ID LECTURE

By: Rezene Berhe (Dr)

Internist

1
 Out line
 AFI:
 Typhus, Typhoid fever, RF, Meningitis, encephalitis, Malaria,
Viral hemorrhagic fever
 Chronic fever:
 Leishmaniasis, Brucellosis, Schistosomiasis
 Parasitoid:
 Filliariasis, Onchocerchiasis, Trypanosomiasis, Nematodes,
Hookworm, Strongloidiasis, Giardiasis
 Tetanus
 Anthrax
 HIV
 Other common bacterial infection
 Rational drug use in ID
2
Fever
 Temperature elevation >38oc
 Characteristics
 Incubation period
 Pattern
 Duration
 Associated symptoms and signs

3
Fever continued
 Incubation period
 Short <10 days
 Bacillary dysentry, Ricketsial infections, RF,
Plague
 Intermediate: 10-21 days
 Typhoid, Malaria, Typhus, HIV, Brucellosis
 Long: >21 days
 Viral hepatitis, Malaria, Amebic liver abscess,VL

4
Pattern
 Periodic fever: Malaria
 Biphasic or saddle back: (short afebrile
period)- Dengue, leptospirosis
 Undulant fever: (waxes and wanes over
days)- Brucellosis, VL, lymphoma
 Relapsing fever: settles spontaneously with
recurrence after intervals of few days or
weeks.
 Hectic fever

5
Duration
 Acute : <2 weeks
 Typhus, Typhoid, Malaria, Meningitis, RF
 Chronic fever: > 2 weeks
 Tb, VL, Brucellosis, HIV

6
Associated symptoms
 Rigors:
 Bacteremia, Severe viral infection
 Malaria
 Neutropenia:
 Viral infection
 Severe sepsis
 Typhoid fever

7
Typhus

8
Rickettsial infection
 Obligate intracellular, Gram negative,
non-flagellated coccobacilli.

 Transmission:
 Insects
 Animals /insects are reservoirs

9
 Contd.
 Three major groups:
 Typhus group
 R. prowazeki-(epidemic typhus)
 Transmision by human body louse
 R. typhi-(endemic murine typhus)
 Transmision by Rat flea

 Spotted fever group

 R. rickettsi
 Transmision by ticks from Rodents

 Scrub typhus
 Orientia tsutsugamushi ( Mite borne)
10
 Epidemic typhus
(louse borne)
 “Fever with stupor or smoke”

 First recognized in 430 BC-great plague of

Athens.

 1685 body louse involvement in the spread of

the disease.

 In 1916 da Rocha Lima identified the etiologic

agent- Rickettsia prowazekii.

11
Contd.
 Transmission:
 Peduculus humanus corporis
 Air borne
 Blood transfusion
 Accidental lab. Exposure.
 Risk factors
 Poor hygiene
 Over crowding-’jail fever’
 Cold areas
 poverty, war, disaster

12
 Contd.
 mechanism:
 Ingestion of blood from rickettsimic patient

 R. prowazekii multiply in mid gut epithelia Cells

 Defecates during its meal

 Auto inoculation by scratching

 Lice dies after 1-2 weeks- red louse syndrome

13
 Pathogenesis
 Proliferation in the small blood vessel endothelial
surface- early febrile illness

 Toxins damages the endothelial cell integrity

 Leakage of fluid
 Occlusive endangiitis
 Micro infarction
 Venous thrombosis and gangrene

 Immune complex deposition- late febrile episode

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Clinical presentation
 Incubation period: 12 days
 fever
 Abrupt onset ,high grade (39-40)
 Resolves by second week
 Myalgia: severe -crouching disease
 Prostration, HA, nausea and vomiting
 Dry cough, epistaxis
15
Contd.
 Congested face

 Depression, delirium,
meningoencephalitis

 Skin rash 2-4 day of fever

 Spottles epidemic typhus

16
Complications
 TM, hemipareis, peripheral neuropathy
 Psychiatric disturbance
 Secondary infection
 Pneumonia, otitis media
 Myocarditis
 Peripheral vessel occlusion
 Recrudescent: (Brill-zinsser disease)
 Due to immuno-supression and old age

17
Diagnosis
 Clinical:
 Epidemic situation and rapid response to treatment

 Serology:
 Heterophile Ab to proteus mirabilis Ox19 and Ox2 strains (weil-felix
test)

 Microaglutination-IFA titer of >1:128

 Isolation by inoculation to guinea pigs or fertile duck eggs.

 PCR

18
Treatment
 General:
 Delousing-1% malathion
 Fluid balance
 Nursing care
 Analgesics, Sedation
 Antibiotics to secondary infection

 Specific:
 Doxycycline stat or till afebrile for 24hr.
 TTC, CAF, Quinolone, Rifampine
 Predensolone??-severe cases ; renal failure.

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Prevention
 Delousing
 Personal and environmental hygiene
 Contact treatment with Doxycycline.

Out come
 Rapid defervescence in 48 hrs
 If untreated mortality 7-40%, in weak and
age reaches 50%.
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Typhoid fever

Typhus abdominalis
Enteric fever

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Introduction
 A systemic disease characterized by fever and
abdominal pain.

 Exclusively human disease caused by an organism of

genus salmonella, family of enerobacterisae.

 First report as separate clinical entity in 1578.

 Pathological difference confirmed in 1832 by

Gerhard.

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23
Contd.
 Transmission:
 S. typhi and S. paratyphi acquired through
contaminated food and water with faces
and urine.
 Human faces as a fertilizer
 Contaminated water

 S. paratyphi is less often water borne-

needs higher infective dose.

24
Risk factors
1. Dose of the organism
2. State of gastric acidity
1. Use of antiacids & H2 blockers
2. Hypoacidity
3. Acquisition through contaminated food

3. Possession of Vi antigen.

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H.Pylori and typhoid fever
 Positivity increases the risk
 Others
 Illiteracy
 Non use of soap
 Ice cream

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Pathogenesis
 Multiplication in the SI lumen.
 First 4 days-stool culture could be positive.
 Proliferation in the mesenteric LN
 Through thoracic duct reaches the blood stream–
primary bacteremia.
 Dissemination to liver and spleen
 Massive multiplication- secondary bacteremia.
 Invasion of most organs
 Gall bladder-chronic carriers
 Peyer’s patches-hyperplasia and necrosis, perforation

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Clinical presentation
 IP:10-20 days (1-10 days for paratyphi)

 First week
 Rising remittent fever
 Malaise , Head ache
 Mild non productive cough
 Constipation

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Contd.
 Second week:
 Sustained high grade fever
 Toxic and apathetic
 Slight abdominal distension
 Relative bradycardia
 Splenomegaly
 Rose spots-pink papules on the upper abdomen
and lower chest -result of bacterial embolization

29
Contd.
 Third week
 More toxic, delirious & confusional state( typhoid
state)
 Abdominal distension worsen
 Diarrhea-foul, green-yellow, watery
 Feeble pulse, rapid breathing
 Lung base crackles
 Death due to toxemia, myocarditis, intestinal
haemorrhage &/ perforation

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Contd.
 Fourth week:
 Fever, mental state and abdominal distension improves
 Intestinal complication may still occur

 Chronic or recurrent fever with bacteremia- some

times associated with schistosomiasis.

 Relapse
 A week after stoppage of antibiotic
 Seen in 10-20%
 Ab & rose spots may appear, blood culture could be positive
 Milder and shorter duration

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32
Complications
 Intestinal haemorrhage and perforation
 Late second and early third week
 Bleeding per rectum
 Sharp fall in body temp. and BP
 Sudden tachycardia
 For perforation:
 Difficult to recognize because of ileus and distension
 Worsening of pain and tenderness
 Free fluid in the abdomen and gas under the diaphragm

33
Complication of TF (perforation)

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Contd.
 Jaundice
 Cholangitis, cholecystitis,
 Haemolysis, hepatitis

 Myocarditis
 Tachycardia, weak pulse
 Hypotension
 ECG abnormality

 Mild bronchitis and bronchopneumonia

35
Contd.
 Neurology
 Delirium, restlessness
 Facial twitching and convulsion
 Paranoid psychosis, catatonia
 Meningism
 Others:
 DIC, HUS, GN, Nephrotic syndrome

36
Laboratory
 CBC-mild leukocytosis
 Later neutropenia, mild anemia, thrombocytopenia

 Culture:
 Definitive Dx-blood or BM culture
 Presumptive evidence-stool or urine culture and clinical picture
 Blood culture:
 Yield -1st WK 90% and 3rd wk 50%
 BM culture positive-90% despite treatment
 Duodenal string test
 Combined yield is >90%
 Stool culture: positive in 30-40% only by 1st wk increases by 3rd wk
 In 90% clear bacteremia by 8th wk
 False positive in chronic carriage

37
Contd.
 Serology:
 Ab against flagellar (H) and somatic (O) Ag –widal
test
 False positive
 Immunization, early infection-serology scar, anamnestic
reaction
 Chronic carrier state:
 Stool culture positive by 3rd month (3%)
 Remained positive >1 year (1-3%)
 Common in women and elderly.

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39
Treatment
 First line
 Fluoroquinolones-cipro and oflo x 10 days
 Fewer Rx failures and rapid resolution
 3rd generation cephalosporine-ceftroxiaone

 2nd line-Azithromycine 1gm/d x 5days

 Alternatives- CAF, Ampicillin, Tmp-Smx

 Severe forms: Fever, delirium, coma, septic shock

and positive culture
 Dexa-3mg/kg loading then 1mg/kg 6hrly x 2 days
 Decreases mortality from 56% to 10%

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41
Rx contd.
 Blood transfusion abd supportive care for
haemorrhage
 Surgical intervention for perforation
 Chronic carriage state:
 Amox, TMP-SMX, cipro, norfloxacine for 6 weeks
 Surgical correction of defects

 Out come:
 Duration of fever 3-5 days
 Mortality <1%

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Prevention
 Personal and environmental hygiene
 Vaccine
 Whole cell killed vaccine, Ty21a attuenated, Vicps
polysaccharide
 Indication:
 Contacts with chronic carriers
 Lab workers
 Travellers
 Monitoring of food handlers

43
Pregnancy and typhoid fever
 In adult females bacteremis typhoid
disease is pregnancy related (47%)
 Treatment
 Ampicillin/Amoxacillin/Cephalosporin
 Complication is less
 It doesn't affect the pregnancy
outcomes

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Relapsing fever

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Introduction
 Recurrent acute episodes of spirochetemia
and fever alternate with spontaneous
spirochetal clearance and apyrexia.

 Two forms:
 TBRF-a zoonosis transmited from rodents to
humans by tick bite
 LBRF-disease of humans transmited by body louse

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Etiology
 Borrelia spp
 B. dutoni agent of TBRF
 B. recurrentis-LBRF
 B. burgdorferi-Lyme disease

 Vector:
 Body louse- transmission is by crashing of
pruritic louse bites

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Risk factors
 Overcrowding, impoverishment,
unhygienic condition
 Prisoners, war, famine
 Cool, rainy season
 Close contacts
 Accidental needle prick

48
Pathogenesis
 Multiplication in blood- (febrile period)
 Sequestration at liver, spleen, BM &
CNS- (remission)
 Activation of mediators of inflammation
 Hageman factor, complement system
 Cytokines: IL-6, IL-8, CRP, TNF-responsible
for JHR

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Contd.
 Edema and swelling of organs

 Histocytic inflamation of myocardium

 Petechial haemorrhage

 Haemorrhagic infarction of the spleen, heart,

liver and brain
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Clinical presentation
 IP: 7 days
 Sudden high grade fever(>40 )
 Chills, rigor, sweats, myalgia, arthralgia
 Dellirium, prostration, photophobia,cough
 Tachycardia, tachypnea
 Meningismus
 Icterus, petechia in 1/3 of patients
 Tender Hepatosplenomegaly
 Symptoms subside after 5 days with spontaneous
crisis

51
52
Complications
 Haemorrhage: GI, CNS
 Coagulopathy
 Neurologic:
 Optic neuritis, lymphocytic meningitis, CN
palsy and coma.
 Pneumonitis
 Myocarditis
 Splenic rapture
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Contd.
 Jarisch-Herxheimer Reaction (JHR)
 Caused by release of mediators-TNF
 Two phases
 Chill phase:
 Toxic T>41, rigors, hyper metabolism
 Increase PVR & decrease in Pul. arterial pressure
 Lasts 10-30 min
 Flush phase:
 Decrease in PVR & increase in Pul. Arterial pressure
 Decrease in T, diaphoresis, decreased effective circulatory volume
 Lasts<8 hrs
 Sleep, exhaustion, recovery with disappearance of spirochetes
 Mortality reaches 20% in malnourished & stressed
population.

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Dx.
 Demonstration of spirochetes in blood also in
BM & CSF
 Giemsa, wright or acridine-orange staining
 Dark field microscopy : yield >70%
 Serology-IFA, western immunoblotting
 Insestive, cross react with B. burgdorferi and T.
pallidum
 CBC: low platelete
 Coagulation profile: PT, PTT, BT-prolonged

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Treatment
 Delousing: permethrine dust or liquid
 Suportive: Rehydration, transfussion
 Antibiotic:
 Procaine penicilline
 TTC
 Monitor for JHR in 1-4 hrs of therapy

56
Treatment of Complications
 JHR
 Supportive, cold sponging
 Monitoring of fluid balance, arterial and venous pressure,
myocardial function
 Pretreatment with Ab to TNF
 Steroid, acetaminophen-no value
 Myocarditis:
 Caution with fluid balance
 Ionotropics
 Digoxine
 Postural hypotention-during recovery

57
Out come
 Fatality rate with Rx is < 5%

 Prevention:
 Personal and environment hygiene
 Living standard
 Early case detection & treatment
 Mass delousing
 Doxy in out breaks of fever

58
CNS infection
 Encephalitis

 Cerebritis

 Abscess

 Meningitis
59
Bacterial Meningitis

 Acute purulent infection with in the

sub-arachinoid space

 Most common of suppurative CNS

infection (Empyema, Encephalitis)

60
Etiology
 S.pneumonia – 50%
 N.meningitidis – 25%
 Group B.Strept – 15%
 L.monocytogenes – 10%
 H.infeluenzae - <10%

61
Predisposing Factors

 S. pneumoniae
 Pneumococcal Pneumonia
 Otitis media and Sinusitis
 Alcoholism
 Diabetes, Splencetomy
 Hypogammaglobulinemia
 Head trauma

62
Contd.
 N. meningitides
 Colonization of nasopharyngeal
 Bacterial virulence
 Host immune defense-complement
deficiency
 Dry season, overcrowding, smoking, recent
viral URTI

63
Contd.
 Transmission via respiratory secretion
 Gram negative diplococcic with
polysaccharide capsule –antigenecity
 Nine sub groups
 A, B, C, Y, W-135, D, 29E, X, Z
 Epidemic-group A & C
 Sporadic-group B
 Group Y= older, chronic underlying illness, African-
American
 Gp Y & W-135=in patient with pneumonia

64
Contd.
 300,000-500,000 cases/year
 Annual incidence:
 1-2cases/100,000-sporadic
 5-10/100,000-hypersporadic
 10 to >100/100,000-pandemic & epidemic
 Peak incidence-winter ,respiratory viral illness
 During epidemic peak among teenagers and
young adults.

65
Cntd.
 Secondary attack rate:
 The risk is 1245x greater than general
population
 Incubation period : 2-3 days
 70% occurs in the 1st week
 13% in 2nd week, 6% in the 3rd week
 11% occurs from 4th -6th week
 400-1000/100,000 in close contacts

66
Contd.
 Meningococci first isolated in 1896
 In Sub-Saharan Africa it occurs every
8-14 years-Meningitis belt—extends 16
and 4 degree north (Senegal-Ethiopia)
 Mean annual rainfall—300-1100mm
 Incidence 400/100,000/yr during
epidemics, between epidemics 40 cases
per 100,000/yr.

67
The sub-Saharan Africa
“meningitis belt.”

68
Contd.
 Outbreak: case definition
 Three or more cases in <3 months
 Common affiliate or reside in the same
area but not close contacts
 Primary attack rate>10cases/100,000
 Strain isolate-N. meningitides of same type.

69
Pathogenesis contd.
 Bacteria colonizes the nasopharynx
 A defect in the barrier by URTI or
dryness
 Transmigration to blood and reaches
the Pia and Arachnoids matters
 Inflammatory response
 Increased permeability of BBB
70
Contd.
 Cerebral vessel thrombosis, vasculitis,
cerebral edema, intracranial
hypertension, cerebral infarction.

 Activated neutrophilis consume neural

tissue oxygen and glucose—anaerobic
respiration—lactate aggravates
neurotoxicity

71
Clinical presentation
 Nausea and vomiting, head ache & fever
 Neck stiffness, photophobia
 Lethargy and confusion
 Petechia, purpura
 Fever, HA, nuchial rigidity in >90%
 Altered mental state >75%
 Seizure-(due to infarction, ischemia,
hemorrhage, edema, toxicity).
 Signs of increased ICP.
72
Complication
 Increase in ICP (>180mmH2O)
 Hydrocephalus
 Hyponatremia
 DIC
 Adrenal insufficiency
 Neurological
 Seizure, hearing loss, gait disturbance, decreased
intellectual function, memory impairment

73
Diagnosis
 CSF:
 Leukocytosis- Normal WBC poor Px.
 Hypogluccorachia
 CSF/serum glucose <0.4-(60%)
 Increased protein
 Gram staining Positive—60%
 Positive culture >80%
 Latex agglutination for Ag-(if positive diagnostic)
 Specificity(95-100%), sensitivity(33-70%)
 Blood culture
74
Treatment
 Emperic therapy
 Penicilline
 Third generation cephalosporine and vancomycine
 Oily CAF

 Specific Rx after culture result

 Dexamethasone -10mg 20min before then every
6hrly for 4 days.
 Decreases production of TNF
 Contact Rx:
 Rifampicine, cipro, ceftriaxone, azithromycine

75
Contd.
 Out break:
 Oily CAF, Penicillin
 Mass vaccination
 Chemoprophylaxis of close contacts

76
Out come
 Mortality:
 Meningococcal meningitis=14%
 H. influenza=38%
 Pneumococcal meningitis=57%

 Poor prognosis
 Age
 State of consciousness
 Seizure
 CSF glucose, protein
 Delay treatment

77
Acute viral meningitis
 Etiology:
 Enterovirus, coxasackie,echo, polio,HIV and HSV-2

 Manifestation:
 Fever, frontal head ache-retroorbital
 Malaise, anorexia, nausea, vomiting
 Lethargy or drowsiness
 Mild nuchial rigidity
 Absent kernig’s and Brudzinskis sign

78
Contd.
 CSF:
 Lymphocytic pleocytosis (25-500/ul)
 Protein and glucose slightly increased
 Normal opening pressure

 CSF PCR

79
Rx.
 Supportive:
 Fluid and electrolyte
 Analgesics

 Antiviral:
 Acyclovir

 Prognosis is excellent
80
Viral encephalitis
 Etiology: HSV-1, VZV, Enterovirus, Arbovirus

 Manifestation
 Febrile illness
 Meningeal involvement
 Confusion, behavioral abnormality
 Altered level of consciousness
 Lethargy to deep coma

81
Contd.
 Focal/diffuse neurological symptoms &
signs
 Aphasia, ataxia, hemi paresis, myoclonus,
tremor
 CN palsy, facial weakness.
 CSF:
 Lymphocytic pleocytosis
 PCR for CMV, EBV, VZV & Enterovirus

82
Contd.
 Supportive
 ICU care-respiratory and BP monitoring
 ICP monitoring
 Fluid restriction-SIADH, avoid hypotonic
fluid
 Antipyretics
 Antiviral:
 Acyclovir IV 10mg/kg 3x/day x 14 days

83
Abscess formation in the basal ganglia in
patients with meningitis

84
Sub dural empyema and diffuse
cerebral edema

85
Ring enhancing abscess with peripheral edema
and mass effect

86
T-2 weighted MRI
Mild ventriculomegaly

87
Malaria

88
Introduction
 “Bad air”-believed to be caused by bad
air.
 Recognized long time ago
 Treatment precedes exact pathogenesis
 Early 20th century etiology recognized

89
 It is a vector borne disease

90
 Etiology :
 Plasmodium species
 It is a haemoparasite affecting all stages of
RBC depend on the type of species.
 P. falciparum-all stages of RBC
 P. Vivax-affects young RBC up to 14 days old
 P. ovale- affects older RBC
 P. malariae- affects reticulocytes

91
 Transmission is via:
 Anopheles mosquito bite
 Anapheles Gambiae:
 Longer lived
 Higher dencity in hyper endemicity
 Bread rapidly
 Bite humans in preference
 Blood transfusion
 Vertical
92
Life cycle
 Asexual reproduction
Sporozoites
Hepatic parenchyma cell asexual multiplication
Merozoites (30,000)
Invades the RBC to become trophozoites
Schizonts---schizogony in 48hrs
Douther merozoites released after rapture of RBC
invasion of other RBC and clinical manifestation

93
 Sexual multiplication
 Schizonts developed to gametocytes
 Taken by anopheles mosquito during its meal
 Mid gut multipication
 Zygote
 Ookinete
 To saivary gland of the mosquito
 Inoculation with sporozoites

94
Epidemiology
 Palpable spleen and parasitic rate in children
2-9 years of age.
 Hypoendemic <10%
 Mesoendemic 11-50%
 Hyperendomic 51-75%
 Holoendemic >75%
 Holoendemic and hyperendemic characterized
by:
 >1 bites/day
 High morbity and mortality during child hood
 In Adults most infection are asymptomatic
95
Distribution of malaria

96
Contd.
 Stable transmission
 Year round transmission

 Un stable transmission
 Erratic focal low transmission
 Protective immunity not acquired
 Seen in hypo endemic area

97
Pathogenesis
 RBC becomes irregular in shape, less
deformable, more antigenic
 Agglutination
 Rosette formation
 Cytoadherence
 Sequestration
 Toxic Hemoglobin polymerizes to innert
hemozoin
98
Clinical presentation
 Fever, Head ache, myalgia, fatigue
 Classical paroxysm of fever, chills, rigor
followed by a drenching sweating recurring
every 48 hrs in tertian and every 72 hrs in
quartan malaria
 Irregular in P. falciparum
 Mild anemia, palpable spleen
 Mild jaundice, palpable liver
 Resolution in 1-3 weeks
 Mortality 0.1% if untreated
99
Severe and complicated
malaria
1.Cerebral malaria
 Def.

 Unarousable coma lasting > 30min with

positive asexual forms of P. falciparum

 Diffuse encephalopathy
 Associated with convulsion
 Mortality -20% , sequele <3%

100
2. Hypoglycemia
 Blood glucose < 40mg/dl
 Causes:
 Abnormal hepatic gluconeogenesis
 Increased consumption by the parasite
 Effect of drugs:
 Quinine increases pancreatic insulin secretion
 Common seen with pregnancy and in children.
 Symptoms are absent
101
3. Anemia
 Haematocrit <15% (Hgb <5gm/dl with
parasite density of > 100,000/ul.
 Cause:
 Increased RBC dstruction
 Hypersplenism
 Coagulopathy
 Bleeding due to stress ulcer

102
4. Acute renal failure
 Urine output < 400ml/24 hrs and no
change with rehaydration
 Serum creatinine > 3mg/dl.
 Cause:
 RBC sequestration in the microcirculation
 Manifested as ATN

103
5. ARDS
 Manifested with progressive worsening
of shortness of breathing
 Can occur after several days treatment
 Pathology is unclear
 Mortality >80%
 Careful with hydration

104
6. Lactic acidosis
 Labored deep breathing
 Dx:
 Venous lactate level >5mmol/lt
 Bicarbonate <15 mmol/lt
 pH < 7.25

105
Contd.
7. Convulsion
 Greater than two seizure in 24hrs.

8. DIC

9. Hypotension
 Systolic BP < 80 mmHg

106
Contd.
10. Hemoglobinuria
 Black water fever
 Can cause renal failure

 Others-included in the 2000 WHO

 Obtundation: Arousable
 Prostration
 Hyperparacytemia: > 20% in any population and
> 5%in non immune.

107
Diagnosis
 1.Peripheral blood smear:
Thin film
 Number of parasitized RBC per ul=

Parasitized RBC/1000 RBC or 200

WBC
 Numbers > 105 severe with increased risk of

dying
 Poor prognosis:

 >20% of parasites with visible pigment

 Phagositised malarial pigment in > 5% neutrophiles

108
Contd.
 Thick film:
 To concentrate the parasite by 20-40 x
 Increases sensitivity
 Count parasites and WBC (200)
 Up to 100-200 field should be examined
before declaring negative

109
Contd.
 2. Antibody based tests/sticks
 Histidine rich protein 2 (pfHRP 2)
 LDH Ag in finger prick blood
 In patients who taken antimalarial and
cleared peripheral pasitemia

 3. CBC:
 Anemia, leukocytosis, thrombocytopenia

110
Contd.
 Prolonged PT and PTT
 RFT
 Serum creatinine
 BUN
 Serum glucose
 Serum Na, HCO3
 LFT, Bilirubine
111
Treatment
Principles:
 Document positivity

 Grade the severity

 Clinical signs
 Parasitic load
 Type of malaria
 Benign human malarias-vivax, ovale and malarae Vs P. falcip
 Classify –complicated Vs uncomplicated
 Asses co morbidity
 Pregnancy
 Children
 Preexisting cardiac and renal failure

112
 Drugs
Three broad groups:
 1.Aryl amino alcohols- quinolone related or like
 Quinine, Quinidine, Chloroquine, Amodoqune, Mefloquine,
Lumefantrine, Primaquine

 2. Antifols:
 Pyrematamine, Proguanil, Chlorproguanil, Trimetoprim

 3. Artemisinin compounds:
 Artemisinin, Dihydroartemesnin, Artemether, Artesunate
 Broadest action against asexual parasites-medium sized rings to
early schizonts
 It has a rapid therapeutic response
 Antibacterial- Sulphonamides, TTC, Macrolides, CAF-slow action

113
Contd.
 Quinine acts in the middle third of life
cycle when there is greatest increase in
parasitic synthesis and metabolic
activity
 Antifols acts a little later
 Both donot act once schizont has formed
also not active against young rings –
artemisnin is preferable

114
Benign human malarias
 P. vivax, P. ovale, p. malarae
 Chloroquine:
 Sensitive
 Dose-10mg/kg base, same after 24hrs, 5mg/kg at 48hrs.
(4+4+2)
 Primaquine:
 For radical cure-prevents recrudescence. Relapse is seen in
50% of those infected.Primaquine eradicates hypnozoites in
80% of patients.
 Dose-15mg/day for 14 days.
 Monitor for vomiting with in 1 hr
 Supportive-antipyretics

115
Contd.
 P. vita and pregnancy
 Increased anemia
 Decreases birth weight by 100gm
 Affects multigravida than primigravida

116
Uncomplicated P. falciparum
 Sulfadoxine- pyremetamine(SP)
 Three tab. Stat
 Resistance is increasing-40%
 Artemisnin(20mg)+lumefantrine(120gmfor 3
days.
 Quinine-po
 Mefloqine
 Artemether(4mg/kg)+Mefloquine x 3d
 Atavaquone+proguanil(malarone)-x 3d
117
Contd.
 Follow up:
 Daily BF till negative
 At 48 hrs parasite decrease by 25%
 Cleared by 7th day
 If both requirement is not mate and adherence
is good suspect drug resistance- use alternate
drugs
 SP Artesunate+mefloquine
 Mefloquine quinine+doxy/clindam or
artesunate+ doxy

118
Drug resistance-WHO def.
 R1 resistance (low grade)
 Recrudescence b/n 7-28 days after completion of Rx
following initial resolution of symptoms and parasitic
clearance
 R2 resistance (high grade):
 Decrease parasitic load by >75% at 48hrs but failed to clear
in 7 days.
 R3 resistance
 Parasitemia does not fall by >75% with in 48hrs.
 Reading;
 treatment failure definitions, early and late treatment
failures

119
Complicated P. falciparum
 A medical emergency
 ABC
 Resuscitate with IV fluids
 Look for existing complication
 Immediate blood glucose, Hct, parasitic
load, renal function, ABG

120
Contd.
 Antimalaria
 Quinine 20mg/kg loading through infusion
 Maintenance-10 mg/kg 8hrly
 Decrease the dose after 48 hrs
 Prevent hypoglycemia
 Iv fluid with 10%
 Encourage po feeding
 Alternate:
 Artesunate iv/im 2.4mg/kg then 1.2mg/kg x5d
 Artemether im 3.2mg/kg stat then 1.6mg/kg

121
Contd.
 Monitoring:
 Parasitemia +Hct every 6-12 hrs
 Exchange transfusion if parasi>15%
 If Hct <20% transfussion
 Blood glucose every 4-6 hours
 RFT daily

122
Mx of complications
 ARF:
 Fluid balance
 Hemofiltration and hemodialysis
 Pulmonary edema
 Position at 450
 Diuretics, oxygen
 PPV if immediate measures fails

123
Contd.
 Seizure
 Diazepam, Phenobarbitol
 Aspiration pneumonia
 Gram negative septicemia
 If conditions deteriorate
 Antibiotic.

124
Chronic complications
 Quartan nephropathy
 Nephrotic syndrome-an immune complex

 Hyper reactive malarial splenomegaly syndrome (HMS)

 Polyclonal hypogammaglobilinemia-IgM
 Polyclonal B cell activation
 Splenomegaly, negative BF, pancytopenia
 Hepatic sinusoidal lymphatic infiltration and kupffer cell hyperplasia
 Response to proguanil
 Rx. Chloroquine-for duration of exposure
 Mefloquine
 Splenoctomy if failed response after 6 months

 Burkits lymphoma

125
Prevention
 Insecticide, barriers
 Avoid mosquito bite at peak feeding times-dusk and down
 Insect repellents-DEET
 Impregnated bed nets
 Chemoprophylaxis
 Chloroquine weekly or proguanil , intermitent SP for
pregnant mothers
 Travellers: (1 wk before and 4 wk after)-atavaquone-
proguanil 3.75/1.5mg /kg daily, mefloquine 250mg wkly,
doxycycline 100mg/d.
 Rapid dx and Rx

126
Spp. In thick blood film.

127
Spp in thick blood film

128
129
130
VIRAL SYNDROMES

131
INFLUENZA
 Orthomyxo virus
 Three types:
 Type A-most frequent cause
 Type B
 Type C
 Spread –person to person

132
Manifestation
 IP : 48 hours
 Fever >39oc
 Head ache, back and leg pain
 Coryzal symptoms
 Inflamed respiratory mucosa

133
Complication
 Hemorrhagic bronchitis, pneumonia
 Fatal viral pneumonia
 Secondary bacterial infection
 Encephalitis, myocarditis

134
Treatment
 Symptomatic
 Steam inhalation
 Antiviral-Amantadine 200mg/d for 3-7 d

135
Viral hemorrhagic fever
 Filofiridae
 Marburg
 Ebola
 IP; 7-10 days
 Abrupt onset of head ache, myalgia and
fever
 Prostration, rash, shock
 Bleeding manifestation
136
LEISHMANIASIS

137
Epidemiology

138
Learning objectives (1)

 Define leishmaniasis
 Enumerate types of leishmaniasis
 Describe Global burden and distribution of the
disease
 Describe distribution of leishmaniasis in Ethiopia
 Cutanous & muco cutaneous

 VL

 Describe life cycle of leishmania

139
Learning objectives (2)

 Explain factors determining distribution of

Leishmanisis
 Identify risk factors for transmission

 Describe factors that determine difference in

clinical manifestation

140
Definition

 Group of disease caused by protozoa parasite

- Leishmania species
 Over 20 species of Leishmania parasite cause the
disease
 L.Donovani, L.Infantum, L.major, L.tropica,

L.braziliensis, L.mexicana, L.aethiopica……

 Transmitted by vector female sand flies
 (phlebotomus species) during blood feeding
 Lutzomyia in south America
 Results in a variety of clinical syndromes ranging
from mild skin lesion to lethal illness.
141
Types of leishmaniasis

 Cutaneous leishmaniasis

 Mucocutaneous leishmaniasis

 Visceral leishmaniasis

142
Types of leishmaniasis

1.Cutaneous leishmaniasis

- It is an infection of the skin macrophages

- Manifested by chronic ulcerative or nodular
lesions
- Usually heals spontaneously
- It is not life threatening

143
 Cutaneous leishmaniasis

 It is the most common Leishmania infection

 10 million cases of CL/annually
 Common in
- Middle East
- Southern Europe
- Asia (S.west,Central,East)
- Africa (North, West, East)
- Latin America

144
 2.Mucocutaneous Leishmaniasis

 It is infection of oropharyngeal +/- nasal

mucosal macrophages
 Results in mutilating lesion and

disfigurement in the face

 Does not heal spontaneously

 Mostly occurs in Latin America, but

occasionally in East Africa

*** Hundred of cases/yr
145
 3.Visceral leishmaniasis

 Also called KalaAzar “ Black disease’’

 Fatal forms of Leishmaniasis
 Most of the viscera/ organs are affected- Spleen,
Bone marrow, Lymph nodes, Liver, Gastro-intestine,
Respiratory Tract
 L.Donovani complex is the causative species
 L.Donovani, L.Infantum, L.Chagasi

146
Ecology

 Most forms of Leishmaniasis are Zoonoses

with man as incidental host

 Transmissions are -
 Zoonotic
 Anthroponotic
 Reservoir hosts are commonly canines and
small mammals

147
The vector:
Phlebotomus orientalis

148
Global burden of VL
 Leishmaniasis Exists in 88 countries, VL in 70 countries
 350 million population is at risk for leishmaniasis
 Annual incidence estimated to be
1.5-2 million cases

 500,000 cases of VL occurs/year

 60,000 deaths occur/year
 90% of cases are from five countries,
India, Bangladesh, Nepal, Brazil and Horn of Africa (with
Sudan-Ethiopia-Kenya-Uganda and Somalia that
harbours 17% of the burden)
149
Global burden of VL

150
How can it exist in all these area
of the world?
 Zoonotic presence
 Diverse animal reservoir
 Sandfly can live in diverse environment

151
 Animal Reservoirs

Dog Nile grass rat (Arvicanthis niloticus)

Spiny mouse (Acomys) Jackal (Canis aureus) Serval (Felis Serval)

152
 EPIDEMOLOGY OF VL IN ETHIOPIA

 Animal Reservoir was not documented in the past, but

recently infected dogs found in Libokemkem (infected
with L. infantum, but not statistically
significative, will need wider studies, “Risk Factors for
visceral Leishmaniasis in a new epidemic site in Amhara region,
Ethiopia”.Seife et. al, submitted AJTMH, 2008)

 Transmission is Anthroponotic
 The main transmitting female sand flies in Ethiopia are,
 Phlebotomus Orientalis
 Phlebotomus Martini
 Phlebotomus Celiae
•“Risk Factors for visceral Leishmaniasis in a new epidemic site in
Amhara region, Ethiopia”.Seife et. al, submitted AJTMH, 2008)
153
EPIDEMILOGY OF VL IN ETHIOPIA

 VL is distributed throughout the lowlands of

Ethiopia
 Reported in five administrative regions of
Ethiopia
 It is reported from 40 different localities

 It is estimated 4,500-5,000 cases/annually

 Caused by L.Donvani and L.Infantum

154
EPIDEMILOGY OF VL IN ETHIOPIA

 Endemic foci are

 Northwest Ethiopia
 Metema and Humera low lands
 Libokemkem/ Addis zemen high lands( new foci
2005)
 Konso and Abaroba in SNNRP

155
EPIDEMILOGY OF VL IN ETHIOPIA

 Reported in five administrative regions of the country

 Eastern Ethiopia – Somali region
 Northeastern Ethiopia
Awash Valley (Upper, Middle & Lower)
Ethio-Djibout Boarder–cases reported
 South and southwest Ethiopia
Dawa, Genale, Konso, Segen, Woito, and Omo River
Valleys
Ethio - Kenyan Boarder
Ethio - Sudanese Boarder

 Eastern Ethiopia – Somali region

156
EPIDEMIOLOGY OF VL IN ETHIOPIA
needs updating

157
EPIDEMILOGY OF VL IN ETHIOPIA

 Breeding sites for the sand flies

 Balantine Trees
 Acacia Forests
 Black cotton soil or Termite Hills
 Favorable Environmental conditions

 Altitude below 1500 meters (low land)

 High level humidity ( To 25-32 oC )

158
159
160
161
Epidemiology of VL in Ethiopia

 Factors for the emergence of epidemic

1. Mass movement of people

2. Change in the habit
3. Decrease in the immunity of the
Population
4. Climate changes
162
why there are different
clinically
 Difference in parasite
 Host immune response

163
What influences epidemiological
distribution?
 Recent resurgence of epidemic
 Change in climate
 Population movement

164
EPIDEMIOLOGY OF VL

165
EPIDIMOLOGY OF VL

166
Key points

 Leishmaniasis is a zoonotic disease

 It is transmitted by female sand fly
 Five regions of Ethiopia have Kalazar
 Endemic in 90 countries
 Control measures include
 sandfly control
 Treatment of case
 Control of the disease on other animals
infected by Leishmania
167
Pathogenesis of leishmaniasis

168
Learning objectives

 Describe Life cycle and transmission process

 Identify the impact of leshmania on body
 Identify the impact of leishmania on immunity
 Understand the impact of immune status on the
clinical manifestation
 Humoral

 Cell mediated

 Explain how body reacts to Leishmania

169
Learning objectives (2)

 Explain why there is variable immunological response

by different persons
 Identify variables that affect clinical outcome without
treatment
 Explain what happens to the parasite in the body
 Identify body defenses

Explain Impact of treatment on immunity

170
 I. The Leishmania Parasite
 causative agent for leishmaniasis
 has two developmental stages
1. Amastigotes
 in vertebrate hosts.
 Ovoid, 2 to 4 m in size (also called LD bodies)

 Intracellular (inside macrophages), few present in peripheral

blood
 Spread all over the body through circulating macrophages

 Also present in PMN cells and monocytes

 Divide by binary fission

 Exit forms

171
amastigotes

172
Amastigots

Extracellular Intracellular

173
2. Promastigotes
 Seen in vectors as well as
cultures

 Fully developed
promastigotes are 15-20
x1-2 micrometer in size.

 Infective form for

humans
 Flagellated form

174
Promastigots

175
II. The Vector
 Sand flies of the genera Phlebotomous (old world)
and Lutzomya (new world) act as the intermediate
hosts.

 of 500 known phlebotomine species, only 30 of them

have been positively identified as vectors of the
disease.

 only the female sand fly transmits leishmania

 in its search for blood, the female sand fly covers a

radius of a few to several hundred metres around its
habitat.

176
The Vector…

 Tiny, sand-coloured, 2 to 3
millimetre-long insect vector

 Have a short, hopping flight style

 They rest in dark, moist places in

habitats ranging from deserts to
rain forests

 Peridomestic sandflies rest in

debris or rubble near buildings

177
 The Vector…
 The main transmitting female sand flies in Ethiopia
are:
 Phlebotomus Orientalis
 Phlebotomus Martini
 Phlebotomus Celiae

 Favourable breeding sites for the sand flies

 Balanite Trees

 Acacia Forests

 Black cotton soil

 Termite Hills
178
 The Vector…
 The female sand fly lays its eggs
 in burrows of certain rodents,

 in the bark of old trees,

 in ruined buildings,

 in cracks in house walls,

 in animal shelters and

 in household rubbish,

 In such environments, the larvae

will find the organic matter, heat
and humidity which are necessary
for their development.

179
 The Vector…

 The population of the sand fly

 increases with onset of the dry seasons and
 peaks at the beginning of the rainy season
 Number sharply fall inJuly/ August

 In Ethiopia the transmission is mostly Anthroponotic

 Peak of VL cases occur in the month of December to

February

180
 III. Transmission
Patterns of Transmission
 Three factor complex transmission

 1.Agent – the protozoa

 2. Sand fly –the vector

 3. Host – susceptible human subject

Man is the sole reservoir of infection.

 Four factor complex transmission

 1.Agent – the protozoa

 2. Sand fly –the vector

 3. Animal – non-human reservoir

 4. Man – causal interaction with endemic habitat

181
 Transmission: Animal Reservoirs

Dog Nile grass rat (Arvicanthis niloticus)

Spiny mouse (Acomys) Jackal (Canis aureus) Serval (Felis serval)

182
182
Transmission…

 Other (rare) forms of transmission

 Blood transfusion
 Contaminated instruments
 Congenital

 Disease patterns in human population

 Sporadic
 Epidemic
 Endemic
183
IV. Life cycle of Leishmania parasite

 Two hosts are essential to complete the life cycle.

 Humans and other vertebrates.

 Phlebotomine sand flies

184
 Life cycle…

 Female sandfly needs blood meal to lay eggs.

 During the process of taking blood meal, the sand fly

ingests Leishmania amastigotes from the skin/blood of
infected man

 In the midgut of the sand fly the amastigotes elongate

and develop into promastigotes.

 Promastigotes multiply by longitudinal binary fission,

migrate to the pharynx and buccal cavity. This process
takes 6-10 days.

185
 Life cycle…
 Promastigotes can be injected in to the skin of a person
while the sand fly takes blood meal from healthy individual

 The Promastigotes phagocytized by the macrophages

 The Promastigotes transform to Amastigotes inside the

macrophage

 The Amastigotes multiply inside the macrophage and

 Macrophages rupture and release the Amastigotes &

spread in the blood stream and infect other cells.

186
187
*Animation*

188
 V. Pathogenesis and Immunity
 Once the parasite is injected to the host, it will be phagocytized by
macrophage

 Infected macrophages rely on Nitric oxide (NO) production as an

innate mechanism of killing parasite, but the Leishmania parasite inhibit
the NO production and multiply in macrophage

 Infected macrophages rupture and Amastigotes are taken by phagocytic

cells

 Macrophage & dendritic cells present the Leishmania antigen to T cells

 Stimulation of T cell result in:

1.Th 1 pattern response
2.Th 2 pattern response

189
 The normal immune response

 Normal host defense in response to a foreign antigen

culminate in a rapid and efficient elimination of a none
self substance
 The process of elimination of foreign antigen involves
effector cells activity and their interaction through soluble
cellular secretions-Cytokines

190
 Immune system

 Innate and Adaptive response

 Mediated through WBC and secreted cytokines
 White blood cells
 Poly morphonuclear
 Neutrophils, basophils and eosonophils

 Mononuclear cells
 Monocyte / Macrophages
 Lymphocytes
 B lymphocytes – secrete imunogloblines

 T lymphocytes

 TH 1 cells – cell mediated immune response

 TH 2 cells – humeral immune response

191
 The normal immune response

Types of the immune response

 Non-specific – mediated through PMN cells, NK cells & non-

activated Macrophages

 Specific -- mediated through activities of CD-4, CD-8, B-

cells, NK cells (ADCC- antibody dependent cytotoxic cells) &
activated Macrophages.

192
Specific Normal immune response

193
 Specific immune response

194
Effect of IL-2

195
 Pathogenesis…

T cell Response

Th 2 pattern Response
Th 1 pattern Response

Effective cellular response Ineffective humoral response

T lymphocyte release IL-4,IL-5,IL-10,

T lymphocyte release IL-2 and INF gamma TNF - B

Activates macrophges to kill Leishmania Inhibit macrophage from killing Leishmania

Leishmanin skin test positive, but no clinical VL High Antibody level and clinical
196 VL
196196
 Pathogenesis...

 When ineffective humeral response occurs, the clinical

features begin to appear with in 2-6 months after the
infection.

 The clinical feature results from massive expansion of

Leishmania in the Spleen, Bone Marrow, Liver & lymph nodes.

 Epithelium of GIT, Respiratory tract and Nasal mucosa

might also be involved

197
 Pathogenesis…

 Further course of the disease depends on the host’s cellular

response.

 Cure correlates with an effective Th1 response and confers

immunity to the infecting strain.

 Infiltration of spleen and bone marrow result in:

 Anemia

 Leucopenia

 Thrombocytopenia

 Impaired antibody production (enlarged

spleen)
 Low CD4 count

198
 Pathogenesis…

 The patient with VL become debilitated as result of anorexia,

protracted fever

 Hypoalbuminemia will occur as result of malnutrition and

Liver impairment

 Finally immune suppression will occur and the patient will be

susceptible to different infections.

199
 Pathogenesis…

Spectrum of the disease

 Sub-clinical infection that resolves spontaneously

to

 Clinical visceral Leishmaniasis after the infection

 Malnutrition, Tuberculosis and HIV increase the

likelihood of infection to progress to disease

200
Effect of Ineffective Humoral Response on the disease progression

death
Severe and
complicated
KA/VL
1st symptoms
of KalaAzar/VL
Parasite load

time
201
Parasite load Effect of Cellular Response on Leishmania infection

sub – clinical infection

time
202
 Kala azar:
humoral immunity

?
Parasite load

cured:
cell mediated immunity

time
203
Effect of treatment on Immunity

 Clinical VL is almost 100 % lethal if left untreated.

 Dug treatment reduces parasites to a level where

“switch” occurs in the immune system

** from ineffective humoral response to effective

cellular immune response.

204
 Effect of treatment on Immunity

humoral immunity
Parasite load

cell mediated immunity

time
205
 HIV+

Poor drug response

Parasite load

no cell mediated immunity

time
206
Effect of treatment on the Immunity

 As result of treatment cellular immune response

occurs
 Any residual parasites are suppressed by T cells
 Level of anti-Leishmania antibody starts to fall
gradually
 Theoretically sterile cure doesn’t occur

207
Effect of treatment on Immunity

 By about 6-12
months Leishmainin
skin test
becomes positive

208
 Effect of treatment on Immunity

 The patient will be life long immuned to visceral

Leishmaniasis as a result of cellular immune response

 If cellular immunity doesn’t return( as HIV infected

patients), then relapse occurs usually with in 6 months .

209
Key points

 Leishmania is obligate intracellular protozoal disease

 Kalazar is sever clinical form of Leishmaniasis
 Cell mediated immune system is effective in control
of disease
 Treatment of the disease with drugs boosts the cell
mediated immunity
 Treatment will not sterile body from parasite

210
 Clinical presentations of VL

2 211
 Learning objectives

 Enumerate symptoms and signs of Kalaazar

 Describe the epidemiological definition (case
definition) of kalaazar
 Describe the range of clinical manifestations and
spectrum of Leishmanisis
 Enumerate concurrent infection that occur with
visceral Lieshmaniasis (Kala azar)
 Explain factors that determine disease spectrum
 Describe natural course of disease with and
without treatment
212
 Introduction to clinical
manifestations

 Disease spectrum:
• self healing (CL)
• fatal disease (VL)
 Depends on
• Species of parasite
• Immune response of the host

2 213
Clinical forms of Leishmaniases
Disease spectrum

Clinical types
 Cutaneous chronic lesion, different forms,
solitary or multiple-self healing
 Diffuse
 Localized

 Muco-cutaneous mutilating lesions on the

mucus membrane

 Visceral (Kala-Azar/ ‘black disease’): systemic

infection
214
Dermal forms (cutaneous)
 Distribution and prevalence
 Dermal
 Localized – number of nodules usually one
to a few
 Diffuse – number of nodules few

215
 Clinical manifestations of VL (Kala-
azar)

Fever
 Virtually all patients
 Continuous and high grade
 Prolonged duration (>2weeks)
 Despite high grade fever, patients are well
unless in advanced stage.

2 216
 Clinical manifestations…

Abdominal swelling and pain

 Dragging sensation

 Due to hepatosplenomegaly where

splenomegaly is common

2 217
 Clinical manifestations …

Weight loss

 Increased metabolism, malabsorption and

decreased food intake
 Concurrent diseases like Tb
 May have severe malnutrition-wasting.

2 218
 Clinical manifestations …

2 219
 Clinical manifestations …

Cough
 Intercurrent respiratory infections

 Interstitial pneumonia due to VL

 Tbc

Diarrhea
 Leishmanial entertis

 Concurrent infections

2 220
 Clinical manifestations …

 Anorexia
 Epistaxis
 Nausea and vomiting
 Weakness and fatigue

2 221
 Rare presentations of VL
 Neurological: psychosis, tremor, ataxia,
polyneuropathy, sensorineural deafness,
epilepsy
 Insomnia, arthralgia, ascites, uveitis
 Skin: hyperpigmentation-kal-azar,
hypopigmentation, Leishmanioma

2 222
 Clinical manifestations of VL in
Ethiopia
Symptoms % with symptoms
Fever 97
Weakness 98
Abdominal swelling 82
Weight loss 77
Sweating 54
Diarrhoea 49
Anorexia 29
Cough 14
2 Epistaxis 6 223
 Signs of VL-physical examination

 Vital signs- fever, PR(tachycaric), Wt, BMI

 HEENT-pale conjunctiva, ?icteric sclera
 LGS-lymphadenopathy, not common in
Ethiopia
 Chest-concomitant respiratory infections
 CVS-signs of heart failure due to severe
anemia
2 224
 Signs of VL…

Splenomegally
 Is a classical sign(95%)

 Non tender smooth surface

 Can be measured in centimeters from the

costal margin along anterior axillary line or

line of growth.
 If long standing and firm, may not regress

with treatment.
2 225
2 226
 Splenomegaly

2 227
 Signs of VL …
Hepatomegaly
 Less common than splenomegaly

 Measured below right costal margin

along the mid clavicular line

 Regression after cure is a rule

 Other signs-edema, jaundice…

2 228
 Signs of VL …

Signs % with signs

Splenomegaly 99
Pallor 87
Wasting 77
Hepatomegaly 69
Febrile 59
Lymph node enlargement 16
Oedema 7
Jaundice 2
2 229
Ascites 2
 Humera, Tigray (from Tropical
medicine)
Signs and symptoms Percentag
e
Splenomegaly 97
Fever 93
Cough 64
diarrhea 52
Hepatomegaly 41
Vomiting 28
Hemorrhage (PT & PTT Normal; 22
due to low platelet count)
2 Edema 16 230
 Clinical manifestations of
VL
Sudan Brazil India
 Fever 95% 95% 99%
 Splenomegaly 95% 99% 98%
 Uncomfortable spleen 85% 50% 50%
 Weight loss (wasting) 80% 98% 87%
 Anaemia 75% 98% 96%
 Lymph node enlargement 75% 30% 90%
 Loss of appetite 70% 20% 30%
 Cough 75% 40% 50%
 Hepatomegaly 60% 90% 98%
 Epistaxis (nosebleed) 50% 30% 10%
 Diarrhoea 40% 60% 50%
 Vomiting 15% infrequent
infrequent
 Jaundice 5% 10%
 Edema 5% 40%

2 231
 Clinical manifestations of VL…
Atypical presentations can occur (WHO manual):

 Occasionally without splenomegaly but with fever,

wasting, diarrhoea, cough, or combinations of
these.

 Simple cutaneous lesions (leishmanioma) may

occasionally precede, accompany or follow VL.

 PKDL may occur before VL in rare cases-(sub

clinical infection), or in Africa occur during
treatment (pre-, during- and after Rx- 8%, 18%
2 and 74% in Sudan respectively). 232
 Clinical manifestations of VL…
Atypical presentations:
 Infections due to L. infantum/ L. chagasi are apparently
often asymptomatic.

 Most individuals who have evidence of exposure to

Leishmania, with a positive leishmanin skin test or positive
serology (typically 3 - 30 % of the population in endemic
areas) do not recall having a clinical illness.

 Infection with L. donovani is thought to be more

frequently clinically apparent than infection with L.
infantum/L. chagasi,

 Sub-clinical VL is always more common than clinical VL.

2 233
 Clinical Case Definition for VL
• Clinical suspect:
- fever > 2weeks plus either of splenomegaly or
lymphadenopathy
 VL clinical case definition:
- fever > 2 weeks, with malaria excluded;
- plus either splenomegaly or lymphadenopathy;
- plus either of weight loss, anaemia, or leucopoenia.
 Confirmed VL case: patient clinically suspected or
with clinical case definition plus serologic or parasitologic
confirmation for VL.
• If a patient does not fit the clinical case definition, then
positive serology is not specific enough to diagnose VL.;
as 5-10% of adults in the endemic area will have +ve
2 anti-Leishmania antibodies. 234
 DIRECT AGGLUTINATION TEST
Case definition & DAT
DAT positive DAT positive
Kala-azar
Kala-azar

Case Definition
Population Population

Sensitivity = 95% Sensitivity = 95%

Specificity = 20% Specificity = 95%

Sensitivity = 100%
Clinical case definition alone
Specificity = 50%
235
 HIV/VL co-infection

 Unusual and non-specific presentations can occur

 Splenomegaly is less frequent
 Prevalence of clinical forms depends on
geographical area
 Rate of co-infection is high in Ethiopia
 Relapse is very common

2 236
 HIV/VL manifestations

2 237
 Complications in VL
 20 infections are common: pneumonia, bronchial
infections, tuberculosis, malaria, diarrhoea or dysentery, viral
infections, bacterial skin infections, otitis media and cancrum
oris (mouth lesions).

 Thrombocytopenia may cause epistaxis (nosebleed), or

bleeding from other sites, and this may precede death.

 Leishmania enteritis may be a cause of diarrhoea and

malabsorption; and pulmonary involvement may mimic
pneumonia.

 Death is mainly due to secondary infection, or haemorrhage

238
 Key points

 VL is wide spread and is an important public

health problem in Ethiopia.
 Fever and Splenomegaly are important features
of VL.
 Secondary infections are common in VL and
they can cause of deaths.
 VL is fatal if untreated.

239
Dermatological DDx

 Boils
 Tb scrofula
 Syphilis
 Etc.

240
DDx

 Typhoid fever
 Tuberculosis
 AIDS
 Brucellosis
 Chronic hepatitis, cirrhosis
 Lymphomas and leukaemia
 Portal hypertension (due to schistosomiasis) and
 Malaria (due to hyperactive malarial
splenomegaly).

241
 Principles of serological
tests

242
Principles of serological
tests.
Objective
At the end of this session participants will:-
 Know how serological tests work.

 Understand type of reaction involved in

each serological test.

 Differentiate Specificity and sensitivity of

a test.

243
 Screening and Confirmatory tests.

When screening for a disease, a test is required to

detect all positive cases i.e. highly sensitive test.

- In this process, a certain number of true negative

cases would be included i.e. False positive.

- Hence, a test that detects only positive cases of the

disease can be used to confirm the diagnosis i.e.
Specific test.

- This is mostly used in the preparation of test

algorisms.

244
 Serological tests are based on the reaction
between Ag and Ab produced by the humeral
immune response against the Ag.

 Antibodies can be:-

- Specific OR
- Non-specific

245
 Serological tests for
V.L

 Formol gel test

 Leishmanin skin test

 DAT (Direct Agglutination

test)
 rK39

 Katex agglutination test

 ELISA

246
 Formol gel test.
 It is based on the presence of marked increase of
specific and non-specific polyclonal globulin (IgG) in
the patients serum.

 It is by adding a drop of 30% formalin to 2ml of

serum and look for the white gel formation after
20min will indicate the presence of a high proportion
of globulin in the sample.

 But it is a non specific test since other infections may

cause high Ab production.
247
Leishmanin skin test
(Montenegro)

 Leishmanin skin Test (Montenegro Reaction)

 The test used for epidemiological/prevalence study.
 Indicates the number of persons that had an
infection with Leishmania at some point in their life.
 The test is conducted by giving interadermal
injection of Leishmania antigen in to inner surface
of the forearm
 An indurations with diameter >5mm within 48-72
hrs is a sign of positive reaction
 Positive reaction is associated with clinical cure.

248
 Cell Mediated
 When the antigen is Immune Response
inoculated under the
skin it induce production
of typical cell mediated
delayed hypersensitive
response.
 It is negative in active
stage of Kala-azar.
 It will be positive after
successful treatment
which changes from
humeral immune
response to cellular.

249
Effect of treatment on Immunity

Humeral immunity

e)
tiv
ga
ne
est
t
k in
Parasite load

(S

cell mediated immunity

(Skin test positive)

time
250
 DAT (Direct Agglutination
Test)
 Is a serological test in which patient blood is tested for
the presence of anti-leishmania antibodies using
leishmania antigens (mostly commercially prepared
promastigots).

 Serial dilution of pts blood is tittered with leishmania

Ag in V-shaped bottom micro titer plates and
incubated 8-12 hrs.
 If there is no Ab, the Ag will sediment to the bottom
of the well and form a sharp blue dot.
 If there is an Ab, there will be a reaction between the
Ag and Ab and the agglutination will be visible as a
cloud (enlarged dot).
251
252
 rK39 dipstick.
 The Ag used in this dipstick is a recombined 39 amino
acids sequence of the leishmania parasite (L. Chagasi).

 Is used to detect anti-rK39 antibody.

 Circulating antibody to rK39 Ag has high sensitivity and

specificity for active V.L.

 Different studies in different countries have shown different

specificity and sensitivity.

 It is a simple test procedure: it takes around 10mins to get

the result.
253
Positive rK39

254
 Katex agglutination
test
 Is used to detect leishmanial Ag in the urine of pts
with VL.

 The test uses latex particles sensitized with Abs

raised against L.donovani Ag.

 It is useful test in indicating treatment failure and

detecting VL in HIV coinfected pt.

255
 Procedure
 Urine sample is first boiled for 5mins to inactivate
substances capable of causing false positive reaction
with the latex reagent.

 Cool the urine to ambient temperature.

 50 µl of sample is mixed with one drop of latex reagent.

 Results are read after mixing for 2min.

 Agglutination indicates positive for VL.

 No agglutination indicates negative for VL.

256
 ELISA
 A micro-well coated with Ag of leishmania parasite
(eg. rK39) and Ab in the pts serum will react with
this Ag. It will be incubated for a certain time and
will be washed to remove excessive Abs.

 An anti-humanglobuline labeled with enzymes

commonly ALP or HRP.

 After incubation a substrate (TMB) will be added

and a color will be produced.

 The intensity of color will be read using ELISA

reader, absorbance is directly proportional to the
amount of Ab present in the sample.

257
Direct ELISA.

258
ELISA

259
??
??

260
 Results:
Versus the MSF treatment algorithm
rK39 DAT-pos or DAT-neg or
Result ASP-pos BL and ASP-neg
Positive 184 3 187
Negative 44 110 154
Total 228 113 341
Sensitivit
80.7% 75.0 – 85.6%
y
97.3% 92.5 – 99.5%
Specificity
98.4% 95.4 – 99.7%
PPV
71.4% 63.8 – 78.6%
NPV 261
 Conclusions : DiaMed-IT-Leish
in Sudan
 good screening test for VL. 90% sensitivity ( vs. DAT 98%)
possibly due to false-positive DAT. Back-up DAT or aspiration
required
 high specificity (99%) = a good diagnostic test
 simple, rapid and cheap (US$1); performed on finger-prick
blood; no cold chain.
 very suitable for field conditions
 facilitates active case finding and decentralisation
 reduces treatment delay
262
 Recommendation:
Diagnostic Algorithm
for Kala-Azar in Sudan

1. Clinical screening and exclusion of malaria

2. rK39 rapid test in clinically suspect 1o KA
 treat if positive
3. DAT on those with negative Opti-Leish test
 treat if positive
4. Aspirate on those with borderline DAT
 treat if positive

5. relapse kala-azar diagnosed by aspiration only

263
 Advantages
 Positive DiaMed-IT-Leish test is a
confirmation of kala-azar, and treatment
can start immediately
 Dramatic reduction of treatment delay in
~90% of KA cases
 Dramatic reduction of DAT tests by 35-
65%
 Dramatic reduction of aspirates in
“hospital” settings
264
 Recommendation:
New Diagnostic Algorithm

Estimated outcomes of recommended diagnostic

algorithm in clinically suspect primary kala-azar cases
with 50% prior probability of clinical case definition

Dipstick True-pos

Missed KA
47% 45%
DAT True-pos

DAT False-pos

3% 4% 1% True-Neg
265
 Management
of
Visceral Leishmaniasis

266
 Learning objectives
 Outline the general principles of management
 Assure the diagnosis of Leishmaniasis is made correctly
 Clinical

 Laboratory

 List supportive measures delivered during treatment

(other than drugs)
 Outline treatment aims
 Explain mechanism of action of the different anti-
leishmania drugs
 Identify the drugs that are effective against Leishmania

267
Learning objectives (2)

 List common and specific side effects

 Anticipate treatment challenges
 Measure treatment outcomes and prognosis
 Outline strategies for follow-up
 Outline measurements of cure

268
 General principle of Management

 General aspect
 Establish diagnosis

 Clinical

 Laboratory

 Assess for complications and co-infections

 Outline management options

 Specific drug management

 Supportive
 Nutritional support and feeding

 Correction of co-morbid conditions

 Anemia, super-infection and co-infection etc

269
Supportive measures during VL treatment

 Adequate nutrition, Vitamin supplements and iron

 Treat dysentery with antibiotics and hydration.

 Treat pneumonia with antibiotics.

 Maintain oral hygiene to prevent

 mouth infections.

270
Supportive measures...

 Maintain skin hygiene and treat skin sepsis.

 Treat malaria and/or tuberculosis if present.
 blood transfusion may be required
 Manage epistaxis
 Vaseline gauze packing, Compressed sponge

“nasal tampon”,
 Posterior epistaxis balloon Vit. C and antibiotics if
needed. Vit. K little value

271
 Specific drug management aims for Kala
azar
 Reduce the parasite burden,
 Prevent resistance
 Avoid toxic drug effect
 Improve complications: anemia, malnutrition & secondary
infections, etc
 ultimately the cell mediated immunity can return which

helps to clear the remaining Leishmania

 ‘sterile cure’ by drug/s is not possible to date.

272
The role of drug therapy

 Balance between effective immunity and parasite

reduction to favor the host
 High level of cell mediated immunity

 Lower parasite load

273
 humoral immunity
Parasite load

cell mediated immunity

time
274
 HIV+

Poor drug response

Parasite load

no cell mediated immunity

time
275
Drugs for Leishmaniasis Treatment

276
 Pentavalent antimony compounds-1st Line

• includes: PentostamTM, GlucantimeTM

• most commonly used form of treatment

• route of administration: intramuscular or intravenous

• half life of the drug is 2 hrs,

277
 Pentavalent antimony …

• elimination of the drug is via the Kidneys

• mechanism of action of Antimonials is unknown

• pentavalent form is converted to the trivalent form

• the trivalent form is the active form.

278
 Pentavalent antimony ….

 Pentostam / SSG (generic form): 100mg/cc

 Glucantime (Meglumin): 85mg/cc

 Dose: 20 mg/kg/day for 30 days

 Both have similar: mechanism of action,

side effect and
efficacy

279
Pentavalent antimony ….

280
 Precaution on SSG treatment
 all patients taking SSG treatment need close follow up
 Special attention to those at high risk of developing SSG
toxicity
 children ( < 2 years)

 old aged (>45 years old)

 patients with cardiac disease
 patients with renal disease
 patients with liver disease
 HIV co-infected patients
 severely ill patients

 severely anemic patients

 severely malnourished patients

281
 Precaution on SSG treatment (2)

 no upper limit of dose (as it depends on wt)

 but split the dose if > 10ml
 lowest dose is 2ml (200mg)
 in severe ascites: - subtract 5kg from an adult
-subtract 2kg for wt 24-40kg
-subtract 1kg for wt 10-23kg
 slow IV SSG is possible for those who could not tolerate IM
route (due to catchexia, pain and injection abscess)

282
 Stop SSG treatment if patient develops:

 Acute pancreatitis
 Jaundice developing during treatment
 Excessively high LFT (raised by ≥ 5x);
 Rise in the level of creatinine
 Any evidence of cardio toxicity
 Uninterrupted vomiting

 Failure to respond favorably in the first 2 weeks

 Declining hematological measurements

283
 AMPHOTERICIN B - 2nd Line

• Amphoterecin B deoxycholate also called FungizoneTM

• administered iv after a test dose of 1mg in 20-30 min

• is administered after adequate hydration.

• Dose: 1.0 mg/kg/d for 30 alternate days (15 mg/kg total

dose)- infused with 1L of 5% dextrose in 2-12hrs

• Efficacy is very good (62-100%)

284
 Amphotericin B - Toxicities
 Infusion related reactions & Thrombophlebitis
 avoided by slow rate of infusion

 premedication Paracetamol

 Nephrotoxicity & anemia can occur (monitoring RFT is

important

 Hypokalemia & myocarditis are serious toxicities

 but these are uncommon (1% of cases)

 Potassium supplementation (1x3 or 3 banana/day

285
Amphotericin B - Toxicities

 Safe during pregnancy

 Avoid Gentamicin, Streptomycin, Paromomycin or
other drugs that can cause renal toxicity.

286
 Amphotericin B lipid formulations

 newer formulations:
 Liposomal Amphotericin B (LAmB)
 Lipid complex Amphoterecin B (AmBLC)

 targets macrophage-rich organs.

 administered intravenously

 long half life: several days

287
 Amphotericin B lipid formulations…

 Reconstitution with 5% DW ;
 volume of 100ml/ 50mg vial

 Dose: 3-5 mg/kg- daily or intermittently for 5-7 doses

over 10-14 days;
 total dose 40mg/kg of body weight

 infused in 30-60 minutes.

 Similar to Amphoterecin B in its efficacy

288
Amphotericin B lipid formulations…

 Toxicity: less toxic than Amphoterecin B

 Useful for those who have severe illness, risk of death,

relapse and unresponsive to SSG
 Cost: very expensive (200-300USD/pt/Rx).

289
 Miltefosine/ ImpavidoTM

• Anti-neoplastic agent.
• It is an Alkylphosphocholine compound.
 Inhibits phospholipid and sterol biosynthesis

• It inhibits cell growth and proliferation .

 Anti-proliferative activity against Leishmania parasite

• The first oral anti-Leishmania drug.

290
 Miltefosine/ ImpavidoTM

• registered for use of VL RX in India since 2002.

• Its use for Cutaneous Leish. not well studied.

• Potential drug for 2nd line treatment of VL.

• Dose: 2-3 mg/Kg/day for 28 days

 Weight > 25 kg - 100 mg po daily

291
 Miltefosine…

• less effective in HIV co-infected patients.

• Toxicity: -GI: diarrhea and vomiting

- vomiting may be severe and intractable

• TERATOGENIC!
- avoid use in pregnancy, Breast feeding & women in child
bearing age (other wise with Contraception).

292
Miltefosine vs SSG study, Humera
Initial Treatment Outcome, MSF

Outcome Miltefosine SSG P-value

88.3% 87.6%
Initial Cure 0.90
(256 / 290) (254 / 290)
Parasitoligical 7.9% 0.7%
<0.0001
Failure (23 / 290) (2 / 290)
2.1% 9.7%
Death <0.0001
(6 / 290) (28 / 290)

293
 Final Treatment Outcome
6-month follow-up

Final Outcome Miltefosine SSG P-value

78.7% 82.2%
Final cure 0.42
(174 / 221) (189 / 230)

13.6% 3.0%
Relapse <0.0001
(30 / 221) (7 / 230)

7.7% 14.8%
Death 0.027
(17 / 221) (34 / 230)

294
 Conclusions from SSG/ Miltefosine study

 Among non-HIV VL cases, there was no significant difference

in initial cure rate, initial treatment failure or mortality b/n
Miltefosine & SSG

 Initial Miltefosine treatment failure was experienced mainly

by HIV co-infected VL cases (17.5% vs 4.6%)

 Miltefosine was less effective but safer than SSG in

population with high HIV prevalence.

295
 Other drugs ???

• Paramomycin (Aminoglycoside): 15 mg/kg/day

intramuscular for 21-28days
 alone or in combination therapy (SSG17/PM17)
 Nephrotoxicity and
 Ototoxicity (transient & reversible)
• Pentamidine: 4 mg/Kg/ d im/iv for 28 days
 Diabetes is the concern (12% incidence of DM in
India)
• ALLOPURINOL: Ketoconazole; Fluconazole; and
Itraconazole.

296
 Immunotherapy ??? Under investigation

• Th1 cytokines
– Interferon gamma (IFNγ) 100 μg/m2/d x 28dys)

– IL-12

– Tumor necrosis factor (TNF).

297
 Combination therapy- “Future Treatment ’’

Rationale for Combination treatment:

•Reduction of drug doses, (minimize toxicity and cost)

•Reduction of length of treatment, (minimize toxicity and

cost)

•Delay the emergence of resistance, and

•Increased anti-microbial activity

298
Supportive measures during VL treatment

I. Nutrition for VL patients:

 Over 30% of VL patients are malnourished

 Malnutrition predisposes to infections due to the

associated lowering of immunity

 VL patients require:
 Adequate nutrition,
 Vitamin supplements and
 Micronutrients including iron

299
 Nutrition...
 Good Nutrition:
 helps to decrease mortality due to VL

 helps patient for speedy recovery from illness

 helps to regain strong immune system

 helps to prevent VL relapse

300
 Time frame for the management of child with
severe malnutrition (health net international)
STABILIZATION PHASE REHABILITATION
Days 1-2 Days 3-7 Weeks 2-6

1. HYPOGLYCAEMIA
2. HYPOTHERMIA
3. DEHYDRATION
4. ELECTROLYTES (K, Magnesium)
5. INFECTION (broad spectrum
Antibiotics)
6. MICRONUTRIENTS (Vitamin &
Mineral)
NO IRON WITH IRON
7. INITIATE FEEDING (F-75) 100
kcal/kg/day
8. CATCH-UP GROWTH (F-100) 150-220
>>>
9. Sensory stimulation & Emotional support

10. PREPARE FOR FOLLOW-UP

301
302
303
 Supportive measures ...

II. Prevent and treat Infections

 Treat Dysentery and Pneumonia.

 Maintain oral hygiene to prevent mouth infections

 Cancrum oris- RX with Metron. & penic., if it occurs.

 Maintain skin hygiene and treat skin sepsis.

 Treat malaria and/or Tuberculosis if present.

304
 Supportive measures during …
III. Treat complications from Kala-Azar
 Blood transfusion may be required

 Epistaxis may occur due to low plat. Count and

mucosal infections.

 Manage epistaxis by:

 Vaseline gauze packing,

 Compressed sponge “nasal tampoon”,

 Posterior epistaxis balloon

 Vit. C and antibiotics if needed.

 Vit. K has little value

305
Treatment Challenges

306
 Treatment challenges…

 Rx Unsatisfactory:
 Feasibility,

 Toxicity,

 Affordability,

 Lack of data and

 Efficacy in HIV co-infection

 Few drugs – crucial to protect them!!

 Rational use

 Surveillance

 Combination

307
 Follow up during treatment-

Response to Therapy

 First 7-10 days:

 Fever disappearing

 Pt. looks stronger

 Pt. has good appetite

 By 14 days after starting treatment:

 Spleen size regressed

 Hemoglobin level improved

 weight gained/?edema

308
 Follow up during treatment…

Response to Therapy

 At the end of treatment:

 Patient is a febrile

 Spleen size smaller than on admission

 Increased Hgb level

309
 Follow up during treatment…
 treat concomitant illnesses: malaria, intestinal
parasitoses, malnutrition and anemia if present

 provide adequate nutrients

 In HIV/VL co-infection: start ART after VL Rx

 ? TOC only if indicated

310
 Treatment Out come
 Clinical or parasitological response-

 Discharged- discharged from KA treatment alive with or

without ToC during the month after completion of the
recommended dose of treatment for.

 Cure:
 Initial clinical cure/ initial parasitological cure
(TOC)
 Definitive cure: free of relapse by 6 months after
initial clinical or parasitological cure;
- decision can be clinical -TOC may not be
needed

311
 Treatment out come…

 Relapse: Patient returns with symptoms & signs consistent

with VL after successfully discharged treated with SSG and
negative ToC and found parasitologically positive for VL

 diagnosis is made only by parasitologic test

 Relapse can be 1st, 2nd, 3rd,etc

depending of the no. of the relapse(s) occurred.

312
 Treatment Out come…

 Defaulters: refers to patients who left the KA treatment

centre before completion of the recommended treatment
duration.

 Treatment failure/unresponsive: KA patients who have failed

to respond despite taking adequate and appropriate
treatment.
 no decrease in parasite load; or
 TOC 4+ for those ToC not done at start of treatment

313
 Treatment Out come…

 KA Death- KA cases died while on treatment for Kala-Azar.

 irrespective of the cause of death.

 Referred/transfer out: KA cases sent to other centre for

better management or for any other reason.

314
 Evaluation of cure

 Cure is best defined as the absence of clinical features

after completion of recommended treatment for VL in
addition to negative parasitologic test for LD bodies.

 Initial cure: right after completion of treatment

 Definitive cure: 6 months following treatment

315
 Evaluation of cure

 Clinical assessment:
 weight gain,
 Regression of spleen size,

 without fever for the last 2-3 weeks,

 Haemoglobin &WBC should be rising.

 Parasitological confirmation of cure is not routinely

necessary
 reserved for cases where response is in doubt

 essential in the treatment of relapses.

316
 Evaluation of cure...

 After treatment the patient should be reviewed:

 at 1st month,

 at 3rd month and

 at 6th month.

 Review for: complaints (fever, rash, mass)

anaemia
spleen size
skin rashes

 Patients should be told to report if they develop symptoms of

VL or skin rash (PKDL).

317
Which technique is appropriate for ToC?

 Appropriate technique for ToC not identified

 Parasitological test
 Invasive, painful and risky procedure

 or Blood PCR
 needs sophisticated laboratory

 or urine Antigen test

 needs improved sensitivity

 needs less objectionable procedure(? Boiling of urine to

inactivate other substances)

318
 Initial Parasitological cure

 also called Test of cure(TOC)

 sample from spleen, LN or BM

 test done on 25-30 days of treatment

 No clinical sign that best correlates with +ve TOC or that

predicts increased risk of relapse
 Pt with TOC 4+ parasitemia can look like healthy

319
 Initial parasitological cure …
ToC should be done (for any patient whose) :
 Clinical response was poor

 Hematologic parameters are not sufficiently good to

permit discharge

 To ensure that discharge is appropriate for those with

difficulty for returning for follow up

 Physician’s decision- individual basis

 ToC is also important for monitoring drug resistance

320
 Initial parasitological cure …

 If –ve TOC, it’s called ‘Effective parasite clearance’.

 Other scenarios;
 If TOC shows scanty positive, continue the same

treatment till two consecutive weekly aspirates are

negative.
 Maximum SSG dose being for 60 days.

 If still positive, treat with 2nd line drug

321
 Cont…

Primary unresponsiveness or non-response cases

 have to be treated with 2nd line drugs

 Clinical judgment always takes priority in treating VL cases

 Each patient needs follow up at 3rd and 6th month visits.

 Assess fever, Splenomegaly, CBC profiles & general condition

of patient.

322
Definitive test of cure

Aspirate done at 6th month of follow up to see for

definitive cure.

 Not a routine practice

 Prediction of positive ToC not possible

 If –ve, it is definitive cure

 If +ve, treat as Relapse

323
 Definitive…

 Relapse is diagnosed when a patient presents with clinical

KA and +ve parasitology after completion of treatment.

 Difficult to differentiate b/n relapse and re-infection

 Hence all returns should be considered as Relapse and

managed accordingly.

324
Effect of 30 days SSG treatment on
Spleen size

Hackett’s grade Before Treatment After Treatment

0 11% 78%
1 21% 12%
2 41% 9%
3 21% 1%
4 6% <1%
5 <1% 0%

325
 Prognosis of VL

 Predictors of bad prognosis:

 AIDS, low CD4+ count
 severe concomitant opportunistic infection
 Thrombocytopenia
 Relapsing course
 ? Without secondary prophylaxis for VL

326
 Prognosis of VL…..

– Duration of illness >5 months

– Age: (extremes) >45yrs and <2 yrs
– Severe anemia
– Very low BMI <13 or Wt/Ht <60%
– Those in a state of collapse
– Vomiting, Pneumonia, diarrhea or bleeding

327
 Key points

 The aim of drug management in VL is to reduce parasite in

the body,
 not to eliminate/ not sterile cure.

 There are few drugs available for VL –rational use is very

important.

 Clinical response is very important marker of treatment.

 HIV negatively affects the treatment out come for VL co-

infected cases.
328
Management of Complications of
Visceral Leishmaniasis

329
Learning objectives

 Anticipate and treat other concurrent infections

 Enumerate complications arising after Rx of VL
 Recognize and treat PKDL.
 Detect and treat Relapse cases.
 Identify Drug toxicities and address their
management

330
Anticipated complications

 Drug side effects and toxicities

 Infections
 Relapse
 PKDL (post Kala azar dermal leishmaniasis)

331
1. Management of major drug toxicity

 Pharmacokinetics of SSG
 SSG is excreted through the kidney

 Has a half life of about 2hrs in the blood

 Minor but common side effects

 nausea, anorexia, metallic test, arthralgia,

myalgias, injection site pain

332
Drug toxicity

 Anti-leishmania drugs have their own potential

toxicity.
 Toxicity differs from drug to drug.
 Potential adverse effects have to be anticipated and
proper precaution should be taken.

333
Drug toxicity

 Minor but common side effects of SSG are common:

 nausea, Anorexia, Metallic test, Arthralgia, Myalgia,
Injection site pain
 fatigue, and thrombophlebitis could occur.

 Moderate side effects are not usual and serious

toxicities are rare.

334
Toxicity cont’d

- Elevated liver enzymes, agranulocytosis, and renal

failure could occur.
- Laboratory abnormalities : elevated amylase
(biochemical pancreatitis),

335
Toxicity cont’d

 Serious SSG toxicities:

i) Pancreatitis:
- Sub clinical elevation of amylase could be as high as
in 90% of cases
- All serious toxicities are common in HIV-VL co-
infected patients

336
Toxicity cont’d

- Persistent vomiting and severe abdominal pain are

strong evidence on clinical ground
- Other related factors like extremes of age, low
Hgb,severe malnutrition increases the risk
- Stop treatment for 2-5 days and determine amylase
and lipase level if possible

337
Toxicity cont’d

 Carries high mortality if not timely acted but has

good prognosis if drug is stopped early
 Weekly amylase determination is important if facility
allows.

338
Toxicity cont’d

ii) Cardiotoxicity
-can lead to unexplained sudden death in less than 1%
of cases.
-usually occurs between 3-28 days.
-different degree of toxicity occurred among different
‘Batches’ of SSG and osmolarity of the drug.

339
Toxicity cont’d

 Serious cardio toxicity occurs in less than 8% of

cases & the Mortality is about 4%
 Features of dangerous cardiotoxocty include
prolongation of QTc [normal value= <0.37sec in
males
<0.4sec in females
 Considered abnormal if the absolute value is
>0.5sec
 Others like ventricular tachycardia,VPB and
ventricular fibrillation could occur.

340
Toxicity cont’d

 ?Baseline ECG and weekly or twice weekly ECG is

important for monitoring and detection of major
toxicity??? Otherwise monitor pulse rhythm

341
 Toxicity cont’d
Prevention of SSG toxicity
 Preventing drug accumulation prevents the toxicity

 Adequate hydration prevents accumulation between

doses.

 Advice patients to drink enough fluids so they pass

adequate urine

 ??Appropriate baseline lab tests has to be done and on

weekly bases if possible.

342
Toxicity cont’d

 It has to be used cautiously in patients with HIV,

older patients, and critically ill patients and needs
close follow up.

 Has to be avoided in patients with advanced renal

failure, cardiac arrhythmias and hepatic failure

343
Toxicity cont’d

Amphotercin B and AmBisome

 Follow for renal toxicity

 AmBisome is safer drug when compared to

Amphotercin B.(incidence of nephrotoxicity is less by

50%)

344
2. Infections

 Patients with VL are severely immunocompromized

and can get bacterial, parasitic, mycobacterial etc.
a) Pneumonia
-needs vigorous treatment
-suggested drugs can be substituted by different
drugs according to availability and sensitivity
pattern

345
Infections

 Needs Iv antibiotics in severe cases.

 Consider Tb in case of lack of response and do

sputum for AFB,ESR

b) Diarrhea
-Can be watery,mucous,or bloody.
-It’s a principal cause of death in VL if there is no safe
water supply

346
Infections cont’d

 Causative agents are:

Dysentery-amoebic or bacillary
Giardia
Salmonella
Campylobacter
E.coli
- because of proper sanitation and high
mortality, any diarrhea has to be treated
aggressively
347
Infections cont’d

-Unless water is from safe source, give ORS made

with boiled water, left to cool
- Replace fluid loss until adequate urine output
. S/E and treat accordingly ,if not possible treat
with antibiotics (ciprofloxacin and tinidazol

348
Infections cont’d

 Close follow up of patient for his blood pressure and

output has to be done to consider possibility of
sepsis
-In this case One has to be generous in giving IV
antibiotics.
- Others like Otits media,cancrum oris and various
skin infections could occur.
- Rationale for ANC(absolute neutrophil count) and
risk of infection

349
 Cpl’n cont’d

 Others like Anemia, bleeding tendency, malnutrition could

occur.

 Severe Anaemia:
• Causes include- BM infiltration, hypersplenisim,
autoimmune hemolysis and bleeding.
• Patients usually have pancytopenia (anemia, leukopenia
and thrombocytopenia).
• Severe anemic patients need transfusion (if facility allows)

350
 3) Relapse

 Definition: If a person returns with symptoms, after

having successfully been treated with antileshmania
and discharged
 Impossible to differentiate new infection from relapse
 All cases are considered relapses

351
Relapse cont’d

 Occurs in up to 5% of patients treated

 Could be as high as 50-80% in HIV/VL Co-infected

patients.
- Most occur in the first 6 Months of initial discharge

352
 Relapse cont’d

Risk factors for relapse

• Previous AIDS Dx and no on ART

• Low CD4+ count
• Previous VL episodes
• Failure to achieve clinical or parasitological cure
during the first episode

353
Relapse cont’d

- serology remains +ve for years after VL Rx ,so

relapse can only be diagnosed parasitologically

- Patients who relapsed have a higher chance of

second relapse ,and higher rate of failing to respond
to Rx= due to host factors (HIV,Tb etc) and because
of parasitic drug resistance

354
Relapse cont’d

 TOC in the Rx of relapses:

-drug resistance is a major concern ,and there
should be two –ve TOC before
discharging relapsed patient at each relapse

- the likelihood of having +ve TOC after treating a

relapse is as high as 10%
- Any further relapse is difficult to treat and cure

355
Relapse cont’d

 Rx of 1st Relapse:
- ?combination therapy preferred if available
- in our situation where SSG for 40-60 days 1st TOC
to be done at day 33 and 2nd TOC by day 40 etc.

356
 Relapse cont’d

- If still has parasite at day 60, consider unresponsiveness

and use Amphoterecin B 1mg/kg every other days for a
total of 15 doses with in 30 days.
1st TOC day 23, 2nd TOC by day 30
- Always consider the possibility of Co-infection with HIV,
and others like TB

357
4. PKDL(Post Kala-azar Dermal
Leishmaniasis

 It is almost always associated with L.donovani

 Macules, papules or nodules , not painful and usually
affecting the face but it may involve other parts of
the body, ulcerations are uncommon
 In 16% of patients, parasites can be demonstrated
by Microscopy in LN or BM aspiration

358
PKDL ....

 Evolution of the rash (Usually start from the perioral

area)
 Types:Pre, Para ,and Post Kala-azar dermal
leishmaniasis
 Diagnosis:
-Clinical Dx
 Treatment- who needs treatment
 Grading of PKDL

359
 PKDL...
 Grade 1 –scattered macular,papular or nodular skin
rash mainly on the face around the mouth, with or
without some lesions on the upper chest and upper
limbs

 Grade 2 – Dense macular, papular or nodular rash

covering most of the face and extending to the chest,
back, upper arm and legs. If lesions are extensive or
blackened ,it’s called Grade II severe and should be
treated

360
PKDL…

 Grade 3= Dense macular, papular or nodular rash

covering most of the body including hands and feet
-crusting ulcers, sloughing, scaling, blackening of skin
and spreading to mucosa of the lips and palate occur
- should be treated.

361
PKDL: Treatment

- SSG 20mg/kg/d for 30days, see for the response

(change in size and distribution of the lesions)
-continue treatment for 40-60days if no response.

362
PKDL: Treatment

Toxicity due to SSG is very rare in PKDL.

- Don’t treat till the lesion disappears

- Miltefosine has been used in certain cases of

unresponsive PKDL in HIV/VL infection

363
364
365
366
367
368
369
370
371
372
373
Key points

 Kalaazar can be complicated by a number of

complications
 Infections

 Toxicity of drugs during treatment

 Relapse after treatment

 Post Kala azar dermal Leishmaniasis

 Proper management of the complication improves the

general outcome of the treatment

374
Treatment of special groups

375
Learning objectives

 Define the special group

 Pregnancy
 Malnutrition
 Defaulter on treatment
 Presence of co-infections
 Enumerate why need special attention
 Provide management strategy for such groups
 Design mechanism of clinical assessment


376
VL and Pregnancy

 Pregnancy accompanied by a
 decrease in cellular immunity

 increase in Humoral immunity

 This physiologic event results in an

 increased risk of infection by some parasitic

agents whose
 immunity is based on T-helper 1 cells like

leishmaniasis

377
VL and Pregnancy Cont’d

 The disease is life threatening for the mother and

may have consequences for the fetus.
 VL has similar clinical presentation and signs during
pregnancy as in others
 Similar yearly incidence of VL in pregnancy as other
healthy adult populations

378
VL and Pregnancy Cont’d

 Higher susceptibility of parasitic infection in

pregnancy
 Safety of the drug has to be considered during
treatment of VL in pregnancy
 FDA has categorized “pregnancy risk categories only
for AmBisome and Amph.B. under Category B =
animal studies show no evidence of harm to the fetus,
 usually safe but benefits must outweigh the risks

 however, there are no adequate and well

controlled studies in pregnant women

379
 VL and Pregnancy Cont’d
 Paramomycin category C= “animal studies have
shown an adverse effect and there are no
adequate and well controlled studies in pregnant
women”
 Category X: Miltefosine “evidence of fetal
abnormalities or risks”
 Category C for SSG: Safety for use during
pregnancy has not been established.

380
VL and Pregnancy Cont’d

 Higher rate of miscarriage occurred during

SSG treatment than with AmBisome in one
study
 SSG passes through the placenta, and in
Mice leads to dose dependent increase in
fetal resorption and LBW
 Insignificant quantity found in breast milk

381
VL and Pregnancy Cont’d

 pregnant ladies should be treated with the

safest drug available.

Rx:AmBisome or Amphoterecin B

Risk benefit has to be outweighed in using

SSG
specially during the first trimester.

382
VL and Malaria

 Malaria is a severe complication of VL

because patients are already weak, have
ineffective spleen function, and are already
anemic.
 B/F or RDT needs to be done on every
patients at admission from endemic areas.
 There are no reliable data up to the rate of
co-infection

383
Malaria/VL cont’d

 Treatment of both at a time needs care and

attention because of overlap of drug side
effects.
 Quinine and SSG results in QT prolongation
and have similarity in other cardiovascular
side effects

384
Malaria/VL cont’d

 Rx: in uncomplicated pf malaria, Coartem has

to be used and the patient can get his SSG
 - In severe malaria, IM Artemether has to
be used

385
Malaria/VL cont’d

 If treatment with quinine is inevitable, stop SSG for

VL while quinine is being used.
 After treatment with quinine is finished, resume SSG
to a total of 30 injections, starting 24hrs after the
last dose of quinine

386
Malaria/VL cont’d

 Consider shortening quinine usage for 3-5 days and

finish with Coartem
 This kind of patients need strict follow up and
appropriate laboratory investigations to monitor
response.

387
Management after drug
interruption
 Drug interruption occurs in two settings:
 medical interruption
 defaulting by patient-rare but could occur in cases of
insecurity/evacuation
Scenarios:
i) If it’s discontinued for less than 5days, resume
treatment where patient has left off and continue till
normal number of doses of Rx has been given

388
Interruption cont’d

ii) if 5-15 days of interruption,

continue Rx till normal number of doses has been
given but do TOC at the end of treatment
iii) If 15 days or more interruption, the
patient needs readmission, for
parasitological testing :
=if positive, restart Rx as day 1 and do TOC before
discharge.
=If test is negative, give Rx till normal number of
doses has been given

389
 Key points
 The available anti-leishmania drugs require special
precaution during management in pregnancy and
malaria co-infection.

 The management of Leishmaniasis treatment

interruption depends on the duration of interruption
of the treatment.

390
 Learning objectives

 Explain the interaction between kalaazar and HIV

 Impact of HIV on kalaazar
 Impact of Kalaazar on HIV
 Identify the peculiarities of HIV kalaazar co-infection
 Diagnosis
 Clinical presentation
 Laboratory results
 Describe the implications on treatment outcome
 Choices of drugs
 Response to drugs
 Treatment outcome
391
391
 Introduction

 VL is an opportunistic infection in HIV-infected patients

(AIDS defining illnesses, WHO).

 Affects similar cells

 Exert synergistic damaging effect on the cellular immune

response.

 HIV facilitates the spread of VL and also complicates its

management.

 VL accelerates the onset of full blown AIDS

392
392
Effects on Immune System

Malnutrition HIV

 CD4 T-lymphocyte number

 CD8 T-lymphocyte number
 Delayed cutaneous hypersensitivity

 CD4/CD8 ratio

 Serologic response after immunizations

 Bacteria killing

393
393
 Peculiarities of HIV-VL co-
infection

 Parasites can be in unusual sites

 Presentations may be atypical
 Mortality is high with co-infection (3.5-4 times
higher)
 Lower response rate for treatment
 Treatment may have serious side effects
 Relapse rate is very high

394
394
Peculiarities HIV-VL co-infection

 Treatment after relapse may be refractory

 Little data on secondary prophylaxis
 Sterile cure is not possible
 HIV increases the chance to develop clinical VL rather
than sub-clinical self healing infection
 Co-infected cases with low CD4 are highly infective

395
395
 Epidemiological Implications of HIV on VL
 HIV infection increases the risk of developing an active
disease by 100 to 1000x in endemic areas.

 VL- HIV co-infection rate is reported to reach up to 15-

30% in Humera

 Groups at higher risk of co-infection in Ethiopia:

 Seasonal migrant labourers

 Sex workers

 Young adults in resettlement areas

 Truck and public transport drivers

 Military personnel deployed in border areas

396
396
Epidemiological Implications …

 Overlapping geographical distribution of VL and HIV

is increasing due to:
 Spread of AIDS from urban to rural areas and

 Spread of VL from rural to urban areas

 Co-infections can lead to epidemiological changes

modifying the traditional patterns of zoonotic VL
 because co-infected patients harbouring a high

number of leishmania in their blood.

397
397
 Epidemiological Implications …

 Fear of future epidemics from the pool of co-infected

patients

 Leishmaniasis can be transmitted through sharing of

needles
 71.1% of co-infected patients in SW Europe are

intravenous drug users.

 In areas where transmission is anthroponotic, VL/HIV

co-infected patients should be targeted as potential
reservoir of infection.

398
398
 Immunologic Interactions b/n VL &
HIV

 VL and HIV both attack the immune system

 resulting profound immunodeficiency

 exert cumulative deficiency of the cellular immune

response since both agents damage similar cells.

 depression of the T-cell response and disturbances

of cytokine networks.

399
399
Microbiological Features

 In HIV +ves, VL is mainly caused by L. infantum or L.

donovani
 Other species such as L. braziliensis, L.
aethiopica, L. tropica and L. major have also been
documented as causative agents

 The anergic state of co-infected patients result in

development of Visceral disease from
dermotrophic parasite and the vice-verse.

400
400
 Clinical Presentations of VL in HIV
Patients

 Changing frequency of usual clinical presentations

 Splenomegaly less frequent (97.4% vs 86.6%).

 Other concomitant OIs can complicate clinical

diagnosis of VL in 42-68% of co-infected
individuals,

 More frequent moderate or severe PKDL.

401
401
 Clinical presentations…

 A relatively avirulent Leishmania strain can

disseminate to the viscera.

 Unusual and non-specific presentations are more

common in co-infected pts.

 Atypical locations can be the first clinical

manifestations.
 Intestinal, pulmonary, oesophago-gastric, lingual,

laryngeal, etc. involvement.

 Fever of Unknown Origin.

402
402
 Diagnostic Implications of HIV on
VL

Microscopy and culture

 Splenic and Bone marrow aspirates

 can yield false –ve results due to associated

pancytopenia.
 Culture has a sensitivity of 63-100%.

 Peripheral Blood
 Parasites are more commonly found in circulating

blood monocytes.
 ~ 50% sensitivity in Giemsa stained peripheral smear.

 ~ 70% for cultures of buffy-coat preparations.

403
403
 Diagnostic implications…

Serological Diagnosis
 diagnostic sensitivity of serological methods is lower in
co-infected patients as compared to none co-infected ( ~
50% vs >90%)

 The sensitivity of different tests:

 20-22% for immunochromatographic rapid test (rK39)

 90% for Direct Agglutination Test (DAT)

 74-85% for immunoblotting.

 at least two different serological tests should be used for

diagnosis.
404
404
 Chemotherapeutic implications of HIV on
VL

 treatment is essentially similar

 1st line drug: Pentavalent antimony compounds

 2nd line drug: Amphoterecin B

 efficacy of antimonials & liposomal amphotericin

B was comparable in most cases,

405
405
 Chemotherapeutic implications of HIV on
VL

 all VL drugs are less effective in HIV patients

 toxicity of pentavalent antimony is greater in HIV

patients
 lower rate of toxicity with liposomal ampho (Laguna F
etal.)
 Miltefosine was less effective, but safer than SSG for
treatment of VL in a population with high HIV prevalence
(Humera study)

406
406
 SSG outcome & HIV status (Humera, 1999)

HIV pos HIV neg

# Treated 27 112

Death rate during treatment 33.3% 3.6%

Final Cure Rate (6m follow-up) 43.5% 92.1%

Trans R Soc Trop Med Hyg, 2001, 95: 668-672

407407
407
 Chemotherapeutic implications…

 frequent treatment failures, higher relapse rate and

more deaths during follow up.

 with each relapse, patients get less responsive to

treatment and eventually become unresponsive

 The time of relapse is usually 3-6 months

 Successive VL relapses are less acute and less typical

408
408
 HIV+

Poor drug response

Parasite load

no cell mediated immunity

time
409409
409
Chemotherapeutic implications…

 positive TOC should not automatically be followed by

further treatment.

 treat relapses of VL only if symptoms are severe.

 treat other OIs if diagnosed.

 counseling and psychosocial support are also equally

important.

410
410
 Prognostic implications

 30 % of HIV/VL patients will die during or within one

month of treatment.

 high mortality due to concurrent illnesses &

complications (pneumonia, diarrhea, vomiting, anemia,
bleeding, SSG toxicity)

 mean survival with optimal treatment is 12 months.

 only 16 % will survive for more than 3 years.

411
411
Prognostic implications…

 bad prognostics (before HAART):

 AIDS
 severe concomitant opportunistic infection
 low CD4+
 thrombocytopenia
 relapsing course

412
412
 Effect of ART on co-infected patients

• access to ART is a high priority for co-infected patients

• ART decreases incidence of new VL cases (overall
reduction 50-65%).

• ART prevents future clinical VL if Leishmania is

accidentally found on bone marrow biopsy/culture of
asymptomatic patients.

• ART increases survival of co-infected patients

– HAART mean survival: 66 months
413
413
 414
414
 Effect of ART…

 relapse is possible in HIV-infected patients on ART (due

to increased survival induced by HAART if CD4+ <200
cells/L, but even if very low HIV-viral load is achieved.

 ART delays VL-relapse

 PIs (Indinavir and Saquinavir) have direct inhibitory

effect on the proteases of Leishmania parasite
415
415
 Secondary Prophylaxis (Maintenance
Therapy)

• Primary prophylaxis is not indicated

• In zoonotic VL with HIV on ART, 2ry prophylaxis prolongs

disease-free interval

• In anthroponotic VL with HIV further research is needed

before maintenance therapy is recommended.

• Secondary prophylaxis can be suspended when the CD4+

count is maintained >200 cells/L for more than 6 months
416
416
 Secondary Prophylaxis…
• Pentavalent antimonials:
• Ampho.B lipid complex:
• Liposomal ampho B:
• Pentamidine:
weeks
• itraconazole + allopurinol:
• Miltefosine:
20 mg/kg/d every 3-4 weeks
3-5mg/Kg/d every 3-4 weeks
3-5mg/Kg/d every 3-4 weeks
4mg/Kg/d(300mg) every 3-4
daily
repeated courses
417
417
 Key points

 HIV prevention and control program activities should

cover VL-endemic areas to raise public awareness.

 VCT services should be established in all centers

providing VL treatment services, to encourage HIV
screening

 VL is an AIDS-defining condition and a valid entry

point to start ART, irrespective of CD4+ count.

418
418
BRUCELLOSIS

419
Definiton
 A bacterial zoonosis caused by a gram
positive rods called brucela spp.
 Source of infection: sheep, goats, camels
 Four major spp
 B. Melitensis: commonest cause of symptomatic
disease in humans
 B. abortis: cattle, buffalo
 B. Suis: swine
 B. canis: dogs
420
 Characteristics of the
organism
 Resistant to drying and freezing
 Alive > 6 months in dump soil and liquid manure
 Survives > 6 weeks in soil contaminated with
infected urine or discharge.
 Remained alive for > 2 months in soft cheeses
made from goat or sheep milk.
 Sensitive to sun light, ionizing radiation and
moderate heat, boiling, pasteurization

421
Risk factors:
 Occupational and domestic exposure to
infected animals and their products
 Contaminated food

 Person to person transmission by blood

or tissue donation is extremely rare

422
Mode of entry
 Mucosal or percutanous exposure
 Inhalational
 Ingestion

PATHOGENESIS
 Replication of intracellular organism in LN
 Chronic localized infection involving the RES, MSK,
GUS
 Local tissue response including granuloma
formation with or without necrosis or caseation or
abscess formation
423
Clinical presentation
 Incubation period: 1 week to several months
 Fever:
 undulating type-fever persists for weeks then
afebrile period then relapses
 Musculoskeletal symptoms
 Acute arthritis of hip or knee
 Low back or hip pain
 Difficulty if walking
 Profuse night sweats, apathy, fatigue, myalgia
 Abrupt or insidious onset
424
Presentation continued….
 Supportive clue
 Occupational or environmental exposure
 Similar illness in the family –seen in 50%
 Physical finding
 Osteomyelitis: lumbar & lower thoracic vertebra-
sclerosis, anterior osteophytes
 No destruction or gibus
 Septic arthritis-of knee, hip, sacroiliac, shoulder,
sternoclvicular-small pericapsular erosion
 Increased incidence of fetal loss
425
Diagnosis
 Culture –blood, CSF, BM, or joint fluid
 Biopsy of sample- definitive Dx. Positive in 50-
70%
 Non caseating granuloma
 CBC: mild anemia, thrombocytopenia, low WBC
 ESR and C-RP: normal
 X-ray
 Serology: positive result
 Titer >1:320 to 1: 640 and rising titer in 2-4 week

426
Treatment
 Treat current infection
 Relieve symptoms
 Prevent relapse
 Always exclude tuberculosis
 RX
 STM 1gm/d for 14-21 days
 + Doxycycline 100mg bid for 6 weeks
 WHO recommendation: Rifampicine 600-900mg/d +
Doxy 100mg bid for 6 weeks
 Complex infection for > 3 months
427
Post exposure prophylaxis
 Low risk-non specific lab exposure
 Rif + Doxy for 3 weeks
 Major exposure
 For 6 weeks
 Relapse seen in 30%
 Follow for up to 2 years

428
Schistosomiasis
Trematodes-Platyhelminths
 Blood flukes
 S. mansonia
 S. japonicum
 S. Intercalatum
 S. mekongi
 S. hematobium
 Hepatic flukes
 Fasciola hepatica
 Intestinal flukes
 Fasciolopsis buski
 Lung flukes
 Paragonimus westermani

429
Transmission
 Definitive host=mammalian/human
 Adults initiate sexual reproduction

 Intermidiate host- Snails

 Asexual reproduction

430
Life cycle
 Ova hatch in water to miracidia
 Inside a Snail changed to Cercaria
 Caracara attach to the skin
 In the SC tissue transforms to schistosomula
 Migration through venous or lymphatic to reach lung
and liver
 Adults descend down to intestinal veins or visceral
veins
 Ova penetrates the wall by enzymatic secretion and
reaches the intestinal lumen or urinary tract

431
Epidemiology
 Infection starts at the age of 3-4 yrs.
 Peaks at 15-20 yrs.
 Decreases after the age of 40 yrs.
 S. mansoni endemic
 Nile valley- Sudan, Egypt
 Arabian peninsula
 Latin America-Brazil
 S. hematobium
 Middle east, Africa, Indian
 S. japonicum
 China, Indonesia, Phillipines

432
Pathogenesis
 Immune complex
 Cercarial associated dermatitis
 Humeral and cell mediated inflammation
 Katayama fever-serum sickness like
 Chronic schistosomiasis
 Cell mediated granulomatous formation and
fibrosis-Symmers-clay pipe-stem fibrosis

433
Risk factors
 Geographic location

 Exposure to fresh water bodies

 Local eating and drinking habits

434
Clinical presentation
 Depends on
 Intensity of infection
 Host factors-age, genetics
 Three stages:
1. Swimmers itch
 2-3 days after invassion
 Itchy maculopapular rash at the affected site
 Commonly seen with S. mansoni & S. japonicum
 Self limiting

435
2. Acute Schistosomiasis
 “Katayama fever”
 Occurs 4-8 weeks after skin invassion
 Fever, generalized LAP
 Hepatosplenomegaly
 Peripheral blood eosinophilia
 Occurs during worm maturation and at the
beginning of oviposition
 Benign. Death reported with heavy exposure
436
3. Chronic schistosomiasis
 Species dependent-(S. mansoni &
S. japonicum)
 Intestinal phase:
 Colicky abdominal pain
 Bloody diarrhea, fatigue, growth
retardation
 Colonic polyposis
 Malabsorbtion

437
Contd.
 Hepato-splenic phase
 Hepatomegaly-granulomatous
 Pre-sinusoidal portal fibrosis leads to portal
hypertension and splenomegaly.
 Esophageal verices-bleeding is tolerable
because of normal liver function.
 Cirrhosis- if it is associated with viral
hepatitis and malnutrition

438
S. hematobium
 Dysurea, frequency, hematuria
 U/A:
 Blood, albumine, bacteria, sediments,
cellular metaplasia
 Urinary bladder granulomas leads to
obstructive uropathy, Squamous cell Ca-
hence it is a human carcinogen.

439
Contd.
 Pulmonary:
 Cough, fever, dyspnea
 Cor-pulmonale due to pul. Hypertension

 CNS-granulomatous depossion
 Epilepsy in S. japonicum
 TM in S. mansoni & S. hematobium

440
Dx.
 Travel hx and exposure to fresh water bodies
 For Katayama
 Peripheral eosinophilia
 High Ab for schistosoma-FAST-ELISA
 Immuno electrotransfer blot(IETB)
 Stool or urine for ova
 Stool:
 kato thick smear –quantifcation
 Concentration method
 Rectal biopsy
 Ultrasound of the abdomen.

441
Treatment
 Phase 1.
 Topical to relief itching
 Phase 2.(Katayama fever)
 Anti schistosomal chemotherapy
 Immunosuppressant-steroid
 Supportive
 Phase 3.
 Chronic form- supportive and treatment of
complication
 Hepatic failure & varices

442
Contd.
 Chemotherapy
 Praziquantel 40-60mg/kg divided in 2-3
doses for 1 day
 Parasitological cure rate-85%
 Decreases egg counts by >90%

 Early hepatomegaly and bladder lesion

resolve after chemotherapy, fibrosis
remained the same

443
Prevention
 Endemic areas:
 Sewage disposal, sanitation
 Health education
 Chemotherapy

 For travelers
 Avoid contact with fresh water bodies
 If exposed follow up visits

444
Filariasis
 Nematodes that dwell in SC tissue and
lymphatics
 Eight filarial species
 Lymphatic filariasis
 W. bancrofti, B. malayi, B. timori
 SC dwellers
 Onchocerca volvulus, Loa loa

445
Life cycle
 Transmission by mosquitoes or arthropodes

 Inoculates infective larvae

 Develops to Adults that circulate in the circulation or

SC tissue.

 Microfilaria formed –(stays for 3-36 months)

 Ingested by arthropode vector and develop to new

infective larva in 1-2 wks

446
447
Lymphatic Filariasis
 Reside in lymphatic channels or LN. It
remained viable for > 2 decades.
 W. bancrofti widely distributed , affects
> 115 million people.
 Found in the tropics and sub topics
 Common in Africa
 Human- the only definitive host.
448
Contd.
 Vector:
 Culex fatigans mosquitoes-urban
 Anapheline or aedean in rural

 B. malayi found in China, India,

Indonessia, Korea, Japan, Malaysia,
Phillipin.

449
Pathology
 Inflammatory damage to the lymphatics by
adult worms (not by microfilaria)
 Lymphatic dilatation and thickening of vessel
wall.
 Incompetence of lymphatic valves
 Lymphedema and chronic stasis changes
 Granulomatous reaction following death of
worms with fibrosis
 Complete lymphatic obstruction

450
Clinical presentation
 The most common manifestation:
 Asymptomatic microfilaremia, hydrocele,
acuteadenolymphangitis(ADL) and chronic
lymphatic disease.
 Early manifestations
 Microscopic hematuria or proteinuria
 Dilated, totuous limphatics – by imaging
 Scrotal lymphangiectasia by ultrasound
451
Contd.
 ADL (acuteadenolymphangitis)
 Fever – high grade
 Lymphatic inflammation
 Transient local edema
 Inflammation is retrograde – extending
from the LN draining the area
 In B. Malayi forms a local abscess –
raptures to the surface

452
Cont.
 Both involves the upper and lower
extremities
 Genital involvement is exclusively with
W. bancrofti infection
 Epididmitis
 Scrotal pain and tenderness

453
Cont.
 Dermatolymphangioadenities (DLA)
 High grade fever, chills, myalgia and head
ache
 Edematous inflammatory plaques
 Vesicles, ulcers, hyper pigmentation
 History of trauma precedes
 Mimics cellulites

454
Cotnd.
 Chronic changes
 Brawny edema
 Early pitting
 Thickening of SC tissue and hyperkeratosis
 Fissuring and hyperplastic changes with super
infection
 Hydrocele- scrotal elephantiasis
 Chyluria- due to obstruction of retroperitoneal
lymphatics

455
Dx.
 Demonstration of micrifilaria in blood, body fluids, hydrocele
 Direct staining
 Concentration with centrifugation(knott’s technique)
 Adult worms are not accessible
 Serology- Ag of W. bancrofti
 ELISA
 Rapid formation imino cromatography
 Sensitivity =96-100%
 Specificity= 100%
 PCR for DNA
 High frequency U/S with Doppler
 Visualizes worms in the scrotum or female breast.
 Eosinophilia
 Increased IgE and antifilarial anti body

456
Microfilaria of W. bancrofti in a
peripheral blood

457
Contd.
 Difference from bacterial lymphangitis
 Assending infection
 Filarial infection a retrograde extension.
 Active disease
 Microfilaremia
 Antigen positivity
 Detection of adult worms on ultrasound

458
Treatment
 Active infection
 DEC (Diethylcarbamazine)
 Has both micro and macro filacidal properties
 Dose-6mg/kg/d x 12days
 Albendazole – macro filaricidal efficacy
 Does – 400mg bid x 21days
 Adult worm carriers without microfilaria- need
 DEC
 Chronic complication
 Surgical correction of hydrocele
 It recurs

459
Prevention
 Impregnated bed nets.
 DEC – prophylaxis
 Mass distribution of chemotherapy
annually
 Albendazole + DEC/Ivermectine

460
Filarial abscess scar in a young
male with W. bancrofti infection

461
Limb lymph edema , inguinal
lymphadenopathy and hydrocele

462
Unilateral left lower leg elephantiasis

463
Lymphedema and typical skin appearance
of depigmentation and warty changes-
verrucosities

464
465
466
Bilateral hydrocele, testicular enlargement
and inguinal LAP

467
Reading assignment
 Subcutneous tissue dwellers
 Onchocerciasis

468
Trypanosomiasis
 Trypanosoma Cruzi Chagas desease
 In Americas
 A zoonosis
 T.brucei gamiense and T.brucei rhodesiense
 African trypanosmiasis
 Human disease

 Chagas disease
 Mild febrile illness
 Chronic chagas’ disease-manifested with
 Rhythm disturbance
 Dilated CMP
 Thromboembolism
 RBBB

469
Sleeping sickness-HAT
 Etiology: T. brucei complex
 East Africa- Rhodesiense
 West Africa- gambiense
 Vector: Tsetse fly-blood sucking genus
Glossina.
 After inoculation multiply in the blood and
other extracellular spaces
 Under goes antigenic variation to evade the
immune system.
470
Pathogenesis
 At the site of inoculation : inflammatory lesion
called chancre-painful.
 Occurs 1 week after the bite.
 Dissemination through blood and lymphatics
to induce a febrile illness-Stage I disease.
 Invasion of the CNS with perivascular
infiltration with mononuclear cells-Stage II
disease.

471
Clinical presentation
 Skin –tender lesion
 Stage I:
 AFI-relapsing type
 LAP-discrete, rubery, non tender located on the
posterior cervical triangle called Winterbottom’s
sign.
 Pruritic maculopapular rash
 Malaise, fatigue, Wt loss
 Hepatosplenomegaly, edema, tachycardia

472
Contd.
 Stage II- CNS invasion
 Progressive day time somnolence alternate
with restlessness and insomnia at night
 Speech- halting and indistinct
 Extrapyramidal signs
 Choreiform movement, tremor, fasciculations
 Ataxia, hypertonia,
 Shuffling gait
 Progress to coma and death

473
Contd.
 West African- Insidious course
 East African- Acute course
 Symptoms appear early-tachycardia with
fever
 Death could be due to: arrhythmias & CHF
before CNS disease occurs
 Takes weeks to months

474
Diagnosis
 Demonstration of the parasite in:
 Body fluids
 Chancre, LN aspiration, BM, blood samples
 Positivity is high in stage I than stage II, in T.b.
rhodesiense than T.b. gambiense
 CSF examination
 Increased pressure, mononuclear cells, protein
and IgM
 Trypanosomiasis in centrifuged CSF
 PCR
475
Treatment
 Depends on:
 Type of the organism
 Stage of the disease
T.b. gambiense
 Stage I :
 Suramine-1gm iv on 1,3,7,14 & 21 day through infusion
 Toxic-renal failure
 Eflornithine-400mg/kg/day x 2 weeks
 Pentamidine
 Stage II
 Eflornithine

476
Contd.
 T.b. rhodosiense
 Stage I:
 Suramine
 Alternate-pentamidine
 Stage II:
 Melarsoprol 2-3.6mg/kg/day iv 3 dosex 3d
 Toxicity with reactive encephalopathy

477
Prevention
 Avoid insect bite
 Protective clothing
 Insect repellent

 Vaccine not available

 Chemoprophylaxis not recommended

478
Intestinal nematodes
(Round worms)
 Associated with
 Poor fecal sanitation
 Contribute to malnutrition
 Decreases work capacity

479
Ascaris lumbricoides
(Round worm)

 The largest intestinal nematodes ,can

reach up to 40cm in length

 Lives in the lumen of jejunum

 Each worm can produces up to 240,000

egg per day
480
Cont.
 Maturation takes place in the soil
 Larva hatched in the intestine
 Invade the mucose
 Migrate through the circulation to the
lungs => alveoli => bronchus
 Swallowed => Intensine => Develop
into adult, then lives for 1 – 2 years
481
Transmission
 Fecaly contaminated soil
 Poor sanitation
 Affects young children
 Transported vegetables as means of
transmission outside endemic areas

482
Clinical presentation
 Lung Phase
 Irritating cough – dry
 Burning substernal discomfort
 Fever (38.5oC)
 Eosinophilia
 Complication– Eosinophilic pneumonitis
(Loffler’s syndrome) => Round/oval
pulmonary infiltrations.
483
Contd.

Intestinal Phase -> Heavy load

 Predispose to intestinal obstruction

 Perforation, intussusception or volvulus
 Biliary colick, cholecystits, cholangitis,
pancreatits, intrahepatic obscess

484
Diagnosis
 Demonstration of ova in stool

 Identification of adult worm

 ERCP

485
Treatment
 The aim is to prevent complications
 Albendazole 400mg stat
 Mebendazole 500mg stat
 Pyrantel pamoate 11mg/kg stat maximum
1gm. Safe in pregnancy.

486
Hook worm
 Etiology:
 A. duodenale
 N. americanus
 Ova changed to larva in soil
 Larva penetrates the skin.
 Through bloods stream reach lungs
 Swallowed => reaches the intestine
and lives for about a decade
487
Clinical Presentation
 Pruritic maculopapular dermatitis => ground
itching
 Pneumonitis – milder degree.
 Epigastric pain – post prandial accentuation
 Diarrhea
 Iron def. anemia, hypoprotenemia
 Risk factor for diseases development:
 Wrom burden
 Prolonged duration of infection
 Inadequate iron intake

488
Diagnosis
 Ova in the stool

 Hypochromic microcytic anemia

 Hypoalbuminemia

489
Rx
 Albensdazole
 Mebendazale
 Pyrantel pamoate x 3 days
 Iron supplementation
 Nutritional support

490
Strongyloidiasis
 Etiology: S. Stercoralis

 Replicates with in the human host =>

autoinfection

 In immuno-compromized host => become

invasive => Disseminate widely

 Can be fatal
491
Transmission
 Fecaly contaminated soil

 Larva penetrates the skin

 Common in hot humid regions

492
Clinical Presentation
 Recurrent urticaria – buttocks & wrists
 Migration –”Larva currens” – Running larva
 Abdominal or epigastric pain aggravated by
food ingestion
 Nausea, diarrhea, Gl bleeding, mild chronic
colitis and weight loss
 Pulmonary symptoms – rare
 Eosinophilia - common

493
Disseminated form=> fatal
 GI, lung, CNS, Peritoneum, liver, kidney
 Risk of bacteremia increases-
 Gram negative sepsis
 Pneumonia
 Meningitis

 Complications are common with HTLV-I

but not with HIV.
494
Diagnosis
 Stool for larva
 Eggs are not detectable in stool

 Rx.
 Ivermectine-200ug/kg/d 1-2 days
 Albendazole
 Thiabendazle

495
Giardiasis
 Intestinal protozoa
 Infection occurs following ingestion of
hardy cyst which excyst in the SI to
fagellated trophozoites.
 Inhabits the proximal SI.
 As few as 10 cysts sufficient to cause
infection in humans.

496
Risk factors
 Day care centers
 poor fecal hygiene
 Anal-oral contact
 Food borne transmission
 Water borne causes episodic infection.
It resists killing by chlorination. Can use
filtration or boiling.
 Can occur as an epidemic or endemic
497
Clinical presentation
 Acute:
 Abdominal pain, bloating, belching, flatus, nausea, vomiting and
diarrhea.
 Duration > 1 week.
 Chronic:
 Increase in flatus, loose stools, Wt loss
 Symptoms can be continuous or episodic
 Complication:
 Malabsorption
 Weight loss
 Growth retardation
 Dehydration
 Rarely causes death
 Course and treatment response is the same with HIV.

498
Diagnosis
 Cysts in feces or trophozoites
 Ag detection in feces

Treatment:
 Metronidazole
 Tinidazole
 If refractory: prolonged therapy with
metronidazole(750mg tid x 21 days)

499
Rhabiditiform larva of strongyloides
stercoralis in slool specimen

500
Strongloides eggs from feces of a new
borne

501
Ascaris lumbricoides egg in feces

502
Ova of trichuris trichiura

503
Reading assignment
 Amaebiasis

 Cestodes
 Taeniasis
 Cysticercosis
 echinococosis

504
TETANUS
 Definition:
 A neurological disorder characterized by
increased by muscle tone and spasm caused
by tetanospasmin, produced by Clostridium
Tetani.
 Etiology:
 C. Tetani a gram positive rods, aerobic found
in soil world wide also found in animal and
human feces.
505
Mode of entry
 Abrasion, laceration, puncture wounds

 Complicates chronic skin ulcers, abscess

and gangrene

 Burns, otitis media, surgery, abortion,

birth, body piercing and drug abuse
506
PATHOGENESIS
 Toxins binds to peripheral motor unit
terminal and axons
 Intraneural transmissions blocks release
of GABA at presynaptic terminal
 Agonist and antagonist recruitment lead
to spasm
 At NM junction blocks release of
transmitters causes weakness or
paralysis
507
 Three forms
 Generalized
 Localized
 Cephalic
 neonatal

508
Clinical presentation
 Incubation period: 1 day-2 month
 Period of onset: 1-7 days
 Increased tone in the maseter muscle
 Trismus or lock jaw
 Dysphagia, pain or stiffness in the neck
 Abdominal rigidity and stiff proximal limb muscles.
Hand & feet are spared.
 Risus sardonicus-facial muscle
 Opisthotonos-back muscle
 Laryngeal spasm, cyanosis
 Fever, ileus, autonomic dysfunction
 Sudden cardiac arrest
509
Complications
 Fracture
 DVT, PTE
 Muscle rapture
 Aspiration pneumonia
 Bed sore
 Rhabdomyolysis

510
DDX
 Poisonong
 Hypocalcemic tetany
 Alveolar abcess
 Drug dystonia
 Meningitis
 Rabies
 Peritonitis
511
Grading
 Grade I (mild):
 Moderate trismus, generalized spasticity
 Grade II (moderate):
 Short lasting spasms, RR>30-35/min, mild
dysphagia
 Grade III (severe):
 Generalized spasticity, prolonged spasms,
RR>40/min, apnaeic episodes, PR>120/min,
severe dysphagia
 Grade IV (V. severe):
 G III + severe dysautonomia HTN on hypotension

512
Treatment
 Principles
 1. Eliminate the source of toxin
 2. Neutralize the unbound toxin
 3. Prevent muscle spasm
 General measures
 Respiratory support
 Nursing in quiet room and ICU
 Hydration and feeding
 Input and output monitoring
513
Specific Rx.
 Wound debridment
 Antibiotic-metronidazole or penicilline
 Antitoxin
 TAT 10,000 iv and 10,000 im
 TIG 3000-6000 u im
 Control spasm
 Diazepam , chlorpromazine 6 hrly
 Baclofen, succinyl choline
 Mx of complication-dysautonomia, respiratory
514
Out come
 Course 4-6 weeks
 Poor prognosis
 Age-extremes
 Co morbidity
 Cephalic
 Higher grades
 Short IP and period of onset

515
ANTHRAX
 Definition:
 An infection caused by Bacillus anthraces
 It is disease of the herbivores-Goat,
Sheep & cattle
 Humans infected by contact with the
agent from infected animals or their
products or via ingestion, inhalation, or
skin contact
516
Contd….
 B.anthracis is a gram positive rods,
sporulating, aerobic, non motile found
in soil
 Mode of entry:
 Skin-cutanous anthrax- in 95%
 Inhalational: in 5%
 Ingestion of raw or undercooked meat-GI
antrax-very rare
517
Pathogenesis
 Multiply in the blood stream

 Produces toxins and cytokines causes

edema, inhibition of PMN leads to shock
and death

518
Clinical presentation
 Cutaneous anthrax
 Site-face, neck, extremity
 Small red macules with in days
 Papules
 Pustules
 Central necrotic-black eshcar with surrounding
edema-painless
 Painful regional LAP
 Fever is uncommon
 Secondary bacterial infection---high grade fever
seen in 10% then death
519
Inhalational anthrax
(wool sorters disease)
 IP: 3 days
 Fever, malaise, dyspnea, stridor
 Mediastinal widening, pleural effusion,
 Death in 24 hours
 Non contagious

520
GI anthrax
 Nausea, vomiting, abdominal pain,
bloody diarrhea and fever

 Ascites

521
Dx.
 Clinical presentation
 Contact history

 Gram staining

Treatment
 Crystalline penicillin iv till edema subsides then po
for 7-10 days.
 Wound debridment
 Post exposure –a 60 days antibiotic : doxycycline
or cipro
 Vaccination-AVA--adsorbed
522
 HIV
(Human immunodeficiency virus)

Virology
Immunology

Pathogenesis

Opportunistic infection

HAART

523
 HIV
 Virology
 Immunology
 Pathogenesis and Natural Course of the
Disease

524
Learning Objectives

 Describe the basic virology and life cycle

of HIV
 Describe the normal immunological
response to HIV-1
 List the mechanisms used by HIV-1 to
evade the normal immune responses
 Explain how HIV causes disease
 Describe the natural course of HIV-1
525
 The HIV Epidemic Unfolds
 Sudden outbreak in USA of opportunistic infections and
cancers in homosexual men in 1981
 Pneumocystis carinii pneumonia (PCP), Kaposi’s sarcoma, and
non-Hodkins lymphoma
 HIV isolated in 1984 - Luc Montanier (Pasteur Institute,
Paris) and Robert Gallo (NIH, Bethesda, USA)
 HIV diagnostic tests developed in 1985
 First antiretroviral drug, zidovudine, developed in 1986
 Exploding pandemic
 Has infected more than 50 million people around the world
 Has killed over 22 million people

526
I. Global Summary of the HIV/AIDS
Epidemic December ,2007
(UNAIDS/WHO)

People living with HIV(PLHIV):

- Total: 33.2 million [30.6 - 36.1 million]
 Adults: 30.8 million [28.2- 33.6 million]
 Women: 15.4 million [13.9– 16.6 million]
 Children under 15 years: 2.5 million [2.2 – 2.6
million]- 7.5%

527
527
Est. PLHIV, End of 2007:
33.2 Million
Eastern Europe
Western Europe
& Central Asia
760,000 1.6 million
North America
East Asia & Pacific
1.3 million
800,000

North Africa South

Caribbean & Middle East & South-East Asia
230,000 380,000 4.0 million

Sub-
Latin America Saharan
1.6 million Africa Australia
& New
22.5
Zealand
million
75,000

528
Est. Number Newly Infected With HIV During
2007: 2.5 Million

Western Eastern
Europe Europe
North 31,000 & Central Asia
America 150,000 East Asia &
46,000 North Africa
South Pacific
& Middle
Caribbean East & South- 92,000
17,000 35,000 East
Asia
Latin Sub- 340,000
America Saharan Australia
100,000 Africa & New Zealand
1.7 million 14,000

529
529
Spread of HIV in Africa, 1990-
2005

Source: UNAIDS, 2006

530
 IV. Current Facts:
HIV in Ethiopia
 National HIV prevalence (single point estimate):
2.3%
 Female: 2.8%

 Male: 1.8%

 Urban HIV prevalence : 7.7%

 Rural HIV prevalence : 0.9%
 HIV prevalence in Addis : 8.5%; Male: 6.8%,
Female: 10.1%.
 The highest HIV prevalence in Ethiopia occurs in
the age group 15-24 531
531
HIV Virology

532
Genetic Origin of HIV-1
 The simian origin of
HIV is broadly
acknowledged
 HIV-1 is most closely
related at a
phylogenetic level to
SIVcpz from P. t.
troglodytes

533
Virology continued…..
 Retroviridae
 Onchoviridae
 HTLV 1 and HTLV 2
 Spumaviridae
 Lentiviridae
 HIV 1 and HIV 2

534
 Classification of HIV
 HIV class: Lentivirus
 Retrovirus: single stranded RNA transcribed to double
stranded DNA by reverse transcriptase
 Integrates into host genome
 High potential for genetic diversity
 Can lie dormant within a cell for many years,
especially in resting (memory) CD4+ T4 lymphocytes
 HIV type (distinguished genetically)
 HIV-1 -> worldwide pandemic (current ~ 33.2 M
people)
 HIV-2 -> isolated in West Africa; causes AIDS much
more slowly than HIV-1 but otherwise clinically similar
535
HIV-1 and HIV-2 Differ in Multiple Ways

 Accessory genes
 HIV-1 vpu
 HIV-2 vpx
 Distribution
 HIV-1 – global pandemic
 HIV-2 – West Africa
 Rate of progression of severe
immunosuppression
 HIV-1 – median time to AIDS = 10 years
 HIV-2 – median time to AIDS = longer, but ?
536
 Classification of HIV-1
 HIV-1 groups
 M (major): cause of current worldwide epidemic
 O (outlier) and N (Cameroon): rare HIV-1 groups
that arose separately
 HIV-1 M subgroups (clades)
 >10 identified (named with letters A to K)
 Descended from common HIV ancestor
 One clade tends to dominate in a geographic region
 Clades differ from each other genetically
 Different clades have different clinical and biologic
behavior
537
Classification of HIV

HIV-1 HIV-21

Group M2 Group N Group O

Clades A, B3, C, D, F, F2, G, H, J, K

Recombinants: Common: AE, AG

Uncommon: AGHK, FD, AFGHJK, AB, BC

1
HIV-1 most common, but HIV-2 now circulating outside Africa,
especially India
2
Most infections due to group M viruses
3
Clade B: 98–99% USA, 90% Europe
538
McCutchenn F, et al. XIII IAC, 2000. Abstract 165
 Origin and Distribution of HIV-1 Clades
 HIV-1 rapidly evolves by two mechanisms:
 Mutation: changes in single nucleosides of the RNA
 Recombination: combinations of RNA sequences
from two distinct HIV strains
 Several common clades (e.g., A/G ad A/E) are
recombinants
 Geographic distribution of HIV group M clades
 A in Central Africa
 B in North American, Australia, and Europe
 C in Southern and Eastern Africa (Ethiopia)

539
Geographic Distribution

540
541
p24
p17 Matrix – p17

P7, P6

kb 9.7
542
543
Life Cycle of HIV.

544
 How HIV Enters Cells
 gp120 env protein binds to CD4 molecule
 CD4 found on T-cells macrophages, and microglial cells

 Binding to CD4 is not sufficient for entry

 V3 loop of gp120 env protein binds to co-receptor

 CCR5 receptor - used by macrophage-tropic HIV variants

 CXCR4 receptor - used by lymphocyte-tropic HIV variants

 Binding of virus to cell surface results in fusion of viral

envelope with cell membrane
 Viral core is released into cell cytoplasm

545
 HIV
HIVReceptors
Receptors
HIV and Cellular Receptors

Copyright © 1996 Massachusetts Medical Society. All rights reserved.

546
 Viral-host Dynamics
 About 1010 (10 billion) virions are produced
daily
 Average life-span of an HIV virion in plasma is
~6 hours
 Average life-span of an HIV-infected CD4
lymphocytes is ~1.6 days
 HIV can lie dormant within a cell for many
years, especially in resting (memory) CD4
cells, unlike other retroviruses
547
HIV Immunology

548
Overview of Adaptive Immune
Response Extracellular
APC infection
Intracellular
infection Free antigen
MHC I presentation
of endogenous
antigen MHC II presentation
of exogenous
antigen

Naïve Naïve
T8 cell B-Cell
Naïve T4
helper cell

Humoral
Cell-mediated Th1 Th2 (plasma cells /
(CTLs) antibodies)

Diagram courtesy of Dr. Samuel Anderson 549

General Principles of
Viral-host Interactions:
 Host: mounts HIV-specific immune responses
 Cellular (cell-mediated) - most important
 Humoral (antibody-mediated)
 Virus: subverts the immune system
 Infects CD4 cells that control normal immune responses
 Integrates into host DNA
 High rate of mutation
 Hides in tissue not readily accessible to immune system
 Induces a cytokine environment that the virus uses to its
own replicative advantage
 Achieved by “activation” of the immune system

550
Cellular Immune Responses to
HIV
 CD8 Cytotoxic T lymphocyte (CTL)
 Critical for containment of HIV
 Derived from naïve T8 cells, which
recognize viral antigens in context of MHC
class I presentation
 Directly destroy infected cell
 Activity augmented by Th1 response

551
 Cellular Immune Responses to HIV
 CD4 Helper T Lymphocyte (Th)
 Plays an important role in cell-mediated response
 Recognizes viral antigens by an antigen
presenting cell (APC)
 Utilizes major histocompatibility complex (MHC) class
II
 Differentiated according to the type of “help”
 Th1 - activate Tc (CD8) lymphocytes, promoting cell-
mediated immunity
 Th2 - activate B lymphocytes, promoting antibody
mediated immunity
552
Humoral Immune Response to
HIV
 Neutralization
 Antibodies bind to surface of virus to
prevent attachment to target cell
 Antibody-dependent cell-mediated
cytotoxicity (ADCC)
 Fc portion of antibody binds to NK cell
 Stimulates NK cell to destroy infected cell

553
 HIV Evasion Methods
 Makes (1010 ) 10 billion copies/day -> rapid
mutation of HIV antigens
 Integrates into host DNA
 Depletes CD4 lymphocytes
 Down-regulation of MHC-I process
 Impairs Th1 response of CD4 helper T
lymphocyte
 Infects cells in regions of the body where
antibodies penetrate poorly, e.g., the central
nervous system
554
Pathogenesis of HIV

555
 Cells Infected by HIV
 Numerous organ systems are infected by HIV:
 Brain: macrophages and glial cells
 Lymph nodes and thymus: lymphocytes and
dendritic cells
 Blood, semen, vaginal fluids: macrophages
 Bone marrow: lymphocytes
 Skin: langerhans cells
 Colon, duodenum, rectum: chromaffin cells
 Lung: alveolar macriphages
556
 General Mechanisms of HIV
Pathogenesis
 Direct injury
 Nervous (encephalopathy and peripheral neuropathy)
 Kidney (HIVAN = HIV-associated nephropathy)
 Cardiac (HIV cardiomyopathy)
 Endocrine (hypogonadism in both sexes)
 GI tract (dysmotility and malabsorption)
 Indirect injury
 Opportunistic infections and tumors as a consequence
of immunosuppression

557
 General Principles of
Immune Dysfunction in HIV
 All elements of immune system are affected
 Advanced stages of HIV are associated with
substantial disruption of lymphoid tissue
 Impaired ability to mount immune response to
new antigen
 Impaired ability to maintain memory responses
 Loss of containment of HIV replication
 Susceptibility to opportunistic infections
558
 Mechanisms of CD4
Depletion and Dysfunction
 Direct
 Elimination of HIV-infected cells by virus-specific
immune responses
 Loss of plasma membrane integrity because of viral
budding
 Interference with cellular RNA processing
 Indirect
 Syncytium formation
 Apoptosis
 Autoimmunity
559
 EM of supernatant
of HIV infected
tissue culture

Budding of HIV from

Infected Tissue
Culture Cell
560
Syncytium Formation
 Observed in HIV infection, most commonly
in the brain
 Uninfected cells may then bind to infected
cells due to viral gp 120
 This results in fusion of the cell
membranes and subsequent syncytium
formation.
 These syncytium are highly unstable, and
die quickly.
561
Apoptosis

Courtesy of CDC 562

 Role of Cellular Activation in
Pathogenesis of HIV
 HIV induces immune activation
 Which may seem paradoxical because HIV ultimately
results in severe immunosuppression
 Activated T-cells support HIV replication
 Intercurrent infections are associated with transient
increases in viremia
 The magnitude of this increase correlates inversely
with stage of HIV disease
 Accounts for why TB worsens underlying HIV disease

563
Role of Cytokine Dysregulation in
Pathogenesis of HIV

 HIV is associated with increased expression

of pro-inflammatory cytokines
 TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma
 Associated with up-regulation of HIV replication
 HIV results in disruption and loss of
immunoregulatory cytokines
 IL-2, IL-12
 Necessary for modulating effective cell-
mediated immune responses (CTLs and NK
cells) 564
Consequence of Cell-mediated
Immune Dysfunction
 Inability to respond to intracellular
infections and malignancy
 Mycobacteria, Salmonella, Legionella
 Leishmania, Toxoplama, Cryptosporidium,
Microsporidium
 PCP, Histoplamosis
 HSV, VZV, JC virus, pox viruses
 EBV-related lymphomas
565
Natural History of
HIV Infection

566
 CD4

Viral Load AIDS

Weeks Years
Time after infection
567
Natural History of HIV-1

Fauci As, 1996 568

 Transmission
 Modes of infection
 Sexual transmission at genital or colonic mucosa
 Blood transfusion
 Mother to infant
 Accidental occupational exposure
 Viral tropism
 Transmitted viruses is usually macrophage-tropic
 Typically utilizes the chemokine receptor CCR5 to
gain cell entry
 Patients homozygous for the CCR5 mutation are
relatively resistant to transmission
569
 Laboratory Markers of HIV
Infection
 Viral load
 Marker of HIV replication rate
 Number of HIV RNA copies/mm3 plasma
 CD4 count
 Marker of immunologic damage
 Number of CD4 T-lymphocytes cells/mm3 plasma
 Median CD4 count in HIV negative Ethiopians is
significantly lower than that seen in Dutch controls
 Female 762 cells/mm3 (IQR 604-908)
 Male 684 cells/mm3 (IQR 588-832)

570
Spread of HIV in Host Tissues

Copyright © 1998 Massachusetts Medical Society.

All rights reserved. 571
Primary HIV Infection
 The period immediately after infection
characterized by high level of viremia (>1 million)
for a duration of a few weeks
 Associated with a transient fall in CD4
 Nearly half of patients experience some
mononucleosis-like symptoms (fever, rash, swollen
lymph glands)
 Primary infection resolves as body mounts HIV-
specific adaptive immune response
 Cell-mediated response (CTL) followed by humoral
 Patient enters “clinical latency”
572
HIV RNA Set Point Predicts
Progression to AIDS
 HIV RNA viral loads after infection can be
used in the following ways:
 To assess the viral set point
 To predict the likelihood of progression to AIDS
in the next 5 years
 The higher the viral set point:
 The more rapid the CD4 count fall
 The more rapid the disease progression to
AIDS
573
 Patterns of HIV Disease Progr
ession

Typical Progressors 7-10 years

85-90 %

HIV <5 %
Infection Rapid Progressors <3 years

<10 % Long-term
Non-progressors >10-20 yr
Normal, Stable CD4

574
Pathogenesis of HIV Infection:
No Progression with Low-level
Viremia
Primary HIV Chronic Non-progressive HIV Infection

CD4

RNA Set Point ~ 103

RNA

575
Pathogenesis: Average
Progression with Median-Level
Viremia
Primary HIV Slowly Progressive HIV AIDS

RNA Set Point ~104

RNA

CD4

1 5 10

Years
576
Pathogenesis: Rapid
Progression with High-Level
Viremia
Primary HIV AIDS

RNA RNA Set Point ~ 106

CD4

2 3

Years
577
HIV RNA Levels Predict
Progression to AIDS

578
CD4 T-cell Count and
Progression to AIDS
 In contrast to VL, baseline CD4 is not a
good predictor of time to progression to
AIDS
 However, as the CD4 count declines over
time, patients will develop opportunistic
infections
 Develop in a sequence predictable according
to CD4 count
 WHO Staging system
579
Key Points
 HIV is a retrovirus, capable of integrating into host
genome and establishing chronic infection
 HIV can be classified into subgroups (clades) which
have characteristic geographic distribution
 The important steps in the lifecycle of HIV include
cell entry, reverse transcription, integration, and
maturation/assembly
 Cell-mediated immunity is critical for containment of
HIV infection and other intracellular infections
 HIV evades host immunity by a variety of
mechanisms
580
Key Points (2)

 HIV activates the immune system to increase

its own replication
 CD4 count declines by both direct and
indirect mechanisms
 HIV RNA set point predicts rate of
progression to AIDS
 CD4 count decline is associated with a
predictable sequence of opportunistic
infections
581
OPPORTUNISTIC INFECTIONS

582
PCP
 A fungal exists in two forms
 Trophs-smaller
 Cysts-larger
 Transmission
 Reactivation of latent infection
 Person to person
 Environmental source

583
PCP cont…
 Effective inflammatory response
 Neutrophilic lung inflammation
 Promotes lung injury
 Diffuse alveolar damage
 Impairing lung exchange
 Respiratory failure

584
PCP cont….
 PCP in AIDS characterized by
 High organism burden
 Fewer neutrophilis
 High diagnostic yield following induced
sputum or BAL
 Better oxygenation and survival

585
PCP cont….
 PCP due to other causes
 Low organism and high neutrophilis
 High rate of mortality :30-60% (compared
to 10-20 % of HIV associated PCP)

586
Diagnosis
 Symptoms +
 CXR: bilateral perihilar infiltrates
 Pleural effusion and LAP are rare
 High resolution CT is more sensitive
 Extensive ground glass attenuation or
cystic lesion
 LDH

587
PCP Diagnosis …
 Sputum induction with saline
 Yield: 50-90%
 BAL: >95%
 Staining
 For Trophic forms: papanicolaou,wright-Giemsa, or
Gram-weigert
 For cysts: Gomori methenamine silver, cresyl echt
violet, toluidine blue o, or calcofluor white.
 Monoclonal antibodies-can stain both trophs
and cysts. Has high sensitivity and specificity.
 PCR
588
Pneumocystis Treatment
 Standard regimen:
 Cotrimoxazole (15-20 mg TMP + 75-100 mg
SMX)/kg/day in 3 doses IV or PO for 3 weeks
 Alternative treatments:
 Dapsone 100 mg qd + Trimethoprim 15 mg/kg/day
PO divided tid x 3 wks
 Primaquine 15-30 mg qd + Clindamycin 600 mg po
q8h x 3 wks
 Atavaquone 750 mg tid po
 Pentamidine 4 mg/kg aerosole
589
 Benefit of Corticosteroids in
Pneumocystis Therapy

590
 High TB burden African countries
Countries Rank in the list of HBCs

Nigeria 4
Ethiopia 7
South Africa 9
Kenya 10
DR Congo 11
Tanzania 14
Uganda 16
Mozambique 18
591
Introduction
 April 2-4, 2008 WHO convened
International meeting on the Three I’s,
(Intensified TB case finding, IPT and TB
Infection Control) Geneva with
stakeholders.
 Came up with recommendations on the

Three I’s
=>”Three I’s should be central part of HIV
care and treatment and also critical for
the continued success of ART scale-up”
592
Tuberculosis in HIV+
Host
Majority Latent TB Infection

Increased to
10% per year

Active TB Disease

Death

593
 IPT

 Prevent TB in HIV infected individuals so that

they may lead a longer, disease-free life.
 reducing the risk of developing TB by 33–67%
for up to 48 months
 IPT combined with ART among PLWH
significantly reduces the incidence of TB

594
Indications

 Adults and children more than five

years
 HIV positive and with no evidence of active
TB and no contraindication
 Children under five years
 History of contact with pulmonary TB
patient and not symptomatic, regardless of
HIV status

595
 ART, IPT and TB Incidence
Incidence  N=6391
(per  Cluster
100py)
randomized trial
No IPT, No ART 7.4
 IPT in Brazil
No IPT, ART 1.5

IPT, No ART 1.0

IPT, ART 0.6

P<.0001 for all

Golub, IAS 2006; # MOPE0395 596

Concerns

 Safety
 INH resistance
 Adherence
 Duration of effectiveness

597
 Safety of IPT
 Transient transaminases common
 Hepatotoxicity is a serious side effect
 Death can occur if INH not discontinued
 With monitoring and education, risks of
hepatitis and death small (0.001%-0.004%)
 Risk increased with older age, alcohol use

598
 Effect of INH Resistance on
Treatment Outcomes
Success Failure  Retrospective cohort
Rate rate
study
Drug 85% 2%
 1148 new TB cases
susceptible  First-line therapy
INH- 82% 4%
resistant
 HRZE or HRZS x 2m
 HR x 4m

Espinal, JAMA 2000; 283:2537-45.

599
Toxoplasmosis
 The presentation is so characteristic that
many guidelines suggest routine
treatment for toxoplasmosis
 A lack of response to such therapy
(symptoms and MRI changes) within 1-2
weeks indicates other possible conditions:
 Central nervous system lymphoma
 Tuberculoma
 Cryptococcoma
600
Treatment Response
 With empiric treatment for
Toxoplasmosis, what should we expect?
 Nearly 90% of patients will respond
clinically within days of starting therapy
 CT and MRI scans show improvement by
14 days following treatment initiation

601
Toxoplasmosis Brain CT Scan

602
 Toxoplasmosis Treatment
 Fansidar: 2 tabs bid x 2 days, then 1 tab qd
 Alternative: Pyrimethamine 200 mg once, followed by
 Pyrimethamine 50-75 mg/day, plus
 Sulfadiazine 1.0-1.5 gm q 6 hrs, plus
 Folinic acid 10-20 mg/d* x 6 wks then half dose
 In Ethiopian setting Co-trimoxazole is considered 1st line
of choice*
 Corticosteroids (dexamethasone 4mg PO or IV q6hrs) used if cerebral edema present,
and discontinued as soon as clinically feasible
*Folinic acid needed with pyrimethamine, but expense limits use in Ethiopia

603
Alternative Regimens

 Pyrimethamine and Folinic acid (standard

dose) PLUS
 Clindamycin 600 mg q 6 hrs, or
 Cotrimoxazole (TMP 5 mg + SMX 25
mg)/kg IV or PO bid, or
 Atovaquone 1.5 gm PO bid, or
 Pyrimethamine and Leucovorin (standard
dose) PLUS Azithromycin 900-1200 mg PO
qd
604
Suppressive Therapy

 Fansidar 1 po qd
 Pyrimethamine 25 mg + sulfadiazine 500 mg +
folinic acid 10-25 mg PO qd
 Cotrimoxazole DS tablet daily – Can be stopped when
the CD4 count remains ≥ 200, but > 350 in Ethiopian
context for 6 months

605
Cryptococcal Meningitis

 Caused by C. neoformans
 Infection acquired through inhalation
 Occurs in advanced disease (CD4<100)
 Rarely, presents as pneumonitis, or as
disseminated disease that includes skin
(umbilicated vesicles, like molluscum)
 Clinical manifestations may be subtle
606
 Clinical Signs of
Cryptococcal Meningitis

Clinical Manifestations % of Cases

Headache 70-90

Fever 60-80

Meningeal signs 20-30

Photophobia 6-18

Seizures 5-10
607
 Cryptococcal Meningitis Treatment
 Fluconazole: 800 mg/d x 2 wks, then 400
mg/d x 8 wks, then 200 mg/d
or
 Amphotericin 0.7 mg/kg/day IV plus
flucytosine 25 mg PO qid for 2 weeks
followed by Fluconazole then 400 mg/d x 8
wks then 200 mg/d
 Treat until CD4 >200 x > 3 mo
608
 CMV
 Typically does not cause disease until CD4
<50
 Manifestations in HIV patients:
 Retinitis
 Unilateral or bilateral visual disturbance
 Confirmed by retina exam showing “scrambled
eggs & ketchup” (exudates & hemorrhages)
 GI disease
 Esophagitis
 Colitis with watery diarrhea, abdominal pain
 Neurologic disorders
609
610
Differential Diagnosis
 Enteropathogenic  Parasites
bacteria  E. histolytica
 Shigella
 G. lamblia
 Salmonella

 E. coli
 Cryptosporidium
parvum
 Mycobacteria  Isospora belli
 M. tuberculosis
 Strongyloides
 M. bovis
stercoralis,
 CMV others
611
 Laboratory Diagnosis
 Direct microscopy of stool, including
leukocyte stain
 Stool culture ; Blood culture
 AFB stain, Modified AFB stain
 Endoscopy and colon biopsy
 Assessment of related effects (CBC,
LFT, RFT, electrolytes, blood sugar,
U/A, VDRL, CD4, viral load)
 Stool assay (C. Diff) 612
Case 1 Chronic Diarrhoea
 Stage 4 HIV (+) patient

 Watery diarrhea, 10 x a day, cramping

abdominal pain, severe dehydration

 Trial of cotrimolxazole ineffective

 Diagnosis?
613
Cryptosporidiosis
 Treatment
 Palliative
 No effective
specific treatment

 ART is very
effective!!!!!
Modified acid
fast stain
614
Case 2 Chronic Diarrhoea
 42-year old man, new patient

 No cotrimoxazole prophylaxis

 Persistent diarrhea, watery stools,

cramping

 Diagnosis?
615
Isospora belli
 Direct stool exam
 Large Oocysts (20-30
µm)
 Cotrimoxazole 2 SS x
4/day for 10 days
 Followed by 2 SS x
2/day for 3 weeks or
 CTX 1 DS bid x 7-10
days
 Secondary prophylaxis
with cotrimoxazole 2 SS

616
 Case 3: Chronic Diarrhoea
 Profuse watery diarrhea, no response to
co-trimoxazole and metronidazole empiric
therapy

 Stool exam is negative for cryptosporidiosis

 The stool sample is positive for

microsporidium

617
 Microsporidiosis
 Modified trichrome
method staining
 With 100 oil
immersion
 Small spores: 1-3 µm
 E. Intestinalis – Rx
w/ Albendazole 400
mg po bid x 2-4
Empiric therapy with ?? weeks or CD4> 200
Albendazole? HAART!
 E. bienuesi – Rx w/
fumagillin 60mg/day
x 14 d 618
 Case 4: Chronic Diarrhoea
 Patient presents
with respiratory
symptoms
 Skin lesions like
creeping eruption
 Diarrhoea

Strongyloides hyperinfection syndrome

R/ Albendazole 400 mg bid 5 days
Can do wet mount or parasite stain on sputum 619
Clostridium difficile
 Underestimated
 Associated with significant
mortality
 Usually in patients who have been
hospitalized
 Treatment: metronidazole 500 mg
3x/day x 7 days

620
 Diagnosis and Treatment of Common
Causes of Diarrhea in AIDS Patients
Agent CD4 Symptom Diagnosis Rx
bloody stool, Stool Metronidazol
E. histolytica any
colitis microscopy e
Giardia any Watery diarrhea “ “

Cryptosporidium <150 Watery diarrhea Modified AFB HAART

Isospora belli <100 Watery diarrhea Modified AFB TMP-SMX

Albendazole
Microsporidium <50 Watery diarrhea Giemsa stain
(20% respond
Watery to Bloody Biopsy,
CMV <50 Ganciclovir
stool, colitis barium study
621
 Oral Thrush  60% of patients
Candida albicans is an per year with CD4
endogenous yeast < 100
 10-20% associated
with oesophageal
candidiaisis
 White painless
plaques on the
buccal or
pharyngeal mucosa
or tongue surface
that can easily be
scraped off
622
Clinical presentations:
 Thrush:
 pseudomembranous (classical) >
80%,
 atrophic,

 erythematous

 Angular cheilitis (perleche)

 Median rhomboid glossitis
623
Pseudomembranous thrush

624
Erythematous thrush

625
Atrophic thrush

626
Angular cheilitis

627
Median Rhomboid Glossitis

628
 Oral and Esophageal Lesion in
HIV/AIDS
Features Candida CMV HSV Apthous Ulcers
Frequency 50-70% 10-20% 2-5% 10-20%

Dysphagia YYY Y Y Y

Odynophagia YY YYY YYY YYY

Thrush 50-70% < 25% <25% <25%

Fever rare often rare rare

Oral ulcers rare uncommon often uncommon

629
 KS Clinical Manifestations
 Can affect almost any organ system
 Most common sites include:
 Skin: Nodular lesions purple or black; can progress to
multiple lesions
 Oral cavity: flat to nodular lesions
 Edema of legs and/or face due to lymphatic
obstruction
 GI tract: can have KS anywhere in GI tract, which can
cause intestinal blockage and bleeding; usually
asymptomatic
 Pulmonary: can spread along bronchi and vessels;
usually asymptomatic
 Diagnosis is usually by observing typical lesions 630
 Staging of Kaposi's Sarcoma

ART alone for T0S0 or ART

T0S1 And chemotherapy
for others

T0 = lesions confined to the skin T1 = tumour-associated oedema or

and/or lymph nodes/ and or minimal ulceration
oral disease*
S0 = No B symptoms, no history for S1 = history of OI and/or oral thrush,
OI, no oral thrush B symptoms present

631
 Kaposi Sarcoma Treatment
 HAART
 Local therapy for skin lesions
 Alitretinoin gel (35-50% response)
 Local radiation (20-70% response)
 Intralesional vinblastine/vincristine (70-90% response)
 Cryotherapy (85% response)
 Photodynamic therapy
 Surgical excision
 Systemic therapy failure of local therapy or
extensive disease
632
 Summary – OIs
 HIV: Progressive Immune Deficiency
 Most comment complications
 Cell mediated immunity
 CD4 < 200
 TB, Crypto meningitis, toxo, PCP, KS,
Lymphoma
 Treatment: OI and HIV
 Complications: IRIS
 Prevention: Early HAART
633
WHO Staging System for
HIV/AIDS in Resource Limiting
Settings

634
Learning Objectives
 Describe how the WHO staging system
is used to assist management of
HIV/AIDS
 List the clinical conditions that
characterize each WHO stage of
HIV/AIDS

635
Introductory Case: Lake
 33 year old male presents to ART clinic
for initial evaluation. He has a history of
Zoster. He reports diarrhea, intermittent
fever, and itching. He stopped working
as a merchant one month ago due to
fatigue.
 What additional information is necessary
for accurate WHO staging of this patient?
636
Introductory Case: Lake (2)
 Diarrhea occurred daily, was non-bloody, and
began 2 months ago
 Fever began 2 months ago
 Wt loss of 8 kg (50 ->42kg) over last 6 months
 History of PTB treatment 1 year ago
 No cough, night sweats
 Exam revealed thrush and papular rash on
trunk and extremities
 CXR normal
 Stool exam normal
 HCT 9 g/dl

637
WHO Staging System for
HIV/AIDS: Overview
 Tool used to guide management of HIV patient in
resource limited settings with limited laboratory
access
 Clinically based; CD4 count not necessarily
required
 Simple, flexible and widely used
 Latest revised version 2006
 Utilizes 4 clinical stages based on the degree of
immunocompromise and prognosis
 I,II, III, IV
 Staging correlates with degree of
immunosuppression
638
WHO Staging System for
HIV/AIDS: Overview (2)
 Performed at each clinical visit
 Diagnosis
 Entry to clinical care (pre-ART)
 Follow-up
 Stage assessment can be adjusted
upwards or downwards over time
according to response to ART and/or
clinical progression
 Staging on ART is referred as T staging
639
WHO Staging of HIV/AIDS
With confirmed HIV infection
 Stage I - asymptomatic

 Stage II - mild disease

 Stage III - moderate disease

 Stage IV - advanced

immunocompromise

640
WHO Stage I
 Asymptomatic or
 Persistent generalized lymphadenopathy
(PGL)

641
Persistent Generalized
Lymphadenopathy (PGL)

642
Courtesy of Charles Seinberg MD
WHO Stage II
 Moderate unexplained weight loss (<10% of
presumed or measured body weight)
 Recurrent respiratory tract infections (RTIs,
sinusitis, bronchitis, otitis media, pharyngitis)
 Herpes zoster
 Angular cheilitis
 Recurrent oral ulcerations
 Papular pruritic eruptions
 Seborrhoeic dermatitis
 Fungal nail infections of fingers
643
Pruritic Papular Eruption

644
Courtesy of Charles Steinberg MD
Pruritic Papular Eruption

645
Courtesy of Charles Steinberg MD
Apthous Ulcer

Source: www.HIVdent.org. Copyright © 1996-2000 David Reznik, D.D.S. 646

Herpes Zoster

Courtesy of Tom Thacher, MD Courtesy of the Public Health Image Library/CDC

647
Molluscum Contagiosum

648
WHO Stage III
 Conditions where a presumptive diagnosis can
be made on the basis of clinical signs or simple
investigations
 Severe weight loss (>10% of presumed or
measured body weight)
 Unexplained chronic diarrhea for > one month
 Unexplained persistent fever (intermittent or
constant for > one month)
 Oral candidiasis
 Oral hairy leukoplakia
 Pulmonary tuberculosis (TB) diagnosed in last two
years
 Severe presumed bacterial infections (e.g.
pneumonia, empyema, pyomyositis, bone or joint
infection, meningitis, bacteremia)
 Acute necrotizing ulcerative stomatitis, gingivitis or
periodontitis
649
WHO Stage III (2)
 Conditions where confirmatory
diagnostic testing is necessary
 Unexplained anemia (<8 g/dl), and or
 neutropenia (<500/mm3) and or
 thrombocytopenia (<50 000/ mm3) for
more than one month

650
Oral Candidiasis

Courtesy of Samuel Anderson, MD Courtesy of Dr. R. Ojoh

651
Oral Candidiasis (2)

652
Source: http://members.xoom.virgilio.it/Aidsimaging
Oral Hairy leukoplakia

Courtesy of Dr. R. Oj

653
WHO Stage IV
 Conditions where a presumptive diagnosis can
be made on the basis of clinical signs or simple
investigations
 HIV wasting syndrome
 Pneumocystis pneumonia
 Recurrent severe or radiological bacterial pneumonia
 Chronic herpes simplex infection (orolabial, genital or
anorectal of more than one month’s duration)
 Oesophageal candidiasis
 Extrapulmonary TB
 Kaposi’s sarcoma
 Central nervous system (CNS) toxoplasmosis
 HIV encephalopathy

654
WHO Stage IV (2)
 Conditions where confirmatory diagnostic
testing is necessary:
 Extrapulmonary cryptococcosis including
meningitis
 Disseminated non-tuberculous mycobacteria
infection
 Progressive multifocal leukoencephalopathy
(PML)
 Candida of trachea, bronchi or lungs
 Cryptosporidiosis
 Isosporiasis
 Visceral herpes simplex infection
655
WHO Stage IV (3)
 Conditions where confirmatory diagnostic
testing is necessary:
 Cytomegalovirus (CMV) infection (retinitis or of
an organ other than liver, spleen or lymph
nodes)
 Any disseminated mycosis (e.g. histoplasmosis,
coccidiomycosis, penicilliosis)
 Recurrent non-typhoidal salmonella septicemia
 Lymphoma (cerebral or B cell non-Hodgkin)
 Invasive cervical carcinoma
 Visceral leishmaniasis
656
Severe Chronic Herpes
Simplex Ulcers

© Slice of Life and Suzanne S. Stensaas

657
Disseminated Cutaneous
Cryptococcosis

658
Disseminated cutaneous
cryptococcosis (2)

659
HIV wasting syndrome
 Weight loss >10% body weight
plus
 Unexplained chronic diarrhea (>1 mo)
or
 Unexplained fever (>1 mo) plus chronic
weakness

660
 HIV encephalopathy
(AIDS dementia complex)
 Dementia - persistent cognitive decline with
preserved alertness
 Complex - concomitantly altered motor
performance and, at times, behavior; myelopathy
may be prominent
 Disabling condition that interferes with activities of
daily living
 Progresses over weeks to months
 Absence of concurrent illness or condition that
could explain findings
 Limited treatment options; ART may be helpful
661
Kaposi’s Sarcoma

662
Kaposi’s Sarcoma

663
Introductory Case: Lake (3)
 The patient was counseled and started
on NVP/3TC/d4T. At his 6 month f/u
visit, he states that his symptoms have
resolved and he has returned to work.
 Examination reveals wt of 47kg and a
persistent papular lesions with evidence
of recent excoriations.
 What additional information is necessary
for current WHO staging of this patient?

664
Introductory Case: Lake (4)
 The patient returns again after 12
months of ART. He has developed
head ache, anorexia, cough, and
unilateral weakness.
 What additional information is needed
for current WHO staging of this
patient?

665
Introductory Case: Lake (5)
 Wt is now 40kg
 Thrush is present
 Spastic left hemiparesis is confirmed
 CXR normal
 Sputum negative for AFB
 Any additional information necessary
for staging this patient?
666
Case Studies

667
Case Study: Betrukan
 Betrukan, 19, meets a man she likes very
much who lives in the same town. Solomon,
handsome, funny and a few years older, has
his own butchery. Solomon is unaware that
he has been living with HIV for 3 years.
Solomon and Bertukan become a couple.
They have unprotected sex as Bertukan, a
secretary for a medical office, has been on
OCPs (oral contraceptive pills) for a year.
668
Case Study: Betrukan (2)
 Ten days later, Bertukan misses work
due to a flu-like illness. She has fever,
her joints ache and her glands are
swollen.
 2 months later, Bertukan decides to be
tested for HIV, but Solomon declines.
Bertukan feels well. Bertukan gets
tested, and is seroreactive.
669
Case Study: Betrukan (3)
1. What are some reasons people might
not get their test results?
2. What is Bertukan’s WHO classification?
3. What is Solomon’s WHO classification?

670
Case Study: Betrukan (4)
 Eighteen months later Bertukan and
Solomon are expecting their first baby. Her
antenatal clinic has been providing HIV
information and PMTCT for some time.
Group education regarding HIV and safe
motherhood includes HIV testing as routine
pre-natal care.
 She discloses her status to Solomon who
has not been feeling well – he has lost 4 kg
in the past few weeks and has been having
diarrhea. He agrees to HIV testing and his
test is positive.
671
Case Study: Betrukan (5)
4. What WHO stage is Solomon now?
5. What should happen next at the clinic?

672
Case Study: Rahel
 37yo Ethiopian woman presents w/1 yr
history of oral candidiasis. HIV Elisa
negative 1 yr ago. Repeat Elisa was
positive and she is referred to your clinic.
 PMH: non contributory
 SH: lives alone, earns 500 birr/mo, no
ETOH, has no current sex partner and no
prior use of condoms or birth control
 ROS: non-contributory.

673
Case Study: Rahel (2)
 Tearful woman
 T37, Wt 55kg,Ht 5’5”
 HEENT: white plaques / pseudomembranes
on posterior pharynx , no OHL, no
adenopathy
 Heart, Lungs, Abd: normal
 Skin: seborrheic dermatitis of face
 Pelvic: thick, white discharge, KOH+
674
Case Study: Rahel (3)
1. What is her current WHO stage?
2. Is she a candidate for ART?
3. What are the immediate health care
issues to be addressed at initial visit?
4. What other issues need to be
addressed before ART is considered?

675
Key Points
 WHO Staging of HIV/AIDS is an important
tool used for management of HIV in resource
limited settings
 Staging is based on clinical conditions that
correlate with the degree of
immunocompromisation and prognosis
 Staging should be assessed at time of HIV
diagnosis, prior to starting ART, and with each
follow-up visit to assess response to ART

676
Initiation and Monitoring of
Therapy

677
Learning Objectives
 Define HAART and identify goals of
Antiretroviral Therapy (ART)
 Describe the preparation and indications
for initiation of ART
 Describe the first line ART regimens in
Ethiopia
 Identify the goals and ways of
monitoring ART
 Explain IRIS and its implications during
monitoring
678
History of ART
 In 1986 AZT was discovered as the first
ARV drug
 Reduced viral replication
 Effect short lived due to the rapid development
of resistance
 Dual therapy showed better results than
monotherapy
 Effect still limited by resistance
 In 1996, HAART was introduced
 Sustained clinical and virological response seen

679
What is HAART?
 HAART stands for Highly Active Anti
Retroviral Therapy
 Similar to ART (can be used
interchangeably)
 A combination of at least three effective
ARV drugs
 Controls HIV replication with reduced
risk of resistance development
 However, it does not eliminate the virus
from the body. It is not a cure
680
 Goals of HAART- Primary
 Reduce HIV RNA (viral load) to undetectable
levels within 4-6 months of ART initiation with
durable suppression
 Increase CD4 cell count, allowing preservation
or improvement of immune function
 Reduce HIV related morbidity thereby
improving quality of life of the patient
 Reduce HIV related mortality

681
Goals of HAART- Secondary
 Reduction of the incidence of HIV by:
 Increasing uptake of HCT
 Prevention of mother to child transmission
 Reducing stigma and discrimination
through raising community’s hope
 Reducing transmission of HIV at the
community level

682
What Factors Determine the
Success of HAART?
 ADHERENCE!
 Appropriate preparation for initiation
 Use of effective first line regimen
 Proper monitoring for side effects and
disease progression

683
 Introductory Case: Meseret
 Meseret, a 25-year-old female, came to the ART
clinic after she was referred from the VCT
center
 She decided to be tested for HIV because she
observed significant but unintentional weight loss in
the last 2 months
 Her boyfriend recently died from chronic couch and
marked weight loss and she believes he had
underlying HIV infection
 She was told that she is HIV positive 3 days ago
 What should be done to prepare Meseret for
HAART initiation?
684
 Preparation for HAART
Initiation
 Baseline clinical and lab evaluation
 Identify and treat OIs
 Assess for the presence of indications for ART
 Clinical staging
 CD4 values
 Assess patient readiness
 Acceptance of HIV status and benefits of ART
 Psychological, financial, socio-cultural issues
 Strong adherence counseling
 Prepare patient follow-up for after initiation of ART
685
Initial Evaluation for Initiation
of ART

686
Introductory Case: Meseret
(2)
 What should be done in the baseline
assessment to evaluate Meseret?

687
The Baseline Assessment
 Baseline health history
 Physical examination
 Clinical staging
 Laboratory testing

688
Baseline Health History
 Current symptoms
 Usual source and pattern of seeking care
 Psychiatric or emotional disorders
 Surgical history
 Date
 Recovery status
 Review of systems
 Past medical illness
689
Baseline Health History (2)
 Childhood Illnesses
 Varicella
 Immunizations
 Family Medical History
 Medical conditions
 Mental health
 Sexually Transmitted Infections (STI)
 Treatment and follow-up
690
Baseline Health History (3)
 Gynecologic and Obstetrical History
 Menstrual history
 Pregnancy history
 Methods of birth control
 PMTCT history
 Children’s HIV Status

691
 Baseline Health History (4)
 Medication History
 Previous/current medications including HAART
 Drug allergy
 Adherence history
 Assess adherence to care and medications
 Assess family/household support
 Nutritional History
 Access to food
 Social history
 Patient beliefs and misconceptions
692
 Baseline Physical Exam
 Do complete physical examination
 Special attention to:
 Weight
 Height (head circumference in children)
 Oral cavity
 Lymph nodes
 Lungs and CVS
 Skin: full exam including recto genital region
 Liver and spleen size
 For women, pelvic exam and pregnancy status
 Funduscopic and neurological evaluation 693
Introductory Case: Meseret
(3)
 When asked her health history, Meseret reports:
 No complaints other than weight loss
 Treated for pulmonary TB one year ago
 No history of STI
 On examination, Meseret looks thin with silky
hair.
 Weight 42 kg (50 kg 6 months back)
 No oral thrush
 No other remarkable finding

694
Introductory Case: Meseret
(4)
 Is Meseret eligible for ART?
 What baseline lab tests would you
request for Meseret?

695
 Baseline Laboratory Testing
 HIV antibody test
 Hemoglobin or hematocrit and WBC with
differential count
 Serum ALT or AST, bilirubin
 Serum creatinine & BUN
 CD4 lymphocyte count
 Pregnancy test (women)
 Other tests are indicated when appropriate based
on patient current and past medical history e.g.
CXR, sonography etc
696
Baseline Laboratory Testing
(2)
 Other tests:
 Serum glucose
 Amylase
 Serum lipids
 Viral load testing

697
 Regimen Drugs Monitoring Tests Frequency
TDF/FTC/EFV CD4 Baseline and every 6 months
First-line 1.

Regimens Pregnancy test 1. Baseline and as indicated

ALT 1. Symptom-directed

Creatinine 1. symptom-directed
D4T/3TC/NVP CD4 count 1. At baseline and 6 monthly (if available)
ALT Symptom-directed
ZDV/3TC/NVP Haemoglobin 1. At baseline, 4th, 8th, and 12 th weeks. thereafter symptom-
directed
1. ALT 1. Symptom-directed
1. CD4 Count 1. Baseline and 6 monthly (if available)
d4T/3TC/EFV 1. Pregnancy 1. Baseline, thereafter as indicated
Test

1. ALT 1. Symptom-directed

CD4 Count 1. At baseline and 6 monthly

ZDV/3TC/EFV Haemoglobin, 1. At baseline, 4th, 8th, and 12 th weeks; thereafter symptom-
directed
1. Pregnancy 1. At baseline, thereafter as indicated
test
1. ALT 1. Symptom-directed

1. CD4 count 1. At baseline and 6 monthly

698
When to Start ART
 Starting Antiretroviral Drugs is NOT AN
EMERGENCY!
 Criteria for initiation must be met
 At least two visits are necessary before
initiation to ensure patient readiness

699
 Indications for ART
 Based on ‘Guidelines for Use of Antiretroviral
Drugs in Ethiopia,’ March, 2008.
 Adapted from the revised WHO guidelines
 Can be used in the presence or absence of CD4
values
 Uses WHO clinical staging, CD4 count and TLC as
appropriate
 Designed for:
 Physicians and other health-care providers
 HIV/AIDS program managers, health planners,
and experts working on drug selection and
procurement
700
Objectives of the Guidelines
 Ensure evidence-based, safe, and
rational use of antiretroviral drugs
 Provide standardized approach to the
use of ARV drugs in the comprehensive
HIV/AIDS care in Ethiopia
 Serve as a reference resource to health
care providers and people living with
HIV/AIDS
701
 Clinical Criteria for ART
Initiation for Adults
 If CD4 count available:
 WHO stage IV irrespective of CD4
 WHO stage III with CD4 ≤ 350/mm3
 CD4 < 200/mm3 irrespective of the clinical stage
 If CD4 count not available:
 WHO stage IV irrespective of TLC
 WHO stage III irrespective of TLC
 WHO stage II with TLC < 1200/ mm3

702
 Introductory Case: Meseret
(5)
 The following lab tests were obtained for
Meseret:
 Hct: 36%
 WBC: 4000/mm3 ; L- 20%
 BUN, creatinine and ALT – within normal limits
 Urine pregnancy test—negative
 CD4- specimen to be sent to regional lab (result
expected in 2 weeks)
 Is she eligible for ART?
703
Introductory Case: Meseret
(6)
 Meseret was counseled by the ART
nurse about:
 Living positively with the virus
 Availability of treatment free of charge
 Need for 100% adherence
 Started with cotrimoxazole 960mg daily
 Made appointment to return in two
weeks
704
 FIRST LINE REGIMEN: ETHIOPIAN
ART PROGRAM 2008

Preferred:
1) TDF EFV
2) AZT

3TC/FTC

Alternatives:
1) d4T
NVP
2) ABC
REGIMENS:
PREFERRED
1. TDF+FTC+EFV
2. ZDV+3TC+EFV
3. ZDV+3TC+NVP

ALTERNATIVES
1. D4T+3TC+NVP
2. TDF+3TC+NVP
3. D4T+3TC+EFV
4. ABC+3TC+NVP
5. ABC+3TC+EFV
6.ABC+3TC+ZDV 705
First-line Regimens
Recommended ARV Regimens for Adults and Adolescents: One of
the following should be used unless there are contraindications:
Preferred :
 TDF+FTC+EFV = triple FDC

 ZDV+3TC+EFV = combivir + EFV

 ZDV+3TC+NVP = triple FDC

Alternatives:
 D4T/3TC/EFV = double FDC (d4T/3TC) + EFV

 TDF/3TC/NVP

 D4T/3TC/NVP=triple FDC

 ABC/3TC/EFV

 ABC/3TC/NVP

 ABC/3TC/ZDV = combivir + ABC 706

Preferred : First-line
Regimens

 TDF+FTC+EFV = triple FDC

 ZDV+3TC+EFV = combivir + EFV
 ZDV+3TC+NVP = triple FDC

707
Alternatives: First-line
Regimens
 D4T/3TC/EFV = double FDC (d4T/3TC)
+ EFV
 TDF/3TC/NVP
 D4T/3TC/NVP = triple FDC
 ABC/3TC/EFV
 ABC/3TC/NVP
 ABC/3TC/ZDV = combivir + ABC
708
 First-line ARV drugs dosage
 Zidovudine (AZT) 300 mg every 12 hours
 Lamivudine (3TC) 150 mg every 12 hours
 Emtracitabine ( FTC) 200 mg daily
 Stavudine (d4T) 30 mg every 12 hours (or 40 mg
every 12 hours if patient weighs >60 kg)
 TDF 300 mg daily
 ABC 300 mg every 12 hours
 Nevirapine (NVP) 200mg daily for the first 2 weeks,
followed by 200mg every 12 hours
 Efavirenz 600 mg daily at night
709
selective settings where ABC
or TDF
1-ANEMIA & neuropathy (unable to use
thymidine analoges for toxicity reasons)
2-pregnancy and TB
3-Pregnancy & hepatitis
4-Hepatitis B coinfection

710
 Special Considerations in
Selecting Regimens
 If there is potential for pregnancy, avoid EFV due to
teratogenicity
 If patient is taking Rifampicin, use EFV instead of
NVP
 If patient has anemia, use d4T instead of ZDV
 Avoid the following in HAART combinations:
 d4T+ ZDV due to pharmacodynamic antagonism
 d4T+ ddI in pregnancy due to greatly increased risk of
lactic acidosis

711
Introductory Case: Meseret
(7)
 Meseret returned in 2 weeks with
enthusiasm to start ART
 CD4 = 150/mm3
 What drugs would you start her with?

712
Key Points on Starting ART
 Not an emergency
 Has to be individualized
 Ensure fulfillment of eligibility criteria before
initiating
 Medical
 Emotional
 Social
 Follow-up
 Access to ARVs ensured
713
Monitoring Therapy

714
Goals of Monitoring ART
 Detect drug toxicity, interactions and
side effects
 Evaluate initial response to therapy
 Assess adherence
 Recognize treatment failure as early as
possible

715
Types of Monitoring
 Clinical assessment
 Laboratory monitoring

716
Clinical Assessment
 Conduct physical examination and
symptom review at each visit
 Compare current status to baseline

717
Clinical Assessment (2)
 History
 Drug side effects: nausea, vomiting, jaundice,
RUQ pain, bad dreams, etc
 Symptoms of OIs such as cough, fever, severe
headache, etc
 Adherence to medications
 Physical exam
 Take weight at each visit
 Look for signs of drug side effects and OIs
718
Laboratory Monitoring
 Should be done on regular basis
according to Ethiopian Guidelines, and
as needed for specific clinical conditions
 Detects side effects (toxicity) of drugs
before clinical symptoms and signs
appear
 Used for early detection of response to
therapy
719
Laboratory Tests for Toxicity
Monitoring
 Hgb/Hct
 WBC and differential, platelet count
 ALT, AST
 Other tests
 Lipid profile for PI or EFV containing
regimens
 Blood sugar for PI containing regimens
 Creatinine for IDV containing regimens
720
Laboratory Tests for
Monitoring
Response to Therapy
 CD4 testing
 Used to monitor immunological response
 With successful therapy, it is expected to rise
about 50-100/mm3 per year
 Viral load testing
 Should be done at baseline, three months after
initiation to detect early treatment success, and at
6 months to see if viral load is detectable
 Successful treatment decreases viral load by at
least 1 log at 6-8 weeks and to undetectable levels
by 24 weeks
721
Recovery of CD4 Cells
Continues for Years after
Starting HAART

722
Source: Binquet C, et al. Am J Epidem, 2000.
 Regimen Drugs Monitoring Tests Frequency

First-line Regimens TDF/FTC/EFV CD4 1. Baseline and every 6 months

Pregnancy test 1. Baseline and as indicated

ALT 1. Symptom-directed

Creatinine 1. symptom-directed

D4T/3TC/NVP CD4 count 1. At baseline and 6 monthly (if available)

ALT Symptom-directed

ZDV/3TC/NVP Haemoglobin 1. At baseline, 4th, 8th, and 12th weeks. thereafter symptom-directed

1. ALT 1. Symptom-directed
1. CD4 Count 1. Baseline and 6 monthly (if available)
d4T/3TC/EFV 1. Pregnancy 1. Baseline, thereafter as indicated
Test
1. ALT 1. Symptom-directed
CD4 Count 1. At baseline and 6 monthly
ZDV/3TC/EFV Haemoglobin, 1. At baseline, 4th, 8th, and 12th weeks; thereafter symptom-directed

1. Pregnancy test 1. At baseline, thereafter as indicated

1. ALT 1. Symptom-directed
1. CD4 count 1. At baseline and 6 monthly

723
Introductory Case: Meseret
(9)
 Next visit after 2 weeks
 Her evaluation includes:
 Symptoms of drug side effects like skin rash
and itching, jaundice
 Assessment of adherence
 Any other new symptom
 Look for icterus, skin rash; measure her weight
 Do ALT

724
Introductory Case: Meseret
(10)
 At her two week visit you find:
 No complaints except mild itching over the
trunk without rash
 No jaundice
 Good adherence
 The dose of NVP increased to 200mg
BID

725
Introductory Case: Meseret
(11)
 At her third post-ART visit (2 months
after initiation of ART), she reported a
cough of 2 weeks duration
 Has associated scanty sputum and low
grade fever
 Chest is clear
 List the differential diagnosis for her
current symptoms
726
Introductory Case: Meseret
(12)
 Differential diagnosis
 Pulmonary TB
 Upper respiratory tract infection
 Pneumonia (PCP, bacterial, fungal)

727
Introductory Case: Meseret
(13)
 Investigations revealed:
 WBC= 5000/mm3; L= 25%
 Sputum for AFB negative
 CXR showed bilateral lower lung nodular
infiltrates with left sided pleural effusion
 Pleural fluid analysis revealed lymphocytic
& exudative fluid

728
Introductory Case: Meseret
(14)
 Presumptive diagnosis of Tuberculosis
was made.
 What went wrong with Meseret?

729
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 IRIS is the occurrence of an
inflammatory condition (OI) a few
weeks to 6 months after the initiation of
ART due to restoration of immune
status
 It may manifest as:
 A new OI occurring for the first time
 Reappearance of a previously treated OI
 Flare up of an existing viral infection like
viral hepatitis or herpes simplex
730
IRIS (2)
 Mechanism:
 When effective ART regimen is given, the
CD4 cells increase in number rapidly
 A previously sub-clinical infection would
trigger an inflammatory response and
tissue damage
 The quiescent infection will become a
clinically apparent disease

731
IRIS (3)
 Timing:
 Usually occurs in patients with very low
CD4 count (<50/mm3)
 IRIS usually occurs within 6 months after
initiation of effective ART
 However, some episodes of IRIS have been
documented up to 18 months after
initiation of ART

732
IRIS (4)
 Clinical manifestations
 Fever is a prominent feature
 Usually the infections have atypical presentation
 (Mediastinal lymphadenopathy and pleural/pericardial effusion in TB)
 Common infections that manifest with IRS include:
 Tuberculosis
 Cryptococcal meningitis
 Herpes simplex and herpes zoster
 CMV retinitis
 Viral hepatitis
 MAC infection

733
IRIS (5)
 Approach to treatment:
 Recognize the situation is IRIS, not
treatment failure
 Continue ART
 Start treatment of the specific OI
 Steroids may be helpful in particularly
severe cases of IRIS e.g. severe dyspnea
or TBC meningitis

734
IRIS (6)
 Implications of IRIS on patient monitoring:
 IRIS may be easily confused with treatment
failure
 Some features of IRIS may mimic drug side
effect and the distinction may be difficult
 Viral hepatitis presenting as IRIS may be difficult to
distinguish from hepatotoxicity due to ARV drugs
 Patients may feel that they are getting worse
with ART
 Negative effect on adherence
735
IRIS (7)
 IRIS versus treatment failure
 IRIS usually occurs within 3-6 months
 IRIS occurs in the face of increasing CD4
count
 Viral load determination is the most reliable
way of differentiating the 2 conditions

736
Introductory Case: Meseret
(15)
 Meseret has TB presenting as IRIS
 Started on RHZE and pyridoxine
 She was continued on d4T and 3TC
 NVP was switched to EFV (800mg)
 Showed significant improvement after 1
month of anti-TB treatment

737
Case Studies

738
Key Points
 The primary goal of ART is to reduce
morbidity and mortality by controlling viral
replication and improving the immune
function
 ART may be started after adequate
preparation of the patient for ART and
based on the presence of indications for
treatment
 Decision on when to start ART and what to
start with is based on the Ethiopian
guidelines
739
Key Points (2)
 The most important factor that
determines the outcome of ART is
adherence
 Proper and scheduled monitoring is
important to detect drug toxicity and
treatment failure early
 Monitoring involves clinical assessment
and laboratory tests
 IRIS may be easily confused with
treatment failure and drug toxicity
740
STI

741
INTRODUCTION TO STIs PREVENTION
& CONTROL

742
 Module Objectives
 Identify how STIs are transmitted and
the factors that influence transmission
 Explain:
 the magnitude of STIs
 the impacts and complications of untreated
STIs
 linkages of STIs with the spread of
HIV/AIDS
 strategies of STIs prevention and control
 Challenges of STIs prevention and control
743
Session I

The Transmission of STIs

744
STI transmission dynamics at population level

General population

Bridging population

Core
transmitters

745
 How STIs disseminate?

Basic Reproductive
rate

Ro = B x c x D
Transmission Rate of Duration
efficiency sex partner of
change infectiousness

746
The Transmission of STIs
 The most common mode of
transmission is unprotected sex
 Other forms of transmission are
 Mother to child
 During pregnancy (HIV & syphillis)
 At delivery (gonorrhea ,chlamydia &HIV)
 Through breast feeding (HIV)

747
Transmission cont…
 Unsafe (unsterile ) use of needles or
injections or contact with blood or blood
products (syphilis , HIV & hepatitis )

748
Factors increasing
transmission of STIs
 Biological factors
 Age, young and old age in women are more
susceptible
 Gender, women more easily infected than males
 Immune status
 Behavioral factors
 changing sexual partners frequently
 having more than one sexual partner
 having sex with ‘casual’ partners, sex-workers or
their clients
 use of alcohol or other drugs before or during sex

749
Factors increasing
transmission of STIs
 Socio-cultural factors
 in most cultures women have very little decision making power
over sexual practices and choices, including use of condoms
 women tend to be economically dependent on their male
partners and are therefore more likely to tolerate men’s risky
behaviour
 sexual violence tends to be directed more towards women by
men
 Women have difficulties to discuss STIs with their male
counterparts

750
Socio-cultural factors cont..
 in some societies the girl-child tends to be married
off to an adult male at a very young age, thus
exposing the girl to infections
 in some societies a permissive attitude is taken
towards men allowing them to have more than
one sexual partner
 Harmful traditional practices
 skin-piercing
 the use of un-sterile needles to give injections or tattoos
 scarification or body piercing
 circumcision using shared knives
751
Session II

Epidemiology of STI

752
Epideniology of STIs
 More than 30 kinds of organisms are transmissible
sexually
 STIs are major public health problems in all
countries
 Globally 340 million new cases of curable STIs
occur every year (69 million are in sub-Saharan
Africa)
 In many developing countries STIs are among the
top five disease for which adults seek health
services
753
Epidemiology continued
 There is little information on the incidence &
prevalence of STIs in Ethiopia
 Except for adult prevalence of HIV and that of
syphilis (2.7%) there is no actual information
or estimate on other STIs in Ethiopia
 Total of 451,686 cases of STIs were reported
between June 1988 & June 2002 in Ethiopia

754
Distribution of STIs
 Prevalence higher in urban than rural
 Higher in unmarried & young adults
(15-24 yrs)
 More frequent among females than
males between the ages of 14-19
 After the age of 19, there is slight male
preponderance

755
The accuracy of STIs statistics
cont….

Symptomatic

Asymptomatic

756
The accuracy of STIs
statistics
 Reasons for underestimation:
 people with symptom-free STIs do not seek
treatment
 health facilities offering treatment for STIs may be
too far away for many people
 people seeking other health care such as
antenatal services may not be routinely screened
for STIs
 many patients perceive a stigma in attending
traditional STI referral clinics, where anyone might
be perceived to be at risk of infection by STIs

757
The accuracy of STI
statistics
 Reasons continued….
 many people may choose to go to
alternative providers, both in the formal
and informal sectors, who do not report
case numbers
 Use of an excessively long list of notifiable
diseases
 Lack of uniformity of reporting
 Cost of services

758
Session III

The Complications and Health

and Economic Impacts of
STIs

759
 Complications of STIs
CAUSE COMPLICATIONS
Gonococcal & chlamydial Infertility in men & women,
epidedimitis, ectopic pregnancy,
infections chronic pelvic pain, urethral
stricture, perihepatitis

Gonorrhea Blindness in infants,

Disseminated gonococcal infection

Chlamydia Chlamydial pneumonitis in infants

760
 Complications continued..
CAUSE COMPLICATIONS
Gonococcal, chlamydial & Pelvic & generalized
anaerobic infection peritonitis

Acquired syphilis Permanent brain &

Heart disease

Congenital syphilis Extensive organ & tissue

damage
Human papilloma virus Cervical cancer, obstructed
labor
761
Impacts of STI
 Health problems described above
 Divorce &family disruption as a result of
infertility
 Cost of STIs drugs may place heavy financial
burden on families , communities, & the
country at large
 Cost of management of complications
 Cost of management of HIV and AIDS
 The indirect costs include lost days of
productive life

762
The link between STI &
HIV
 Certain STIs facilitate the
transmission of HIV
 The presence of HIV can make
people more susceptible to the
acquisition of STIs
 The presence of HIV increases the
severity of some STIs and their
resistance to treatment
763
Clinical features of various STIs
Influenced by co infection with HIV
 Syphilis can have atypical presentation with
tendency to rapidly progress to neuro syphilis
 Atypical lesions of chancroid are common
 Recurrent or persistent genital ulcers caused
by HSV2 are common
 Human papilloma virus produces exophytic
genital warts that may be large & extensive

764
Treatment of conventional STIs is also
affected when HIV infection co-exist

 Risk of treatment failure with single

injection of benzathine pencillin in
patients with primary syphilis
 Topical anti fungals are less effective
 Severe genital herpes may require
suppression of recurrence with acyclovir

765
Session III

Strategies for STIs

Prevention and Control

766
Prevention and Control of STIs
Involves
 Early diagnosis and treatment
 Promotion of safer sexual behavior
 Promotion of health care-seeking behavior
 Targeting vulnerable groups
 Sexually active teenage girls
 Women or men who have several sexual partners
 Sex workers and their clients
 Men or women whose jobs separate them from their
regular sexual partners for long periods of time

767
Primary prevention
 Safer sexual behaviours
 abstention from sexual activity altogether
 delaying the age of sexual debut
 life-long mutual monogamy
 engaging only in non-penetrative sex acts
 engaging in penetrative sex acts only if
condoms (male or female) are used

768
Secondary prevention
 promoting STIs care-seeking behaviour,
through:
 public education campaigns
 providing non-stigmatizing and non-discriminatory
health facilities
 providing quality STIs care
 ensuring a continuous supply of highly effective
drugs

ensuring a continuous supply of condoms

769
Secondary prevention
 rapid and effective treatment of people with STIs:
 comprehensive case management of STIs syndromes
 to make a correct diagnosis
 to provide correct antimicrobial therapy for the STI syndrome
 to educate on treatment compliance
 to educate on the nature of the infection, safer sexual
behaviour, safe sex acts and risk reduction in order to prevent
or reduce future risk-taking behaviour
 to demonstrate the correct use of condoms and provision of
condoms
 to advise on how the patient’s partners may be treated and to
issue a Partner Referral card for the patient to pass on to
his/her partner(s).

training of service providers in case management

770
Secondary prevention
 case finding and screening:
 examining minimally symptomatic women attending clinics
for maternal and child health and family planning
 partner notification and treatment
 education, investigation and treatment of targeted
population groups (vulnerable groups)
 testing of blood donors for syphilis, HIV and hepatitis B
 community-based screening
 Provision of prophylactic antibiotics against major
STIs for victims of sexual violence
 Integration of STIs services within primary care

771
Session IV

Challenges of Controlling STI

772
Challenges are due to:
 Factors relating to health system
 Biological factors
 Social & behavioral factors

773
Health System Factors
 Health service may be unavailable, too far
away , expensive, or considered stigmatizing
 There may be little emphasis on education &
other efforts to prevent infection
 Health services may not have effective drugs
 Difficulty of partner management

774
Biological factors

 70%-80% of infected women may be

asymptomatic and so will not seek
treatment
 Such people will continue to be
infected, risking complications and
perhaps infecting others

775
Social &behavioral factors
 Reluctance to seek health care
 Ignorance or misinformation
 A preference for alternative health care
service
 Reluctance to follow safe sex practices
 The social stigma often attached to
STIs
776
Social & behavioral factors cont…
 Failure to take full prescribed course of
treatment
 Difficulty of notifying sexual partners

777
Approaches to STIs
Management

778
Classical approaches to STIs
management
 Etiologic diagnosis – using lab to
identify the causative agent
 Clinical diagnosis –using clinical
experience to identify causative agent

779
Etiologic management
 Advantages:-
 Avoids over treatment

 Conforms to traditional clinical training

 Satisfies patients who feel not properly

attended to
 Can be extended as screening for the

asymptomatic patients

780
Problems of etiologic approach
 Requires skilled personnel &consistent supplies
 Treatment does not begin until results are available
 It is time consuming & expensive
 Testing facilities are not available at primary level
 Some bacteria are fastidious &difficult to culture
(H.ducrey, C.trachomatis)
 Lab. results often not reliable
 Mixed infections often overlooked
 Miss-treated/untreated infections can lead to
complications and continued transmission

781
Clinical Management
 Advantages:-
 Saves time for patients

 Reduces laboratory expenses

 Disadvantages:-
 Requires high clinical acumen

 Most STIs cause similar symptoms

 Mixed infections are common &failure to treat may

lead to serious complications

 Doesn’t identify asymptomatic STIs

782
Syndromic Approach
 Syndrome – is group of symptoms
patient complains & clinical signs you
observe during examination
 Different organisms that cause STIs
give rise to only limited number of
syndromes
 There are seven syndromes (aim is to
identify &manage accordingly)

783
 Identifying syndromes
SYNDROME MOST COMMON CAUSE
Vaginal discharge Vaginitis(trichomniasis, candidisis,
bacterial vaginosis, Gardenella
vaginalis)
Cervicitis(gonorrhea, chlamydia)
Urethral discharge in men Gonorrhea, chlamydia

Genital ulcer Syphilis, chancroid, herpes

Lower abdominal pain Gonorrhea, chlamydia, mixed

anaerobes
Scrotal swelling Gonorrhea, chlamydia

Inguinal bubo LGV, Chancroid

784
Neonatal conjunctivitis Gonorrhea, chlamydia
 Why Syndromic Approach?
 STIs sign and symptoms are rarely specific to a
particular causative agent
 Laboratories are either non-existent or non
functional due to lack of resources
 Dual infections are quite common and both
clinician and laboratory may miss one of them
 Waiting time for lab results may discourage
some patients
 Failure of cure at first contact

785
 Syndromic management key
features
 Problem oriented (responds to patient’s
symptoms )
 Highly sensitive & does not miss mixed
infections
 Treats the patient at first visit
 Can be implemented at primary health
care level

786
Key features cont…
 Use flow charts with logical steps
 Provides opportunity & time for
education &counseling

787
The four steps in syndromic
STI case management
 History taking and examination
 Syndromic diagnosis and treatment,
using flow charts
 Education and counseling on STI and
HIV testing and safer sex, including
condom promotion and provision
 Management of sexual partners

788
Frequently raised issues on the
syndromic approach
 Issues related to scientific ground
 It is based on wide range of epidemiological
studies
 Validation studies have confirmed comparable
accuracy of syndromic & lab diagnosis with
limitation of syndromic management only to
vaginal discharge
 Syndromic case management of STIs in Tanzania
has shown decrease transmission HIV& STI in
population (MWANZA TRIAL)
789
Frequently raised issues on
the syndromic approach
 Issues related to simplicity of
management
 Simplicity allows other health workers other than
doctors to use the approach to make a diagnosis
 It allows health workers more time to offer
education for behavior change

790
Frequently raised issues on
the syndromic approach
 Issues related to service provider’s
clinical skills and experience
 studies have shown clinical judgment
misses 50% of cases
 Issues related to use of multiple
drugs
 studies have shown that it is less expensive

791
Frequently raised issues on
the syndromic approach
 Issues related to treating a single
pathogen causing STI based on
prevalence
 Many patients required to return to a
health centre for treatment do not do so

792
Frequently raised issues on
the syndromic approach
 Issues related to the use of simple
laboratory tests such as Gram’s
stain
 it should not be at the expense of delayed
treatment or at risk of patient non return

 Remember that effective treatment of people

with STIs is the best way of interrupting the
cycle of transmission

793
Limitations of syndromic
management
 Misses sub-clinical infection

 Needs validation study

 Require prior research to determine

the common causes of particular

syndromes

 Needs training
794
Session III

Using the flow-charts

795
Syndromic flow-charts
 A flow chart is a diagram (map) representing
steps to be taken through a process of
decision making
 Can be used at any health facility
 prompt treatment is provided at initial visit
 many people with STIs have access to treatment
 provides opportunity for preventive & promotive
measures

796
Each flow chart is made up of
three steps
 The clinical problem (patient’s presenting
symptom)
 Problem box

 A decision to make usually by answering yes

or no to a question
 Decision box

 An action to take (what you need to do)

 Action box

797
 Clinical Problem Decision Box

Enlarged and Painful Inguinal

Lymph nodes?

Take History & Examine

Ulcer (s) Use Genital

Yes Ulcer Flow Chart
Present?

No

Action Box 798

Syndromic Management

799
Module Objectives
 name the decisions and actions on each
of the national flow-charts
 use the national flow-charts to make a
syndromic diagnosis for a variety of STI
cases
 list the correct drug therapies and
dosages for each diagnosis

800
Session I

Urethral Discharge

801
 Clinical presentations
 Burning sensation on urination &
urethral discharge are common
symptoms of urethritis in men
 N.gonorrhea & C.trachomatis are
common causes
 T.vaginalis is found to be the second
most common cause exceeding
C.trachomatis in Ethiopia

802
Clinical signs with urethritis
Gonorrhoea Chlamydia
Incubation: 6days 2-3 weeks

Dysuria: 70-80% 40%

Discharge: 90% <80%

a lot a little

803
Complications caused by NG
and CT
 N. Gonorrhea  N. gonnorhea or
 Disseminated gonococcal C. trachomitis
infection (1-2%)
1. Epididimitis
2. Conjunctivitis
 C. trachomitis 3. Urethral stricture
 Reiter's syndrome 4. PID
5. Infertility
6. Ectopic pregnancy
7. Enhanced transmission
of HIV ( five fold)
804
Examination of patients
with urethral discharge
 The patient should not urinate for at least 2 hours
before examination
 Look for evidence of spontaneous discharge and note
the color, quality and quantity of the discharge
 Scant discharge may produce crusting at the urethral
meatus and meatal redness suggestive of urethritis
 If no discharge is found, the urethra should be
milked to bring the discharge forward
 Some patients could have morning milking syndrome
mimicking urethritis because of fear of acquiring
gonorrhea following unsafe sex

805
 Figure 1. Urethral Discharge Syndrome

Patient complains of
Urethral discharge or dysuria

Take history and examine

Milk urethra if necessary
Educate
No Any other STI No HIV counseling and testing
Discharge
Present Review if symptoms persist
confirmed Promote use and provide
Yes Yes condoms
Treat for Gonorrhea and Chlamydia
Educate and Counsel Use appropriate flow
Promote use and provide condoms chart
Offer HIV counseling and testing
Notify & mange partner(s)
Advise to return in 7 days if symptoms
persist

806
Recommended treatment for
urethral discharge and burning on
urination
Ciprofloxacin500 tablet mg po stat
Or
Spectinomycin 2 grams IM stat
PLUS
Doxycycline 100 mg po bid for 7 days
Or
Tetracycline 500 mg qid for 7 days

Or
Erythromycin 500mg qid for 7 days if the patient has
contraindications for tetracyclines (eg: children, pregnancy)

807
Recurrent/Persistent
Urethritis
 Could be due to inadequate
treatment or poor compliance, re-
infection or infection by drug-
resistant organisms
 Trichomonas vaginalis could as well
be responsible

808
Management of
Recurrent/Persistent Urethritis
 Look for objective signs of urethritis
 Re-treat with initial regimen if non-compliant
or re-exposure occurs
 Effective regimens not identified in those with
persistent symptoms without signs
 Consider morning milking syndrome due to
fear of acquiring STD

809
Figure 2. Persistent/Recurrent urethral discharge in men

Patient complains of
Persistent/recurrent urethral discharge or dysuria

Take history and examine. Milk urethra if

necessary

Ulcer(s) present Educate

Discharge No No Promote and provide condoms
or any other HIV counseling & testing
confirmed
genital d.
Yes Yes
Use appropriate flow chart

Does history suggest re-

infection or poor Yes Repeat urethral discharge treatment for
compliance? gonorrhoea and chlamydia

No
Treat for Trichomonas vaginalis
Educate
Promote and provide condoms
Offer HIV counseling & testing
Notify & manage partner(s)
Return in 7 days

Improved Educate
Yes
Promote use and provide condoms
Offer HIV counseling & testing
No 810
Refer
Recommended treatment for
infection with T. vaginalis

 Metronidazole 2 gm p.o. stat

 Patient should be warned to avoid use
of alcohol while taking metronidazole

811
Session II

Genital Ulcers

812
Genital Ulcers

 Causes include
 T.pallidum(syphillis)
 H.simplex type 2(genital herpes)
 H.ducrey(chancroid)
 C.trachomatis L1, L2, L3, (LGV)
 Klebsella granulamatis( Granulma
inguinale)

813
Syphilis
 Chronic infection caused by T.
pallidum
 Transmission
 Sexual
 Mother to child
 Rarely through contaminated blood

814
Syphilis cont’d
 Incubation period 21 days ( 10-90 days
and depends on inoculum's dose)
 Diverse presentation
 Primary syphilis
- Solitary genital ulcer
- Non tender hard ulcer
- Painless inguinal adenopathy

815
Syphilis cont’d
 Secondary syphilis
- Disseminated spirochetemia
- 8 weeks after infection
- Skin rash is common feature
- Alopecia ; moth-eaten appearance
- Atypical facial plaques
- Mucosal ulcerations
- Condylomata lata
- Painless generalized lymphadenopathy

816
Syphilis cont’d
 Latent syphilis: where there are no
clinical signs but syphilis serology is
reactive

1. Early latent = infection less than one year

2. Late latent= infection occur for over one

year
817
Syphilis cont’d
 Tertiary syphilis
- Gumma
- Cardiovascular: aortitis leading to valve
incompetence and aneurysm
- Neuro-syphilis

818
Neurosyphilis
• Stroke like presentation
( meningovascular)
• Asymptomatic but positive VDRL on
CSF
• Tabes dorsalis
• Paralysis of the insane
• Cranial palsy (cranial nerve VIII, III,
optic atrophy)
819
 Genital Herps
Feature Primary Non Recurrent
primary
Lesions Many , Fewer Few,
bilateral unilateral
Mucosal Usual Uncommon Rare
involvement
Lymphadenopa Usual Occasional Uncommon
thy
Neuropathy Common Uncommon Rare
Systemic Usual Occasional Rare
symptoms
820
Usual duration 2-4 weeks 1-3 week 7-10 days
Chancroid
 Lesions are painful, progressing from a small papule
to pustule and then to ulcer with soft margins
described as soft chancre
 Inguinal adenopathy that becomes necrotic and
fluctuant (buboes) follow the ulcer
 Not found to be a common cause of genital ulcer
syndrome in the validation study
 The incubation period is usually 2-10 days
 Transmitted exclusively by sexual contact
 A cofactor for HIV transmission; high rates of HIV
infection among patients

821
Lymphogranuloma Venereum
(LGV)
 Caused by C. trachomatis serovars L1, L2, or
L3
 LGV primarily infects the lymphatics
 Most common clinical manifestation is tender
inguinal and/or femoral lymphadenopathy-
most commonly unilateral
 Women and homosexually active men may
have proctocolitis or inflammatory
involvement of perirectal or perianal
lymphatic tissues resulting in fistulas and
strictures
822
Lymphogranuloma Venereum
(LGV)
 A self-limited genital ulcer sometimes
occurs at the site of inoculation
 By the time patients seek care, the
ulcer usually has disappeared
 There is little information on the
prevalence of LGV as a cause of genital
ulcer in Ethiopia.

823
Granuloma inguinale
 Chronically progressive ulcerative disease
without systemic symptoms
 The aetiologic agent is Calymmatobacterium
granulomatis
 Incubation period generally is 1-4 weeks,
may be up to 1 year
 It is transmitted primarily by sexual contact
 There is little information on the prevalence
of Donovanosis as a cause of genital ulcer in
Ethiopia.

824
Complications of genital
ulcer syndrome
Disease Etiology Complications

Syphilis T. pallidum secondary syphilis, Latent syphilis,

Aortitis with valvulitis, Aortic aneurys
Gumma, Neurosyphilis
G. herpes Herpes Recurrence,
simplex virus
Aseptic meningitis and encephalitis
Chancroid H. ducreyi Penile auto-amputation

LGV C. trachomatis, Genital oedema, Salphingitis,

L1,L2,L3 Infertility, PID
Garanuloma C. Genital pseudoelephantiasis,
inguinale granulomatis 825
Adhesion, Urethral, vaginal or rectal
 Figure 3. Genital Ulcers syndrome
Patient complains of genital ulcer

Take history and examine

Solitary non-recurrent Educate & counsel

Is ulcer, vesicle recurrent No No
and non vesicular ulcer Offer HIV counseling & testing
or more than three ulcer Promote & provide condoms
present?
present?
Yes
Yes
Treat for HSV2 Treat for syphilis, chancroid and
HSV2

Educate and counsel

Promote and provide condoms
Offer HIV counseling and testing
Ask the patient to return in 7 days
Partner management

No Ulcers improving? No Refer

Ulcers healed?

Yes
Yes

Educate and cousel

Promote & provide condoms Continue treatment to complete 10 days
Offer HCT Services course
Notify and mange partner(s)
826
Recommended treatment for non
vesicular genital ulcer

Benzathine penicillin 2.4 million units IM stat

Or (in penicillin allergy)

Doxycycline 100 mg bid for 14 days
Plus
Ciprofloxacin 500mg bid orally for 3 days.
Or
Erythromycin tablets 500 mg qid for 7 days

827
Recommended treatment for vesicular,
multiple first episode genital ulcer

Acyclovir 400 mg tid for 10 days.

Or
Acyclovir 200mg five times per day for 10
days

828
Recommended regimens
for recurrent infection
 Acyclovir, 800 mg orally, twice daily for
5 days
OR
 Acyclovir, 400mg orally, 3times daily for
5 days
OR
 Acyclovir, 200 mg orally, 5 times daily
for 5 days
829
Recommended regimens
for suppressive therapy

 Acyclovir, 400mg orally, twice daily,

continuously

 Note:
 Some experts recommend discontinuing acyclovir
after one year of continuous use so that the
recurrence rate can be reassessed
 The lowest continuous dose that will suppress
recurrences in an individual can only be
determined empirically

830
Session IV

Vaginal Discharge

831
Common causes of vaginal
discharge
 Neisseria gonorrhoeae
 Chlamydia trachomatis
 Trichomonas vaginalis
 Gardnerella vaginalis
 Candida albicans

832
Causes contd…
 Bacterial vaginosis (Gardnerella
vaginalis) is the leading cause of
vaginal discharge in Ethiopia followed
by candidiasis, trichomoniasis,
gonococcal and chylamydia cervicitis in
that order

833
Initial evaluation of patients
with vaginal discharge include

 Risk assessment

 Clinical speculum examination to

determine site of infection

834
Risk factors for cervicitis
 Age less than 25 years
 Having multiple sexual partner in the
last three months
 Having new partner in the last three
months
 Having ever traded for sex

835
 Difference between vaginitis
&cervicitis
VAGINITIS CERVICITIS
Trichomoniasis, candidiasis, Gonorrhea & chlamydia
bacterial vaginosis

Most common cause of Less common cause of

vaginal discharge vaginai discharge
Easy to diagnose Difficult to diagnose

No complications Major complications

Partner treatment Partner treatment needed

unnecessary
836
Complications of cervicitis and
vaginitis

 PID
 Premature rupture of membrane
 Pre -term labour
 Infertility
 Chronic pelvic pain.

837
 Figure 4. Vaginal Discharge (Speculum and Bimanual)

Patient complains of vaginal discharge or

vulval itching/burning

Take history, examine patient (External, speculum and bimanual) and assess
risk

No
Educate and counsel
Abnormal
Promote and provide condoms
discharge
Offer HCTservices
present?
Yes

Yes
Use flowchart for Lower
Lower abdominal tenderness or
abdominal pain
cervical
motion tenderness ?
No

Was risk assessment* Treat for Chylamydia, Gonorrhoea, Bacterial vaginosis and
Yes
positive Trichomoniasis

No

Treat for Bacterial Vaginosis Vulvar edema/curd like Treat for

Yes
discharge, Erythema, Candida
Excoriation present albicans

No

Educate and counsel

Promote and provide condoms 838
Offer HIV counseling &testing
 Recommended treatment for vaginal
discharge
RISK ASSESMENT POSITIVE RISK ASSESMENT NEGATIVE
Ciprofloxacin tablets 500 mg Metronidazole 500 mg
po stat bid for 7 days
or
Plus
Spectinomycin 2 gm IM stat
Clotrimazole vaginal tabs
Plus
200 mg at bed time for
Doxycycline 100 mg po bid
for 7 days 3 days
Plus
Metronidazole 500 mg bid
for 7 days
839
 Recommended regimens for
pregnant women
 Metronidazole is not recommended for use in
the first trimester of pregnancy
 Treatment may be given where early
treatment has the best chance of preventing
adverse pregnancy outcomes
 Metronidazole, 200 or 250 mg orally, 3 times daily
for 7 days, after first trimester
 Metronidazole 2g orally, as a single dose, if
treatment is imperative during the first trimester
of pregnancy

840
Session V

Lower Abdominal Pain

841
PID
 PID – Ascending infection of the uterus ,
fallopian tubes, ovaries, &peritoneum
 Sexually transmitted
 Causes include N.gonorrhea,
C.trachomatis & Anaerobes i.e (poly
microbial)
 Bilateral lower abdominal pain & vaginal
discharge support diagnosis

842
PID contd..
 Other causes of lower abdominal pain
such as appendicitis &, ectopic
pregnancy should be ruled out
 Women with HIV & PID may have
severe disease

843
Diagnosis of PID
 Diagnosis is often difficult &
inconsistent clinical presentations are
common

 History should include

 Erratic bleeding
 Missed period
 Recent delivery
 Miscarriage

844
Diagnosis contd….
 Physical examination
 Check temperature
 Palpate abdomen for tenderness,
guarding & mass
 Check for vaginal bleeding &abnormal
discharge

845
Diagnosis contd….
 Empiric treatment should be initiated in
sexually active young women and other
women at risk for STIs if the following
minimum criteria are present and no
other cause(s) for the illness can be
identified:
 uterine/adnexal tenderness or
 cervical motion tenderness.
846
Complications of PID
 Peritonitis and intra-abdominal abscess
 Adhesion and intestinal obstruction
 Ectopic pregnancy
 Infertility
 Chronic pelvic pain

847
Indications for hospitalizations
in PID
 Uncertain diagnosis
 Acute abdomen can not be excluded
 Pelvic abscess is suspected
 Severe illness precludes management on an
outpatient basis
 Pregnancy
 The patient is unable to follow or tolerate an
outpatient regimen
 The patient has failed to respond to
outpatient therapy
848
Lower abdominal pain flow
chart

849
 Figure 5: Lower abdominal pain

Patient complains of
Lower abdominal pain

Take history (including gynaecological)

And examine (Abdominal and vaginal)

Any of the following present

Missed/overdue period
Known pregnant Is there cervical excitation
Recent delivery/abortion/ No tenderness or lower abdominal Any other
No
miscarriage
tenderness and vaginal illness
Abdominal guarding and/or rebound
tenderness discharge? found
Abdominal mass
Abnormal vaginal bleeding Yes
Yes
Manage for PID Manage appropriately
Yes No
Review in 3 days

Refer patient for surgical or Patient has improved Refer patient

Gynaecological opinion and
Assessment
Yes
Before referral set up an IV Continue treatment until completed
Line and resuscitate the patient if required. Educate and counsel
Offer HIV counseling &testing
Promote and provide condom
Ask patient to return if necessary or if symptom persist
Partner management
850
 Recommended treatment for
PID
Out patient In patent
Ciprofloxacin tablet 500 mg po Ceftriaxone 250 mg IV/IM daily
stat
OR OR
Spectinomycin 2 gm im stat Spectinomycin 2 gm im bid
Plus Plus
Doxycycline tablet 100 mg po bid Doxycycline 100 mg bid for 14
for 14 days days
Plus Plus
Metronidazole 500 mg bid for 14 Metronidazole 500 mg bid for 14
days days or chloramphenicol 500 mg
Admit if there is no improvement IV qid.
within 72 hours
851
Session VI

Scrotal Swelling

852
Scrotal swelling
 Causes depend on the age of patients
 C.trachomatis & N.gonorrhea are common
causes in patients younger than 35 years
 Scrotal swelling in patients older than 35
years is commonly caused by gram negative
bacteria & TBC
 Other infectious causes of scrotal swelling
could be brucellosis, mumps, onchocerciasis
or infection with W. babcrofti

853
Scrotal swelling
 In pre-pubertal children the usual etiology is
coliform, pseudomonas or mumps virus
 Mumps epidedimorchitis is usually noted
within a week of parotid enlargement
 Other causes of scrotal swelling
 testicular torsion
 Trauma
 Tumor
 incarcerated inguinal hernia

854
 Complications of scrotal swelling
caused by STI
 Epididymitis
 Infertility
 Impotence
 Prostatitis

855
Scrotal Swelling Flow
Chart

856
Figure 6: Scrotal Swelling

Patient complains of Scrotal

swelling/pain

Take history and examine

Swelling/pain No Reassure patient and educate

confirmed? Provide analgesic if necessary
Promote and provide condoms
Offer HIV counseling &tasting
Yes

Testis rotated or Treat for Gonorrhea and Chlamydia infections

No
elevated, Educate and counsel
Or history of trauma? Promote and provide condoms
Offer HIV counseling &tasting
Notify and manage partner(s)
Yes Review within 7 days if necessary

Refer immediately for surgical

opinion

857
Recommended treatment
of scrotal swelling
Ciprofloxacin 500 mg po stat
Or
Spectinomycin 2 gm im stat
Plus
Doxycycline 100 mg PO bid for 7 days
Or
Tetracycline 500 mg PO bid for 7 days.
858
Session VII

Inguinal Bubo

859
Inguinal Bubo

 a painful, often fluctuant, swelling of the

lymph nodes in the inguinal region (groin)
 The common sexually transmitted pathogens
that are associated with inguinal bubo include
 C. trachomatis (serovar L1, L2, and L3)
 H. ducreyi
 C. granulomatis

860
Inguinal Bubo

 Sometimes T. pallidum can be a cause of

inguinal lymphadenopthy
 unlike the other causes, it doesn't generally
produce necrosis and abscess collection in the
lymph nodes.
 In conditions where the clinical examination
doesn't reveal a fluctuant bubo, syphilis should be
additionally considered and treated accordingly
 Surgical incisions are contraindicated and the pus
should only be aspirated using a hypodermic
needle.

861
Inguinal Bubo Flow Chart

862
Figure 7: Inguinal Bubo

Patient complains of inguinal

swelling

Take history and

examine

Inguinal/femoral No Any other STI No Educate and counsel

bubo(s) present? Offer HCT services
Present? Promote and Provide condoms
Yes
Use appropriate
flowchart

Ulcers present Yes Use genital ulcer flowchart

No

Treat for LGV,GI and Chancroid

Aspirate if fluctuant
Educate on treatment compliance
Counsel on risk reduction
Promote and provide condoms
Notify and mange partner(s)
Offer HIV counseling and testing
Advise to return in 7 days
Refer if no improvement
863
Recommended treatment

Ciprofloxacin 500 mg bid orally for 3 days

Plus
Doxycycline 100mg bid orally for 14 days
Or
Erythromycin 500 mg po qid for 14 days

 Some experts advice to extend the treatment of

inguinal bubo, in particular the one caused by LGV,
for 3 weeks. The decision on how to treat inguinal
bubo therefore may need individual judgment

864
Session VIII

Neonatal Conjunctivitis

865
Neonatal Conjuctivitis

 Neonatal conjuctivitis (ophthalmia

neonatorum) is defined as purulent
conjuctivitis occurring in a baby less
than one month of age.
 Sight-threatening condition
 The most important causes are
gonorrhoea and chlamydia
 If caused by gonorrhoea, blindness
often follows

866
Contd.
 In developing countries, gonorrhoea accounts
for 20-75% and chlamydia for 15-35% of
cases of neonatal conjuctivitis
 Common presentation are redness, swelling
of the eye lid &discharge from the eye (sticky
eye)
 For babies older than one month, the cause is
unlikely to be an STI

867
Prevention of neonatal
conjuctivitis
 As soon as the baby is born, carefully
wipe both eyes with dry, clean cotton
wool;
 Then apply 1% silver nitrate solution or
1% tetracycline eye ointment into the
infant’s eyes; other options: 0.5%
Erythromycin ointment or 2.5%
povidone iodine solution;
868
Neonatal Herpes

 Most mother of infants who acquire neonatal herpes

lack histories of clinically evident genital herpes
 The risk for transmission to the neonate from an
infected mother is high (30%-50%) among women
who acquire genital herpes near the time of delivery
 Low (<1%) among women with histories of
recurrent herpes at term or who acquire genital HSV
during the first half of pregnancy
 Because recurrent genital herpes is much more
common than initial HSV infection during pregnancy,
the proportion of neonatal HSV infection acquired
from mother with recurrent herpes remains high

869
Neonatal Herpes
 Prevention of neonatal herpes depends both on
preventing acquisition of genital HSV infection during
late pregnancy and avoiding exposure of the
infection to herpetic lesions during delivery
 In women with active genital herpetic lesions delivery
by caesarean section is recommended to prevent
neonatal herpes
 Abdominal delivery does not completely eliminate the
risk for HSV transmission to the infant
 In addition to severe skin disease, the neonate may
develop aseptic meningitis or encephalitis and it is
frequently fatal

870
Neonatal Conjuctivitis
Flow Chart

871
Figure 8: Neonatal Conjunctivitis

Neonate with eye discharge

Take history and examine

Bilateral or unilateral swollen Reassure mother

eyelids with purulent discharge No
Advise to return if necessary

Yes
Treat for Gonorrhoea and

Chlamydia
Treat mother and partner(s)
for gonorrhoea and chlamydia
Educate mother
Counsel mother
Advise to return in 3 days
No
Improved Refer

Yes
Reassure Mother

872
 Recommended treatment for
neonatal conjuctivitis
SYNDROME TREATMENT
Neonatal conjuctivitis Ceftriaxone 50mg/kg IM stat-
maximum dose 125 mg
OR
Spectinomycin 25 mg/kg IM
stat- maximum dose 75mg
Plus
Erythromycin 50 mg/kg PO
in four divided doses for
14days

873
Recommended treatment
for neonatal herpes
 Acyclovir 10 mg /Kg IV three times
daily for 14 days for localized mucosal
or dermal infections
 Acyclovir 20 mg /Kg IV three times
daily for 21 days for disseminated
infections

874
Session IX

Remarks on Drugs Used for

Treatment of STIs

875
 Remarks on Drugs Used for
Treatment of STIs

 ERYTHROMYCIN should be taken in empty

stomach because bio availability is affected by
food, GI upset is recognized side effect
 CIPROFLOXACIN should not be given to
pregnant women or children
 SPECTINOMYCIN could cause renal damage
requires parenteral administration

876
 Remarks on Drugs Used for
Treatment of STIs
 CEFTRIAXONE expensive &may not be
available
 DOXY CYCLIN & TETRACYCLIN
contraindicated in pregnant women &children
 TETRACYCLIN should not be taken with milk
 ACYCLOVIR the only drug available for
treatment of herpes in Ethiopia, it is safe
&can be used during pregnancy acyclovir
cream is not effective for treatment genital
herpes

877
Antibiotics used for treatment of
herpes should preferably be

 More than 95% effective

 Single doses
 Orally taken
 Cheaper & available
 Safer

878
 Session X

Follow up Visit for Patients

with STI

879
Follow up visit for patients
with STIs
 Importance of follow up visit
 Ensure care &exclude incubating STIs particularly
syphilis
 Some patients may not respond to initial
treatment &reassessment may be needed
 The response to treatment may not be dramatic
with concomitant HIV
 VCT could be offered during follow up visit

880
PARTNER MANAGEMENT

Principles and Approaches

881
Advantages of Partner
Notification
 Break cycle of infection
 Eliminate asymptomatic infection
 Prevent re-infection
 Prevent complication by early detection
 Education & risk reduction counseling

882
Principles
 Treatment of all the patient’s sexual partners
for the same STI as the patient, and treating
any new STI identified are the main features of
partner management
 As the management is syndromic, the
treatment must be given presumptively and the
partner treated even if there are no symptoms
or signs of STI
 Identifying the source has no particular value
because the aim is to treat all partners – or all
those partners we can reach – and their
partners in turn
883
Principles
 Voluntary participation
 Professional approach
 Confidentiality
 Accessibility
 Quality assurance
 Do no harm

884
Approaches to Partner
Management

1. Patient referral (passive contact

tracing)

2. provider referral (active contact

tracing)

885
Patient Referral

886
Patient referral could be done in
several ways

 By directly explaining about the STI &

the need for treatment
 Asking the partner to attend a health
center without specifying the purpose
of the visit
 By giving a partner a card to attend the
center

887
Issues in educating &
counseling the patient
 Anticipating the need to talk to partners about STIs
may provoke feelings as uncomfortable as those the
patient first felt when told that he or she had a
disease that was sexually transmitted
 The success of patient referral depends on health
care providers communication skills
 Explain the importance of treating all patients’

partners
 Remind the patient how to avoid re-infection

 Help the patient decide how to communicate with

the partner

888
 Patient Referral Cards
 Patient referral cards facilitate partner
management
 A referral card could be extremely useful to help
identify the necessary treatment for any partner
referred by a patient with STI
 The card can contain any extra information that
is required, but should never threaten anyone’s
confidentiality or risk them being stigmatized

889
Patient Referral Cards cont…
 Make a habit of giving one or more to
every patient with an STI syndrome
 It is much easier to do this than it is to
remember to ask if a new patient has
been referred to you by someone else

890
Provider Referral

891
Provider Referral
 Provider referral can be used when:
 Patients refuse to refer partner

 Patient has agreed to refer partners but they have

not come for treatment

 Called “combination referral”

 The service provider might be the person who

treated the initial patient or someone whose role
includes searching for and treating partners
 The service provider asks the partner to attend the
clinic for treatment by face to face contact, through
telephone or by writing a letter

892
Provider Referral Cont….
 In some settings outreach or community
health workers may be able to ask partners to
come into a clinic to see a health worker
without explaining the reason of the visit
 Possible if index patients are prepared to
disclose full contact information and gave
consent
 It is resource intensive

893
Challenges of referrals

894
Challenges
 Patient refuses to refer partner(s)
 A partner fails to come for treatment
 Options:
 Offer the patient a duplicate course of
treatment for partner

895
Treating Partners

896
Treatment of partner
 History taking, treating, educating &
managing partners is exactly the same
as the index patient

897
Partner management
continued
SYNDROME OF INDEX TREATMENT OF PARTNER
PATIENT
Urethral discharge Treat for gono & chlamydia
Patient treated for `vaginitis & Treat for gono & chlamydia
cervicitis
Patient treated for vaginitis No partner treatment needed
PID Treat for gono & chlamydia
Scrotal swelling Treat for gono &chlamydia
Inguinal bubo Treat for LGV
Neonatal conjunctivitis Treat for gono &chlamdia
Genital ulcer Treat for syphilis &chancroid
898