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INFECTIOUS DISEASE PATHOLOGY

Lecture 2

Prepared and presented by
Marc Imhotep Cray, M.D.
Scanning electron micrograph of Staphylococcus aureus bound to the surface of a human neutrophil. “Granulocytic Phagocytes,” by Frank R. DeLeo and William M. Nauseef.
Companion SDL Course

See: Infectious Disease Video Course-Introduction to Infectious Diseases,
Prof. Barry Fox, UW SOM and PH.
Marc Imhotep Cray, M.D.
Principles of Infectious Disease
 Infection remains a major cause of disease worldwide, due to
(1) emergence of new or resistant organisms and
(2) cost of effective control strategies in resource-poor regions
 Infectious agents are divided into the following categories:
 Prions – misfolded proteins devoid of nucleic acids, which
cause transmissible spongiform encephalopathies
 Viruses – RNA- or DNA-containing pathogens that rely on host
cells for replication
 Bacteria – prokaryotes capable of independent replication but
lacking a nucleus
 Eukaryotic pathogens – fungi, protozoa and helminths
Marc Imhotep Cray, M.D.
Principles of Infectious Disease (2)
 Many organisms live symbiotically in human body as colonizing
normal flora, often benefiting the host (e.g. vitamins K and B12,
produced by gut flora)

 In contrast, disease results when pathogenic organisms
produce virulence factors that damage host cells
 Primary pathogens cause disease in healthy hosts
 Opportunistic pathogens cause disease only in immune-
compromised host

Marc Imhotep Cray, M.D.
Detection Of Infection
A variety of methods are used:
 Nucleic acid amplification tests (NAAT): Can not only identify
viruses and bacteria but also detect strain types and toxin or
resistance genes
 Culture:
 Largely supplanted by NAAT for viruses
 Bacterial culture is still widely used for identification and
antibiotic sensitivity testing, but can be slow and not all
organisms grow in culture
 Specialized mass spectrometers can be used for rapid
identification of organisms in blood cultures
Marc Imhotep Cray, M.D.
Detection of Infection (2)
Immunological tests:
 Host antibodies can be detected using various in vitro
immunological assays
 A rise in titer between acute and convalescent serum
samples indicates recent infection tests may be negative
in immunocompromised pts

 Interferon-gamma release assays detect infection through
release of interferon from sensitized host T cells exposed to
bacterial peptides

Marc Imhotep Cray, M.D.
Reservoirs Of Infection
 Human reservoirs: Colonized or infected individuals may act as
reservoirs, carrying organisms on skin, throat (e.g. meningococci),
nose, bowel (e.g. Salmonella) or blood (e.g. hepatitis B)

 Animal reservoirs: Animals are a source of human infections
(zoonoses), e.g. Salmonella from poultry, TB and brucellosis from
Milk Spread may continue from cases to other humans (e.g. Q
fever)

Mycobacterium bovis (Bovine Tuberculosis) in Humans
http://www.cdc.gov/tb/publications/factsheets/general/mbovis.pdf

Marc Imhotep Cray, M.D.
Reservoirs of Infection (2)
 Environmental reservoirs:
 Environmental pathogens include Legionella in air
conditioning or water, and enteropathogens (typhoid,
cholera, Cryptosporidia or hepatitis A) in water

 Soil may harbor spores of clostridia (tetanus) or anthrax

Marc Imhotep Cray, M.D.
Transmission Of Infection
This occurs by several routes:
 Respiratory – inhalation
 Fecal–oral – ingestion
 Sexually transmitted– via mucous membranes
 Blood-borne – inoculation
 Via vector or fomite: an animal or object bridges gap between
host and reservoir

Marc Imhotep Cray, M.D.
Transmission of Infection(2)
Health care-acquired infection
Health care-acquired infections (HAIs) affect 6–10% of all hospital
admissions  create a significant clinical and economic burden

 (1)Close proximity of hospital inpatients, (2)widespread use of
antibiotics and (3) ease of transmission by health-care workers have
led to selection of multidrug-resistant organisms such as MRSA
and vancomycin-resistant enterococci (VRE)
 Spread of these organisms, plus infections such as Clostridium difficile
and norovirus, may lead to outbreaks of infection and necessitate ward
or hospital closure

Marc Imhotep Cray, M.D.
Prevention of Infection
 HAIs have to be managed by comprehensive antibiotic policies
and careful adherence to strict infection control protocols
 Although environmental cleanliness and clean clothing are
cosmetically important, recent evidence has confirmed absolute
importance of hand hygiene in control of HAI
 Use of alcohol hand lotion by all health-care workers
between every patient contact is an effective alternative to
soap and water in prevention of most HAI, but not
Clostridium difficile

Marc Imhotep Cray, M.D.
Clostridium difficile (Antibiotic-associated colitis)
 C. difficile produces 2 toxins:
 Toxin A, enterotoxin, binds to brush border of gut Pseudomembranous colitis. Yellow
 Toxin B, cytotoxin, causes cytoskeletal disruption via pseudomembranes (arrow) on endoscopy
actin depolymerization  pseudomembranous
colitis  abd pain, diarrhea (occasionally bloody
diarrhea), leukocytosis
 Often 2° to antibiotic use, especially clindamycin,
cephalosporins or ampicillin
 Diagnosed by detection one or both toxins in stool by
PCR
 Treatment: metronidazole or oral vancomycin Le T and Bhushan V. Microbiology. In: First Aid for
the USMLE Step 1 2015
 For recurrent cases, consider repeating prior
regimen, fidaxomicin, or fecal microbiota transplant
Outbreak control
An outbreak of infection is defined as occurrence of any disease
clearly in excess of normal expectancy
Confirmation requires evidence of identical genotype in
organisms isolated from case
 Cases are sought by testing and then plotted on an outbreak
curve [Epidemic (Epi) Curves]
 Case control studies may be used to establish the source
 Good communication of data to health-care workers is needed
to achieve control
Many countries have systems of compulsory notification of
contagious conditions to public health authorities to assist
outbreak control
Marc Imhotep Cray, M.D.
Interpretation of Epidemic (Epi) Curves during
Ongoing Outbreak Investigations

Example of an epidemic (epi) curve during a multistate outbreak
investigation of Salmonella Heidelberg infections, 2013-2014.
http://www.cdc.gov/foodsafety/outbreaks/investigating-
outbreaks/epi-curves.html
Marc Imhotep Cray, M.D.
Immunization
 Passive immunization means administering antibodies to a
specific pathogen produces temporary protection after
exposure
 as antibodies are obtained from blood, this may carry
risks of bloodborne infection
 Active immunization uses whole live attenuated organisms
or components of organisms to prevent disease by inducing
immunity

Marc Imhotep Cray, M.D.
Immunization (2)
 Vaccination may be applied to entire populations or to
subpopulations at specific risk through travel or occupation
 Usually goal is to prevent infection, but vaccination against
human papillomavirus (HPV) was introduced to prevent
cervical cancer
 Vaccination is successful when number of susceptible hosts in
a population becomes too low to sustain transmission (herd
immunity)
 Naturally acquired smallpox was eradicated by vaccination
in 1980
 A similar program aims to eradicate poliomyelitis
Marc Imhotep Cray, M.D.
Obtaining a history in diagnosis of infectious diseases
Component Feature Examples of Infection
History of present illness Age West Nile virus, neuroinvasive
disease much more common in
the elderly
Pregnancy Pregnant women at increased risk
for serious varicella pneumonia;
risks to fetus with various
infections (GBS) or treatments

Site of acquisition (home, skilled Multi-drug-resistant bacteria
nursing facility (SNF), hospital) more commonly cultured from
patient in a SNF or hospital

Season Influenza epidemics limited to fall
through early spring
Symptoms (duration, severity, Bacterial meningitis excluded if
pattern) symptoms last >1 week

Marc Imhotep Cray, M.D. Redrawn from: Hammer GD and McPhee. Pathophysiology of Disease: An Introduction to Clinical Medicine, 2014
Obtaining a Hx in Dx of ID cont.
Component Feature Examples of Infection
Past medical history (including Immunocompromise (eg, HIV, Pneumocystis jirovecii pneumonia
medications, allergies, and organ transplant, corticosteroid in patients with AIDS
immunizations) use, chemotherapy, asplenia)
Comorbid disease (eg, chronic Limb-threatening soft tissue
obstructive lung disease, diabetes infections in diabetic patients
mellitus, alcohol abuse)
Transfusions Blood-borne infections such as
cytomegalovirus or hepatitis C virus
Redrawn from: Hammer GD and McPhee. Pathophysiology of Disease: An Introduction to Clinical Medicine, 2014

Marc Imhotep Cray, M.D.
Obtaining a Hx in Dx of ID cont.
Component Feature Examples of Infection
Habits and exposures Substance use (eg, alcohol, cigarettes, Endocarditis associated with
type and route of illicit drugs use) injection drug use due to seeding
of bloodstream with skin bacteria
Sexual contacts Risk for sexually transmitted
infections such as syphilis
Outdoor activities Arthropod-borne infections (eg,
Rocky Mountain spotted fever)
Pets Zoonotic infections (eg, cat scratch
disease)

Redrawn from: Hammer GD and McPhee. Pathophysiology of Disease: An Introduction to Clinical Medicine, 2014

Marc Imhotep Cray, M.D.
Obtaining a Hx in Dx of ID cont.
Component Feature Examples of Infection
Social history Occupation Q-fever in veterinarians

Congregated living facility Transmission of infection from an ill contact
(eg, influenza, Shigella , norovirus)

Homelessness Tuberculosis, scabies

Travel Internationally acquired infections (eg, malaria)

Family history Transmittable diseases Tuberculosis

Review of systems Symptoms by organ system History of headache raises concern for central
nervous system infection; diarrhea raises
concern for gastroenteritis
Marc Imhotep Cray, M.D.
Physical Examination
1. Skin
2. Hands and nails
3. Oropharynx
4. Head and neck
5. Eyes
6. Neurological
7. Heart and lungs
8. Abdomen
9. Musculoskeletal
10. Genitalia and rectum

Marc Imhotep Cray, M.D.
1. Skin
Observation
 Temperature
 Generalized erythema
 Sweating
 Rash
 Weight loss
 IV injection track marks
 Respiratory distress
 Surgical scars
 Altered consciousness
 Prosthetic devices, e.g.
 Pallor
central venous catheters
 Jaundice
 Tattoos

Marc Imhotep Cray, M.D.
Sandpaper rash on trunk and in axilla of a Scarlatiniform rash comprising small papules
7-year-old boy with scarlet fever. and erythema on trunk of a febrile child with
strep pharyngitis.

FIGURE 34-1 FIGURE 34-2
Usatine RP. et al. The Color Atlas of Family Medicine. New York: McGraw-Hill, 2013

Marc Imhotep Cray, M.D.
Scarlet fever vs Rheumatic fever
 Scarlet fever is a fever caused by Group A beta hemolytic Streptococcus
bacteria which cause infection, particularly strep throat
 Bacteria produces toxins  toxins (SPE =streptococcal pyrogenic exotoxin)
cause rashes in body which are more evident under the arms and in the
groin
 Treatment for scarlet fever penicillin or erythromycin
 If not treated, it can cause rheumatic fever and sepsis
 Rheumatic fever is a complication of scarlet fever, particularly strep throat
 Also caused by a GAS infection
 Occurs after a month of having strep throat signs of rheumatic fever are
arthritis or painful, swollen joints and fever If toxins from strep throat
descend into heart, it can cause rheumatic heart disease (M1 protein)
o In long term, it may damage heart valves that may place pt. at risk for
endocarditis and (or) can cause heart failure
Marc Imhotep Cray, M.D.
Scarlet fever vs Rheumatic fever (2)
 Rheumatic fever affects young people usually from ages 5 and above up to
17 years old
 Scarlet fever also affect the young people
 Scarlet fever is diagnosed through blood tests
 Results show leukocytosis, neutrophilia, high ESR, and C-Reactive
protein also shows elevated anti-streptolysin O (ASO titer)
 Rheumatic fever is diagnosed through Jones Criteria made by Dr. Duckett
Jones in 1944 revised by the American Heart Association
 Jones Criteria is made up of major and minor criteria
o Rheumatic fever is confirmed with presence of one major criterion
plus two minor criteria and presence of infection, or two major
criteria plus presence of infection

Marc Imhotep Cray, M.D.
2. Hands and nails Palmar erythema in a man with cirrhosis secondary to
alcoholism.
 Finger clubbing
 Splinter hemorrhages
 Janeway lesions
 Signs of chronic liver
disease
 Vasculitis lesions

Usatine RP. et al. The Color Atlas of Family Medicine. New
York: McGraw-Hill, 2013

Marc Imhotep Cray, M.D.
3. Oropharynx
 Dental caries Strep pharyngitis showing tonsillar exudate and
 Tonsillar enlargement or erythema.
exudate
 Candidiasis
A 27-year-old woman complains of 2 days of sore
throat, fever, and chills. She is unable to swallow
anything other than liquids because of severe
odynophagia. She denies any congestion or cough.
On examination, she has bilateral tonsillar erythema
and exudate .Her anterior cervical lymph nodes are
tender. Based on the presence of fever, absence of
cough, tender lymphadenopathy, and tonsillar
exudate, she is diagnosed with a high probability of
group A β-hemolytic Streptococcus (GABHS) FIGURE 35-1
pharyngitis and prescribed antibiotics. Usatine RP. et al. The Color Atlas of Family Medicine. New
York: McGraw-Hill, 2013
Marc Imhotep Cray, M.D.
3. Oropharynx cont.
Viral pharyngitis in a young adult showing enlarged
cryptic tonsils with some erythema and exudate.
A 19-year-old woman presented with a
3-day history of fever, sore throat,
malaise, and headache. Physical exam
revealed a temperature of 39 °C, cervical
lymphadenopathy, and a whitish
tonsillar exudate. Of the following, which
is the most likely cause?
(A) Haemophilus influenzae
(B) Moraxella catarrhalis
(C) Neisseria gonorrhoeae
(D) Streptococcus pyogenes
(E) Viral
Usatine RP. et al. The Color Atlas of Family Medicine.
Marc Imhotep Cray, M.D.
New York: McGraw-Hill, 2013
4. Head and neck
Acute otitis media in left ear of a 15-month-old
 Lymphadenopathy patient with marked erythema and bulging of
tympanic membrane. Malleus and light reflex are
 Parotidomegaly not visible.
 Abnormal tympanic
membranes
A 15-month-old boy is brought by both parents to his
family physician with a 2-day history of fever, irritability,
and frequent tugging of his left ear. This was preceded by a
1-week history of nasal congestion, cough, and rhinorrhea.
On otoscopy, his left tympanic membrane (TM) appears
erythematous, cloudy, bulging, and exudative. His left TM
fails to move on pneumatic otoscopy. The physician
diagnoses acute otitis media and decides with the parents
to prescribe a 10-day course of amoxicillin; the child
recovers uneventfully.
Usatine RP. et al. The Color Atlas of Family Medicine.
New York: McGraw-Hill, 2013
Marc Imhotep Cray, M.D.
5. Eyes Roth spots that are retinal hemorrhages with
white centers seen in bacterial endocarditis.
Can also be seen in leukemia and diabetes.
 Conjunctival petechiae
 Painful red eye in uveitis
 Loss of red reflex in endophthalmitis
 Roth’s spots in infective endocarditis
 Hemorrhages and exudates
 of cytomegalovirus retinitis
 Choroidal lesions of tuberculosis

FIGURE 50-2
Usatine RP. et al. The Color Atlas of Family Medicine.
New York: McGraw-Hill, 2013

Marc Imhotep Cray, M.D.
Bell’s palsy secondary to leprosy. The hypopigmented
6. Neurological patches on his back are further signs of the leprosy.
FIGURE 233-2
Neck stiffness
Photophobia
Delirium
Focal neurological signs

Usatine RP. et al. The Color Atlas of Family Medicine. New
York: McGraw-Hill, 2013
Marc Imhotep Cray, M.D.
CXR showing a consolidation in left upper lobe;
7. Heart and lungs note oval lucency that represents cavitation within
infiltrate. This patient had Klebsiella pneumonia.
 Tachycardia, hypotension
 Murmurs or prosthetic heart
sounds
 Pericardial rub
 Signs of consolidation
 Pleural or pericardial effusion

FIGURE 53-5
Usatine RP. et al. The Color Atlas of Family Medicine. New
York: McGraw-Hill, 2013
Marc Imhotep Cray, M.D.
8. Abdomen Tense ascites in a woman with cirrhosis from her
alcoholism. An umbilical hernia is also seen from
increased intraabdominal pressure.
 Hepatosplenomegaly
 Ascites
 Renal angle tenderness
 Mass lesions
 Surgical drains

FIGURE 61-5
Usatine RP. et al. The Color Atlas of Family Medicine. New
York: McGraw-Hill, 2013

Marc Imhotep Cray, M.D.
9. Musculoskeletal
Septic left knee joint in a young girl who presented
with knee pain, fever, and limited ability to ambulate.
 Joint swelling, erythema or
tenderness
 Localized tender spine suggestive
of epidural abscesses or discitis
 Draining sinus of chronic
osteomyelitis

FIGURE 95-16
Usatine RP. et al. The Color Atlas of Family Medicine. New
York: McGraw-Hill, 2013

Marc Imhotep Cray, M.D.
Speculum exam showing mucopurulent
10. Genitalia and rectum discharge with a friable appearing cervix.

 Ulceration or discharge
 Testicular swelling or nodules
 Inguinal lymphadenopathy
 Prostatic tenderness
 Rectal fluctuance

FIURE 80-4
Usatine RP. et al. The Color Atlas of Family
Marc Imhotep Cray, M.D. Medicine. New York: McGraw-Hill, 2013
Clinical Examination of
Patients with Infectious Disease
Illustrated Summary:

Innes JA Ed. Davidson's Essentials of Medicine. Edinburgh, UK. Elsevier, 2016
Marc Imhotep Cray, M.D.
Presenting Problems in Infectious Diseases
 Fever
Fever implies an elevated core temperature of > 38°C (100.4°F)
 Clinical features are used to guide appropriate investigations, include:
● CBC and differential
● U&Es (urea and electrolytes), liver function, glucose and muscle enzymes
● ESR and CRP
● Autoantibodies.
● CXR and ECG
● Urinalysis and culture
● Blood culture
● Throat swab
Additional tests are indicated by local symptoms and
Temp Conversions:
if the patient is immunocompromised °C x 9/5 + 32 = °F
Marc Imhotep Cray, M.D. (°F - 32) x 5/9 = °C
Pyrexia of unknown origin (or FUO)
 Pyrexia of unknown origin (PUO) is a common presenting
problem defined as a consistently elevated body temperature of
> 38°C persisting for > 3 wks with no diagnosis after initial
investigation
 Many causes of PUO (next slide) Two or more causes of fever
may coexist

 Fever in old age (>65yo) merits special attention

Marc Imhotep Cray, M.D.
Etiology of FUO
Infections (~30%)
• Specific locations: abscess at any site, cholecystitis/cholangitis, UTI,
prostatitis, dental, sinus, bone and joint infections, endocarditis
• Specific organisms: TB (particularly extrapulmonary), brucellosis, viruses
(cytomegalovirus (CMV), Epstein–Barr virus (EBV), HIV-1), fungi (Aspergillus,
Candida)
• Specific patient groups: imported infections, e.g. malaria, dengue,
leishmaniasis, enteric fevers, nosocomial infections, HIV-related infections, e.g.
Pneumocystis jirovecii, disseminated Mycobacterium avium, cytomegalovirus
(CMV)

Marc Imhotep Cray, M.D.
Etiology of FUO cont.
Malignancy (~20%)
• Lymphoma, myeloma and leukaemia
• Solid tumors (renal, liver, colon, stomach, pancreas)
Connective tissue disorders (~15%)
• Older patients: temporal arteritis/polymyalgia rheumatica
• Younger patients: systemic lupus erythematosus (SLE), Still’s disease,
polymyositis, vasculitis
• Rheumatic fever
Miscellaneous (~20%)
• IBD, alcoholic liver disease, granulomatous hepatitis, pancreatitis
• Myeloproliferative disease, haemolytic anaemia
• Sarcoidosis, atrial myxoma, thyrotoxicosis, hypothalamic lesions
• Familial Mediterranean fever, drug reactions, factitious fever
No diagnosis or resolves spontaneously (15%)
Marc Imhotep Cray, M.D.
Fever in old age
• Temperature measurement: fever may be missed because oral
temperatures are unreliable rectal measurement may be needed  core
temperature is increasingly measured using eardrum reflectance
• Associated acute confusion: common with fever, especially in those with
underlying cerebrovascular disease or dementia
• Prominent causes of FUO: include endocarditis, TB and intra-abdominal
sepsis,
• Non-infective causes include polymyalgia rheumatic, temporal arteritis and
tumors
• Common infective causes in the very frail (e.g. nursing home residents):
include pneumonia, urinary infection, soft tissue infection and gastroenteritis

Marc Imhotep Cray, M.D.
THE END

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Sources and further study:
 Innes JA Ed. Davidson's Essentials of Medicine, 2nd Ed.. Edinburgh, UK. Elsevier, 2016
 Bloch KC. Ch. 4 Infectious Diseases, Pgs. 61-87 In: Hammer GD and McPhee Eds. JS.
Pathophysiology of Disease : An Introduction to Clinical Medicine, 7th Ed. New York: McGraw-
Hill Education, 2014
 Usatine RP. et al. The Color Atlas of Family Medicine. New York: McGraw-Hill, 2013

eLearning (IVMS Cloud)
 Infectious Disease
 Microbial biology & Immune System
 Rural Medicine Global Health (Focus on Ethiopia)

Textbooks:
 Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010
 Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York:
McGraw-Hill, 2016

Marc Imhotep Cray, M.D. 43