisciplinary team approach. inhibitors, NRTIs), nucleotide analogues (nucleotide
Confidentiality must be strictly observed and care taken reverse transcriptase inhibitors, NtRTIs) and non-
over establishing who is aware of the patient's diagnosis nucleoside analogues (non-nucleoside reverse transcriptase
and who is excluded from that knowledge. Psychological inhibitors NNRTIs).
support is needed not only for the patient but also for
family, friends and carers. Dietary assessment and advice ■ Nucleoside analogues (NRTIs) inhibit reverse transcrip
should be freely accessible. Clear advice on reducing the tion by binding to viral DNA and also act as DNA
risk of HIV transmission must be provided and future chain terminators. NRTIs need to be phosphorylated
sexual practices discussed. Information must be available intracellularly for activity to occur. These were the first
to allow people to make informed choices about child- group of agents to be used against HIV, initially as
bearing. The implications for existing family members monotherapy and later as dual drug combinations.
should be considered. General health promotion advice Usually two drugs of this class are combined to provide
on smoking, alcohol, diet, drug misuse and exercise the 'backbone' of a HAART regimen. Zidovudine and
should be given, particularly in the light of the emerging lamivudine have been combined into a single tablet,
cardiovascular, metabolic and hepatotoxicity risks (Combivir), and zidovudine, lamivudine and abacavir
associated with HAART (see p. 149). into Trizivir, which helps reduce the pill burden.
NRTIs have been associated with mitochondrial
Antiretroviral drugs (ARVs) toxicity, a consequence of their effect on the human
mitochondrial DNA polymerase. Lactic acidosis is a
The complexity of treatment regimens against HIV recognized complication of this group of drugs.
infection increases with the rising number of available ■ Nucleotide analogues (NtRTIs) have a similar mechan
compounds and the growth in new information about ism of action but do not require intracellular phosphoryl-
their use. Drugs of five different classes (Table 2.53) are ation for activity. Tenofovir, a monophosphorylated
currently available in the UK, with several others close to thymidine derivative, is the only licensed compound
release. Various events in the HIV life cycle have been of this group.
identified as potential targets for antiretroviral therapy. ■ Non-nucleoside analogues (NNRTIs) interfere with
Inhibitors of HIV reverse transcriptase and of HIV reverse transcriptase by direct binding to the enzyme.
144
Human immune deficiency virus (HIV) and AIDS

Table 2.53 Antiretroviral drugs available in the UK


Drug Daily dose and pill Metabolism/food Side-effects
burden
Abacavir Hypersensitivity reaction, fever, rash,
Nucleoside reverse transcriptase inhibitors (NRTIs) (nucleoside analogues) vomiting. Association with mitochondrial
400 mg o.d. (> 60 kg), dysfunction and lactic acidosis
250 mg o.d. (< 60 kg) Nausea, diarrhoea, peripheral neuropathy,
1 capsule/day pancreatitis. Association with mitochondrial
dysfunction and lactic acidosis
200 mg o.d.
300 mg x 2 tablets/day No food restrictions Headache, nausea, skin pigmentation
Didanosine/DDI 30-60 minutes before food

Emtricitabine (PTC) No food effects Renal


excretion Modify dose if Nausea, headache, rash, peripheral
creatinine clearance is < neuropathy, myelosuppression. Association
50 mLYmin with mitochondrial dysfunction and lactic
Lamivudine/3TC 150 mg x 2 2 No food effects, well acidosis
tablets/day absorbed with high Polyneuropathy. May be able to tolerate
bioavailability reduced dosage. Megaloblastic changes.
Association with mitochondrial dysfunction
Stavudine/D4T 40 mg x 2 High bioavailability. and lactic acidosis
2 capsules/day x 3 Competes with zidovudine Polyneuropathy, aphthous ulceration.
Reduce to 30 mg x 2 for for phosphorylation so do Association with mitochondrial dysfunction
persons less than 60 kg not use together and lactic acidosis
0.75 mg x 3 Nausea, headache, insomnia, skin and nail
3 tablets/day pigmentation, myelosuppression,
megaloblastic changes. Myelopathy with
250-300 mg x 2 2 extended use. Association with
capsules/day mitochondrial dysfunction and lactic
acidosis
No food effects
Zalcitabine/DDC As for component drugs

As for component drugs


Zidovudine/AZT
Well absorbed with good
bioavailability. No food
effects

1 tablet twice daily


Combivir (AZT plus 3TC)
1 tablet daily o.d.
Kivexa abacavir/3TC
1 tablet twice daily
Triizivir
(abacavir/AZT/3TC)
Nucleotide reverse transcriptase inhibitor (NtRTI)
Tenofovir 245 mg o.d. After food Hypophosphataemia, renal toxicity
1 tablet daily
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg o.d. Metabolized by cytochrome
1 capsule at night P450 (3A mixed inducer
and inhibitor). Do not take
with high-fat foods

Nevirapin
e 200 mg o.d. for High bioavailability, Rash, Stevens-Johnson syndrome,
first 14 days then long half-life, wide central nervous system effects (vivid
200 mg x 2 2 tissue distribution. dreams, agitation, hallucinations, and
tablets/day Induces its own depression amongst others).
metabolism, hence Contraindicated in pregnancy
dose escalation. No Rash, Stevens-Johnson syndrome,
food effects hepatic toxicity
Protease inhibitors (single drugs)
Amprenavir 1200mgx2 Cytochrome P450 inhibitor Diarrhoea, nausea, rash, oral paraesthesia,
16 capsules/day High-fat meals lead to abnormal liver function, body fat
May be used in reduced plasma drug levels redistribution and abnormal plasma lipids
lower doses boosted
with ritonavir
Atazanavir 400 mg o.d. Fewer lipid abnormalities Hyperbilirubinaemia
* 2 tablets/day than other protease
Can boost with ritonavir inhibitors Cont'd
145
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Table 2.53 (Cont'd) Antiretroviral drugs available in the UK


Drug Daily dose and pill Metabolism/food Side-effects
burden
Protease inhibitors (single drugs) Take 1 hour before or 2 nail dystrophy, alopecia,
Indinavir 800 mg x 3 Food reduces plasma levels. Nephrolithiasis and crystalluria, dry skin,
6 capsules/day
hours after food. Drink hyperbilirubinaemia, fat redistribution,
additional 1.5 L raised plasma lipids, hyperglycaemia
water/day
Nelfinavir Take with food. Diarrhoea, fat redistribution, raised plasma
1250 mg x2 10 Cytochrome P450 lipids, hyperglycaemia
tablets/day 3A inhibitor
Take with meals. Potent Nausea/vomiting, diarrhoea, taste
Ritonavir 600 mg x 2 12 cytochrome P450 3A4 distortion, perioral paraesthesia, fat
capsules/day Most inhibitor redistribution, hepatotoxicity,
commonly taken at hyperglycaemia, pancreatitis
lower doses to boost
other compounds Take with food Nausea, diarrhoea, abdominal pain, fat
Saquinavir (soft gel) 1200 mgx3 redistribution, abnormal plasma lipids,
or hyperglycaemia
1800 mg x2
18 capsules/day
Protease inhibitors boosted with ritonavir
Take with food Diarrhoea, nausea, fat redistribution,
3 capsules x 2 abnormal plasma lipids
Lopinavir R 6 capsules/day Pro-drug of amprenavir
700 mg plus ritonavir No food effect Similar to amprenavir As
Fosamprenavir 100 mg x 2 100
mg/800 mg x 2 6 With a light meal/snack ritonavir and indinavir As
Ritonavir/indinavir capsules/day 400
mg/400 mg x 2 12 With a light meal ritonavir and saquinavir
Ritonavir/saquinavir capsules/day 500
mg/200 mg x 2 Nausea, abnormal LFT
TipranavirVritonavir
Fusion inhibitors
Enfurvitide (T20) 90 mg x 2 Reaction at the injection site
-subcutaneous
injection
* Not yet licensed in the UK
They are generally small molecules that are widely cytochrome P450 system. This is used to therapeutic
disseminated throughout the body and have a long advantage, boosting blood levels of PI by blocking drug
half-life. NNRTIs affect cytochrome P450. They are metabolism with small doses of ritonavir. Pis have been
ineffective against HIV-2. The level of cross-resistance linked with abnormalities of fat metabolism and control
across the class is very high. All have been associated of blood sugar, and some have been associated with
with rashes and elevation of liver enzymes. deterioration in clotting function in haemophiliacs.

Protease inhibitors (Pis) act competitively on the HIV Fusion inhibitors. Enfurvitide (T20) is the only licensed
aspartyl protease enzyme, which is involved in the compound in this class of agents. It is a peptide derived
production of functional viral proteins, and enzymes. In from HIV GP41 that inhibits GP41-mediated fusion of
consequence, viral maturation is impaired and immature HIV with the target cell. It is synergistic with NRTIs and
dysfunctional viral particles are produced. Most of the Pis. Although resistance to enfurvitide has been described,
protease inhibitors are active at very low concentrations there is no evidence of cross-resistance with other drug
and in vitro are found to have synergy with reverse- classes Because it has an extracellular mode of action
transcriptase inhibitors. However there are marked there are few drug-drug interactions. Side-effects relate
differences in toxicity, pharmacokinetics and resistance to the subcutaneous route of administration in the form of
patterns which influence prescribing. Cross-resistance is injection site reactions.
common across the PI group, which makes it difficult to
use the drugs sequentially. There appears to be no activity Newer drugs NRTIs include alovudine (MIV-310) and
against human aspartyl proteases (e.g. renin), although SPD-756 which appear to have activity against NRTI-
there are clinically significant interactions with the resistant strains. New NNRTIs include capravirine in
146
Human immune deficiency virus (HIV) and AIDS
phase III trials. New Pis include tipranavir with activity progression and death. The outcome for patients initiating
against Pi-resistant viral isolates and TMC 114, also therapy below 200 CD4 cells/mm3 is less good than for
with a good activity against resistant isolates. Entry those who start at higher counts. The UK recommendation
inhibitors in development include compounds that block is that therapy should be started before the count falls
CD4 attachment and inhibitors of chemokine co-receptors below 200.
CXCR4 and CCR5. Early studies of HIV integrase and The risk of disease progression for individuals with a
maturation inhibitors are now in progress. count greater than 350 is low, and treatment may be
deferred. Therapy should be considered for people with a
Starting therapy CD4 count between 350 and 201 cells/mm3. Those who
Treatment regimens for HIV infection are complicated may have a higher risk of disease progression, e.g. those
and require a long-term commitment to high levels of with high viral loads (> 60 000 copies/mL) or rapidly
adherence. Risks of therapy include serious side-effects, falling CD4 count (losing more than > 80 cells/year) may
drug interactions and the potential for development of consider earlier intervention. Co-infection with hepatitis
resistant viral strains. The full involvement of patients C virus may call for earlier intervention (see p. 372).
in therapeutic decision-making is essential for success. Treatment for primary HIV infection is only
Various national guidelines and treatment frameworks recommended either within a clinical trial or to alleviate
exist (e.g. BHIVA Guidelines, DHHS Guidelines, and IAS symptoms.
Recommendations). A combination of clinical assessment Special situations (seroconversion, pregnancy, post-
and laboratory marker data, including viral load and CD4 exposure prophylaxis) in which antiretrovirals may be
counts, together with individual circumstances, should used are described on page 151.
guide therapeutic decision-making. The current UK
recommendations are shown in Table 2.54. In situations Choice of drugs
where therapy is recommended but the patient elects The drug regimen used for starting therapy must be
not to start, then more intensive clinical and laboratory individualized to suit each patient's needs. Treatment is
monitoring is advisable. initiated with three drugs, two NRTIs in combination,
Clear clinical benefit has been demonstrated with the with either a boosted protease inhibitor or NNRTI (Tables
use of antiretroviral drugs in advanced HIV disease. 2.53 and 2.55).
Treatment should be recommended for all patients with The choice of which drugs to include in initial therapy
symptomatic HIV disease, AIDS or a CD4 count that is is governed by effectiveness, adherence issues, side-effect
consistently below 200 cells/mm3. In such situations there profile, potential drug reactions, availability and the
is a significant risk of serious HIV-associated morbidity resistance and cross-resistance patterns of the drugs.
and mortality. Given that long-term patient adherence is essential to
In asymptomatic patients the absolute CD4 count is gain the most enduring viral suppression and to impede
the key investigation used to guide treatment decisions. A the emergence of drug resistance, it is crucial that patients
count below 200 cells/mm3 is associated with disease be fully involved in therapeutic decision-making through-
out and be treated with drug regimens that are manage-
able as part of their day-to-day lives. Current UK
Table UK recommendations for guidance (BHIVA 2003) prioritises ease of adherence and
2.54 starting minimization of toxicity over the likely development of
therapy*
Clinical Laboratory resistant mutations following failure of therapy.
Treatment
presentation markers recommendation Selection of the two NRTIs to form a backbone is
Symptomatic Any CD4 Treat increasingly influenced by ease of administration as no
conclusive comparative efficacy data exist. Abacavir,
HIV infection, count or viral
AIDS load
didanosine, lamivudine, tenofovir and zidovudine are all
Established, CD4 < 200, Treat
licensed for use in naive patients. Stavudine has become
asymptomatic any viral load associated with lipodystrophy and is not recommended.
infection Of the NNRTIs, efavirenz and nevirapine are both
CD4 201-350 Consider treatment recommended options and comparable in potency.
based on viral Efavirenz has the advantage of once-daily dosing but is
load, rate of CD4 associated with CNS side-effects such as dysphoria and
decline, coexisting insomnia. Nevirapine is taken twice daily and has a
clinical conditions, higher incidence of rash and hepatotoxicity.
patient preference The protease inhibitor class have demonstrated excel-
CD4 > 350 Defer treatment lent efficacy in clinical practice. Pis combined with a low
Primary HIV Treatment only dose of ritonavir to provide a pharmacokinetic advantage
infection recommended in a
are now most commonly used in naive patients. Using
clinical trial or for
this approach, the half-life of the active drug is increased,
severe symptoms.
which may allow simplification of dosing regimens,
* After British HIV Association (BHIVA) guidelines for the treatment
potency may be enhanced and the risk of resistance
of HIV-infected adults with antiretroviral therapy, 2003
minimized.
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Table 2.55 Initial HAART regimens - choice of initial therapy*


Regimen Recommendation Advantages Disadvantages
Recommended Equivalent/superior surrogate No randomized clinical trial (RCT)
2 NRTIs + NNRTI marker trials compared with Pl- end-point data Shorter follow-up
based regimens at 104 weeks of Single mutations may lead to cross
follow-up class resistance No RCT clinical
Easier adherence end-point data Possible increased
Evidence of improved surrogate toxicity
2 NRTIs + boosted PI Recommended end-point efficacy for lopinavir/ and drug interactions
ritonavir compared to a single PI
Better PK
Easier adherence
Less resistance at virological failure No RCT clinical end-point data
Spares PI and NNRTI classes Short-term surrogate marker data
3 NRTIs suggest less potent than
Not usually NNRTI or PI Less effective at
recommended except high viral loads
for patients with low
viral load and major
adherence concerns
* After British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy, 2003
Although previous studies have suggested that three Patients should be monitored for drug toxicity, including
NRTIs were able to produce good levels of viral sup- full blood count, liver and renal function and fasting
pression in ARV-naive patients, more recent comparative lipids and glucose levels.
data show this approach to be less efficacious than
combining two NRTIs with either an NNRTI or a PI. The Drug resistance
combination is no longer recommended unless there are Resistance to ARVs results from mutations in the protease
other pressing individual issues. Recent clinical trail data and reverse transcriptase genes of the virus. HIV has a
have shown early virological failure of the combinations rapid turnover with 108 replications occurring per day.
of tenofovir + abacavir + lamivudine and tenofovir + The error rate is high, resulting in genetic diversity within
didanosine + lamivudine. These combinations should not the population of virus in an individual. This mixture
be offered. will include drug-resistant mutants. When drugs only
partially inhibit virus replication there will be a selection
Monitoring therapy (Box 2.20) pressure for the emergence of drug-resistant strains. The
Virological success of HAART is a viral load of less than rate at which resistance develops depends on the
50 copies/ mL within 3-6 months of therapy. This is frequency of pre-existing variants and the number of
feasible for those starting therapy for the first time but mutations required. Resistance to zidovudine occurs with
may not be a realistic objective for heavily pretreated an accumulation of mutations, whilst a single-point
patients. Once ARV has been initiated the viral load mutation will confer high-level resistance to all three
should be measured at 4 weeks to assess efficacy. A viral NNRTIs.
load of 1000 copies/mL should be achievable by this HIV antiretroviral drug resistance testing has become
stage if treatment is to be considered adequate. The routine clinical management of the HIV patient. Genotypic
durability of the virological response is linked both to the assays to determine the genetic structure of the RT and
rate of viral load fall and the absolute nadir attained. Viral protease genes of HIV are available. The tests are based
load and CD4 count should be measured at 12 weeks and on PCR amplification of virus and give an indirect measure
then at 3-monthly intervals. Regular clinical assessment of drug susceptibility in the predominant variants. Such
should include weight, blood pressure and urinalysis. assays are limited both by the starting concentration of
virus, most assays requiring at least 1000 copies/mL of
blood, and by their poor ability to detect minority strains.
Box 2.20 Monitoring patients on highly active For results to be useful, samples must be analysed when
antiretroviral therapy (HAART) the patient is on therapy, as once the selection pressure of
Clinical history and examination therapy is withdrawn, wild type virus becomes the
Weight predominant strain and resistance mutations present
HIV viral load earlier may no longer be detectable.
Lymphocyte subsets The use of genotypic assays with appropriate inter-
Full blood count pretation in patients for whom therapy is failing has
Liver and renal function shown significant virological benefits. Phenotypic assays
Fasting lipid profile
provide a more direct measure of susceptibility but the
Blood glucose
complexity of the assays limits availability and no
148!
Human immune deficiency virus (HIV) and AIDS
additional advantage has been demonstrated. In the UK, Lipodystrophy
increasing numbers of patients are infected with viral A syndrome of lipodystrophy in patients with HIV on
strains originating in sub-Saharan Africa, which may HAART comprising characteristic morphological changes
require modification of the assay and the interpretation of and metabolic abnormalities is now well described. It is a
the results. major complication for patients, being highly stigmatizing,
There is evidence for the transmission of HIV strains and is a cause of drug discontinuation. The main charac-
that are resistant to all or some classes of drugs. Studies teristics, which may be found individually or in
of primary HIV infection have shown prevalence rates combination, are a loss of subcutaneous fat in the arms,
between 2-20%. Prevalence of primary mutations associ- legs and face (lipoatrophy), deposition of visceral, breast
ated with drug resistance in chronically infected patients and local fat, raised total cholesterol, HDL cholesterol and
not on treatment ranges from 3% to 10% in various triglycerides, and insulin resistance with hyperglycaemia.
studies. Advantages exist for genotypic analysis prior to The syndrome is potentially associated with increased
initiating treatment. cardiovascular morbidity. A clinical case definition has
been developed to attempt to standardize the definition
Drug interactions of the syndrome. The aetiology is still unclear although
Drug therapy in HIV is highly complex and the potential Pis and NRTIs have been implicated. The highest
for clinically relevant drug interactions is substantial. Both incidence occurs in those taking combinations of NRTIs
Pis and NNRTIs are metabolized through cytochrome and Pis. Stavudine seems to be associated with the
P450 dependent pathways. However both classes of drug lipoatrophy component of the process. The syndrome is
are able to variably inhibit and induce cytochrome P450, difficult to treat, and switching or stopping therapy may
influencing both their own and other drug metabolic not always reverse the processes, although switching
rates. Situations occur where both inducers and inhibitors away from a stavudine and/or Pi-based therapy is
of cytochrome P450 are prescribed simultaneously. recommended. Dietary advice and increasing exercise
Induction of metabolism may result in sub-therapeutic may improve some of the metabolic problems and help
antiretroviral drug levels with the risk of treatment body shape. The introduction of glitazones, metformin
failure and development of viral resistance, whilst and growth hormone has been investigated with variable
inhibition can raise drug levels to toxic values and outcomes. Statins and fibrates are recommended to
precipitate adverse reactions. Additionally, conventional reduce circulating lipids. Pravastatin has a low likelihood
(e.g. rifamycins) and complementary therapies (e.g. St of interactions with protease inhibitors. On the other
John's Wort) affect cytochrome P450 activity and may hand, simvastatin is contraindicated as it has high levels
precipitate substantial drug interactions. Therapeutic of drug interactions with Pis. Surgical approaches
drug monitoring (TDM) indicating peak and trough are useful in improving facial appearance following
plasma levels may be useful in certain settings. lipoatrophy. Polylactic acid injections (New-Fill) have
provided improvement in some patients.
Complications of antiretroviral therapy
Side-effects are a common problem in HAART (see Table Mitochondrial toxicity and lactic acidosis
2.53). Some are acute and associated with initiation of Mitochondrial toxicity, mostly involving the nucleoside
medication, whilst others emerge after longer-term analogue class leads to raised lactate and lactic acidosis,
exposure to drugs. As increasing numbers of patients which has in some cases