G

1. 1
ID LECTURE
By: Dejen G,MD

2. 2
Out line
 AFI:
 Typhus, Typhoid fever, RF, Meningitis, encephalitis, Malaria,
Viral hemorrhagic fever
 Chronic fever….Schistosomiasis, trypanosomiasis
 Parasitoid:
 Filliariasis, Onchocerchiasis, Nematodes, Hookworm,
Strongloidiasis, Giardiasis
 Tetanus
 Anthrax
 HIV

3. 3
Fever
 Temperature elevation >38oc
 Characteristics
 Incubation period
 Pattern
 Duration
 Associated symptoms and signs
 According to studies of healthy individuals 18–40 years of age, the mean
oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at 6 A.M.
and higher levels at 4–6 P.M
 Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings
 It then rises by ~0.6°C (1°F) with ovulation and remains at that level until
menses occur. Body temperature can be elevated in the postprandial state.

4. 4
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

5. 5
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--- abscess

6. 6
Duration
 Acute : <2 weeks
 Typhus, Typhoid, Malaria, Meningitis, RF
 Chronic fever: > 2 weeks
 Tb, VL, Brucellosis, HIV

7. 7
Associated symptoms
 Rigors:
 Bacteremia, Severe viral infection
 Malaria
 Neutropenia:
 Viral infection
 Severe sepsis
 Typhoid fever

8. 8
Typhus

9. 9
Rickettsial infection
 Obligate intracellular, Gram negative,
non-flagellated coccobacilli.
 Transmission:
 Insects
 Animals /insects are reservoirs

10. 10
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)

11. 11
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.

12. 12
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

13. 13
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

14. 14
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

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

16. 16
Contd.
 Congested face
 Depression, delirium,
meningoencephalitis
 Skin rash 2-4 day of fever
 Spottles epidemic typhus

17. 17
Complications
 TM, hemiparesis, peripheral neuropathy
 Psychiatric disturbance
 Secondary infection
 Pneumonia, otitis media
 Myocarditis
 Peripheral vessel occlusion
 Recrudescent: (Brill-zinsser disease)
 Due to immuno-supression and old age

18. 18
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

19. 19
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.

20. 20
Prevention
 Delousing
 Personal and environmental hygiene
 Contact treatment with Doxycycline.
Out come
 Rapid defervescence in 48 hrs
 If untreated mortality 7-40%

21. 21
Typhoid fever
Typhus abdominalis
Enteric fever

22. 22
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.

23. 23

24. 24
Contd.
 Transmission:
 S. typhi and S. paratyphi acquired through
contaminated food and water with faeces
and urine.
 Human faeces as a fertilizer
 Contaminated water
 S. paratyphi is less often water borne-
needs higher infective dose.

25. 25
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.

26. 26
H.Pylori and typhoid fever
 Positivity increases the risk
 Others
 Illiteracy
 Non use of soap
 Ice cream

27. 27
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

28. 28
Clinical presentation
 IP:10-20 days (1-10 days for paratyphi)
 First week
 Rising remittent fever
 Malaise , Head ache
 Mild non productive cough
 Constipation

29. 29
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

30. 30
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

31. 31
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%
 Rose spots may appear, blood culture could be positive
 Milder and shorter duration

32. 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. 33
Complication of TF (perforation)

34. 34
Contd.
 Jaundice
 Cholangitis, cholecystitis,
 Haemolysis, hepatitis
 Myocarditis
 Tachycardia, weak pulse
 Hypotension
 ECG abnormality
 Mild bronchitis and bronchopneumonia

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

36. 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. 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 and those infected
with S.hematobium

38. 38
Treatment
 First line
 Fluoroquinolones-cipro and oflo x 10 days
 Fewer Rx failures and rapid resolution
 3rd generation cephalosporine-ceftriaxone
 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%

39. 39
Rx contd.
 Blood transfusion and 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%

40. 40
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

41. 41
Pregnancy and typhoid fever
 In adult females bacteremic typhoid
disease is pregnancy related (47%)
 Treatment
 Ampicillin/Amoxacillin/Cephalosporin
 Complication is less
 It doesn't affect the pregnancy
outcomes

42. 42
Relapsing fever

43. 43
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

44. 44
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

45. 45
Risk factors
 Overcrowding, impoverishment,
unhygienic condition
 Prisoners, war, famine
 Cool, rainy season
 Close contacts
 Accidental needle prick

46. 46
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

47. 47
Contd.
 Edema and swelling of organs
 Histocytic inflamation of myocardium
 Petechial haemorrhage
 Haemorrhagic infarction of the spleen, heart,
liver and brain

48. 48
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

49. 49

50. 50
Complications
 Haemorrhage: GI, CNS
 Coagulopathy
 Neurologic:
 Optic neuritis, lymphocytic meningitis, CN
palsy and coma.
 Pneumonitis
 Myocarditis
 Splenic rupture

51. 51
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.

52. 52
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
 Insenstive, cross react with B. burgdorferi and T.
pallidum
 CBC: low platelet
 Coagulation profile: PT, PTT, BT-prolonged

53. 53
Treatment
 Delousing: permethrine dust or liquid
 Suportive: Rehydration, transfussion
 Antibiotic:
 Procaine penicilline
 TTC
 Monitor for JHR in 1-4 hrs of therapy

54. 54
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
 Digoxin
 Postural hypotention-during recovery

55. 55
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

56. 56
CNS infection
 Encephalitis
 Cerebritis
 Abscess
 Meningitis

57. 57
Bacterial Meningitis
 Acute purulent infection with in the
sub-arachinoid space
 Most common of suppurative CNS
infection (Empyema, Encephalitis)

58. 58
Etiology
 S.pneumonia – 50%
 N.meningitidis – 25%
 Group B.Strept – 15%
 L.monocytogenes – 10%
 H.infeluenzae - <10%

59. 59
Predisposing Factors
 S. pneumoniae
 Pneumococcal Pneumonia
 Otitis media and Sinusitis
 Alcoholism
 Diabetes, Splencetomy
 Hypogammaglobulinemia
 Head trauma

60. 60
Contd.
 N. meningitides
 Colonization of nasopharyngeal
 Bacterial virulence
 Host immune defense-complement
deficiency
 Dry season, overcrowding, smoking, recent
viral URTI

61. 61
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

62. 62
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.

63. 63
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

64. 64
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.

65. 65
The sub-Saharan Africa
“meningitis belt.”

66. 66
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.

67. 67
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

68. 68
Contd.
 Cerebral vessel thrombosis, vasculitis,
cerebral edema, intracranial
hypertension, cerebral infarction.
 Activated neutrophilis consume neural
tissue oxygen and glucose—anaerobic
respiration—lactate aggravates
neurotoxicity

69.  Meningitis can present as either an acute fulminant illness that
progresses rapidly in a few hours or as a subacute infection that
progressively worsens over several days.
 The classic clinical triad of meningitis is fever, headache, and
nuchal rigidity.
 A decreased level of consciousness occurs in >75% of patients
and can vary from lethargy to coma.
 Nausea, vomiting, and photophobia are also common
complaints.
69

70.  Seizure occur as part of the initial presentation of
bacterial meningitis or during the course of the illness
in 20–40% of patients.
 Focal seizures are usually due to focal arterial
ischemia or infarction, cortical venous thrombosis
with hemorrhage, or focal edema.
 Generalized seizure activity and status epilepticus
may be due to hyponatremia, cerebral anoxia, or,
less commonly, the toxic effects of antimicrobial
agents such as high-dose penicillin.
70

71.  Raised ICP is an expected complication of bacterial meningitis
and the major cause of obtundation and coma in this disease.
More than 90% of patients will have a CSF opening pressure
>180 mmH2O, and 20% have opening pressures >400 mmH2O.
 Signs of increased ICP include a deteriorating or reduced level
of consciousness, papilledema, dilated poorly reactive pupils,
sixth nerve palsies, decerebrate posturing, and the Cushing
reflex (bradycardia, hypertension, and irregular respirations).
 The most disastrous complication of increased ICP is cerebral
herniation.
 The incidence of herniation in patients with bacterial meningitis
has been reported to occur in as few as 1% to as many as 8%
of cases.
71

72.  Specific clinical features may provide clues to the diagnosis of
individual organisms.
 The most important of these clues is the rash of
meningococcemia, which begins as a diffuse erythematous
maculopapular rash resembling a viral exanthem; however, the
skin lesions of meningococcemia rapidly become petechial.
 Petechiae are found on the trunk and lower extremities, in the
mucous membranes and conjunctiva, and occasionally on the
palms and soles.
72

73. 73
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.

74. 74
Complication
 Increase in ICP (>180mmH2O)
 Hydrocephalus
 Hyponatremia
 DIC
 Adrenal insufficiency
 Neurological
 Seizure, hearing loss, gait disturbance, decreased
intellectual function, memory impairment

75. 75
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

76. 76
Treatment
 Emperic therapy
 Penicilline
 Third generation cephalosporine and vancomycine
 Oily CAF
 Specific Rx after culture result
 Dexamethasone -10mg 20min before antibiotic
administration then every 6hrly for 4 days.
 Decreases production of TNF
 Contact Rx:
 Rifampicine, cipro, ceftriaxone, azithromycine

77. 77
Contd.
 Out break:
 Oily CAF, Penicillin
 Mass vaccination
 Chemoprophylaxis of close contacts

78. 78
Out come
 Mortality:
 Meningococcal meningitis , H. influenza and GBS=3-7%
 Pneumococcal meningitis=20%
 In general, the risk of death from bacterial meningitis increases with (1) decreased level of
consciousness on admission, (2) onset of seizures within 24 h of admission, (3) signs of
increased ICP, (4) young age (infancy) and age >50, (5) the presence of comorbid
conditions including shock and/or the need for mechanical ventilation, and (6) delay in the
initiation of treatment. Decreased CSF glucose concentration [<2.2 mmol/L (<40 mg/dL)]
and markedly increased CSF protein concentration [>3 g/L (>300 mg/dL)] have been
predictive of increased mortality and poorer outcomes in some series.
 Poor prognosis
 Age
 State of consciousness
 Seizure
 CSF glucose, protein
 Delay treatment

79. 79
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

80. 80
Contd.
 CSF:
 Lymphocytic pleocytosis (25-500/ul)
 Protein and glucose slightly increased
 Normal opening pressure
 CSF PCR

81. 81
Rx.
 Supportive:
 Fluid and electrolyte
 Analgesics
 Antiviral:
 Acyclovir
 Prognosis is excellent

82. 82
Viral encephalitis
 Etiology: HSV-1, VZV, Enterovirus, Arbovirus
 Manifestation
 Febrile illness
 Meningeal involvement
 Confusion, behavioral abnormality
 Altered level of consciousness
 Lethargy to deep coma

83. 83
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

84. 84
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

85. 85
Abscess formation in the basal ganglia in
patients with meningitis

86. 86
Sub dural empyema and diffuse
cerebral edema

87. 87
Ring enhancing abscess with peripheral edema
and mass effect

88. 88
T-2 weighted MRI
Mild ventriculomegaly

89. 89
Malaria

90. 90
Introduction
 “Bad air”-believed to be caused by bad
air.
 Recognized long time ago
 Treatment precedes exact pathogenesis
 Early 20th century etiology recognized

91. 91
 It is a vector borne disease

92. 92
 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
and reticulocytes
 P. ovale- affects reticulocytes
 P. malariae- affects older RBCs

93. 93
 Transmission is via:
 Anopheles mosquito bite
 Anapheles Gambiae:
 Longer lived
 Higher dencity in hyper endemicity
 Bread rapidly
 Bite humans in preference
 Blood transfusion
 Vertical

94. 94
Life cycle
 Asexual reproduction
Sporozoites
Hepatic parenchyma cell asexual multiplication
Merozoites (10,000- >30,000)
Invades the RBC to become trophozoites
Schizonts---schizogony in 48hrs
Dougther merozoites released after rupture of RBC
invasion of other RBC and clinical manifestation

95. 95
 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

96. 96

97. 97
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

98. 98
Distribution of malaria

99. 99
Contd.
 Stable transmission
 Year round transmission
 Un stable transmission
 Erratic focal low transmission
 Protective immunity not acquired
 Seen in hypo endemic area

100. 100
Pathogenesis
 RBC becomes irregular in shape, less
deformable, more antigenic
 Agglutination
 Rosette formation (infected-uninfected)
 Cytoadherence
 Sequestration
 Toxic Hemoglobin polymerizes to innert
hemozoin

101. 101
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

102. 102
Severe and complicated
malaria
1.Cerebral malaria
 Def.
 Unarousable coma lasting > 30min with
positive asexual forms of P. falciparum
 Diffuse symmetrical encephalopathy
 The onset can be gradual or sudden ff
convulsion
 Mortality -20% in adults , sequele <3%

103.  Corneal reflex is preserved except in
deep coma
 Abdominal and cremasteric reflexes are
absent
 15% retinal hemorrhage
103

104. 104
2. Hypoglycemia
 Blood glucose < 40mg/dl
 Causes:
 Abnormal hepatic gluconeogenesis
 Increased consumption mainly the host and to
lesser extent by the parasite
 Effect of drugs:
 Quinine increases pancreatic insulin secretion
 Common seen with pregnancy and in children.
 Clinical dx is difficult bc physical signs of … are
absent( the neurologic impairment caused by hypoglycemia confuses with that caused by
malaria)

105. 105
3. Anemia
 Haematocrit <15% (Hgb <5gm/dl with
parasite density of <10,000/ul.
 Cause:
 Increased RBC dstruction
 Hypersplenism
 Coagulopathy
 Bleeding due to stress ulcer

106. 106
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
 In survivors, urine flow resumes in a median of 4 days, and serum creatinine
levels return to normal in a mean of 17 days. Early dialysis or hemofiltration
considerably enhances the likelihood of a patient's survival, particularly in acute
hypercatabolic renal failure

107. 107
5. ARDS (non cardiogenic PE)
 Manifested with progressive worsening
of shortness of breathing
 Can occur after several days treatment
 Pathology is unclear
 Mortality >80%
 Careful with hydration
 can also develop in otherwise uncomplicated vivax malaria, where recovery is
usual

108. 108
6. Lactic acidosis
 Labored deep breathing
 Dx:
 Venous lactate level >5mmol/L
 Bicarbonate <15 mmol/L
 pH < 7.25
 Lactic acidosis is caused by the combination of anaerobic glycolysis in tissues where sequestered parasites
interfere with microcirculatory flow, hypovolemia, lactate production by the parasites, and a failure of
hepatic and renal lactate clearance. The prognosis of severe acidosis is poor

109. 109
Contd.
7. Convulsion
 Greater than two seizure in 24hrs.
8. DIC
9. Hypotension
 Systolic BP < 80 mmHg

110. 110
Contd.
10. Hemoglobinuria
 Black water fever
 Can cause renal failure
Septicemia may complicate malaria and Salmonella bacteremia has been associated specifically with P.
falciparum infections
 Others-included in the 2000 WHO
 Obtundation:
 Prostration
 Hyperparacytemia: > 10% in any population and
> 5% in non immune.
 Jaundice with other vital organ dysfunction
(hemolytic, hepatic injury and cholestatic)

111. Summary
111

112. 112
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 identified as pigment-containing trophozoites and
schizonts
 >20% of parasites with visible pigment
 Phagositised malarial pigment in > 5% neutrophiles

113. 113
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

114. 114
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

115. 115
Contd.
 Prolonged PT and PTT
 RFT
 Serum creatinine
 BUN
 Serum glucose
 Serum Na, HCO3
 LFT, Bilirubine

116. 116
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

117. 117
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

118. 118
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

119. 119
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

120. 120
Contd.
 P. vivax and pregnancy
 Increased anemia
 Decreases birth weight by 100gm
 Affects multigravida than primigravida

121. 121
Uncomplicated P. falciparum
 Sulfadoxine- pyremetamine(SP)
 Three tab. Stat
 Resistance is increasing-40%
 Artemisnin(20mg)+lumefantrine(120gm for 3
days.
 Quinine-po
 Mefloqine
 Artemether(4mg/kg)+Mefloquine x 3d
 Atavaquone+proguanil(malarone)-x 3d

122. In summary, the options now recommended for
treatment of uncomplicated falciparum malaria in
alphabetical order are:
■ Artemether plus lumefantrine,
■ Artesunate plus amodiaquine,
■ Artesunate plus mefloquine,
■ Artesunate plus sulfadoxine-pyrimethamine,
■ Dihydroartemisinin plus piperaquine
122

123. 123
Contd.
 Follow up:
 Daily BF till negative
 At 48 hrs parasite decrease by 75%
 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

124. 124
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.

125. 125
Complicated P. falciparum
 A medical emergency
 ABC
 Resuscitate with IV fluids
 Look for existing complication
 Immediate blood glucose, Hct, parasitic
load, renal function, ABG

126. Antimalarial drugs
126

127. 127
Contd.
 Monitoring:
 Parasitemia +Hct every 6-12 hrs
 Exchange transfusion if parasite>15%
 If Hct <20% transfussion
 Blood glucose every 4-6 hours
 RFT daily

128. 128
Mx of complications
 ARF:
 Fluid balance
 Hemofiltration and hemodialysis
 Pulmonary edema
 Position at 450
 Diuretics, oxygen
 PPV if immediate measures fails

129. 129
Contd.
 Seizure
 Diazepam, Phenobarbitol
 Aspiration pneumonia
 Gram negative septicemia
 If conditions deteriorate
 Antibiotic.

130. 130
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
 Burkitt’s lymphoma

131. 131
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

132. 132
Spp. In thick blood film.

133. 133
Spp in thick blood film

134. 134

135. 135

136. 136
VIRAL SYNDROMES

137. 137
INFLUENZA
 Orthomyxo virus
 Three types:
 Type A-most frequent cause
 Type B
 Type C
 Spread –person to person

138. 138
Manifestation
 IP : 48 hours
 Fever >39oc
 Head ache, back and leg pain
 Coryzal symptoms
 Inflamed respiratory mucosa

139. 139
Complication
 Hemorrhagic bronchitis, pneumonia
 Fatal viral pneumonia
 Secondary bacterial infection
 Encephalitis, myocarditis

140. 140
Treatment
 Symptomatic
 Steam inhalation
 Antiviral-Amantadine 200mg/d for 3-7 d

141. 141
Viral hemorrhagic fever
 Filofiridae
 Marburg
 Ebola
 IP; 7-10 days
 Abrupt onset of head ache, myalgia and
fever
 Prostration, rash, shock
 Bleeding manifestation

142. 142
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

143. 143
Transmission
 Definitive host=mammalian/human
 Adults initiate sexual reproduction
 Intermidiate host- Snails
 Asexual reproduction

144. 144
Life cycle
 Ova hatch in water to miracidia
 Inside a Snail changed to Cercaria
 Ceracaria 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

145. 145
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

146. 146
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

147. 147
Risk factors
 Geographic location
 Exposure to fresh water bodies
 Local eating and drinking habits

148. 148
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

149. 149
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

150. 150
3. Chronic schistosomiasis
 Species dependent-(S. mansoni &
S. japonicum)
 Intestinal phase:
 Colicky abdominal pain
 Bloody diarrhea, fatigue, growth
retardation
 Colonic polyposis
 Malabsorbtion

151. 151
Contd.
 Hepato-splenic phase
 Hepatomegaly-granulomatous
 Pre-sinusoidal portal fibrosis leads to portal
hypertension and splenomegaly.
 Esophageal varices-bleeding is tolerable
because of normal liver function.
 Cirrhosis- if it is associated with viral
hepatitis and malnutrition

152. 152
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.

153. 153
Contd.
 Pulmonary:
 Cough, fever, dyspnea
 Cor-pulmonale due to pul. Hypertension
 CNS-granulomatous depossion
 Epilepsy in S. japonicum
 TM in S. mansoni & S. hematobium

154. 154
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.

155. 155
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

156. 156
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

157.  Patients with both HIV infection and schistosomiasis
excrete far fewer eggs in their stools than those
infected with S. mansoni alone; the mechanism
underlying this difference is unknown.
 Treatment with praziquantel may result in reduced
HIV replication and increased CD4+ T lymphocyte
counts.
157

158. 158
Prevention
 Endemic areas:
 Sewage disposal, sanitation
 Health education
 Chemotherapy
 For travelers
 Avoid contact with fresh water bodies
 If exposed follow up visits

159. 159
Filariasis
 Nematodes that dwell in SC tissue and lymphatics
 Eight filarial species of these, four—Wuchereria bancrofti, Brugia malayi,
Onchocerca volvulus, and Loa loa—are responsible for most serious filarial
infections
 Lymphatic filariasis
 W. bancrofti, B. malayi, B. timori
 SC dwellers
 Onchocerca volvulus, Loa loa

160. 160
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

161. 161

162. 162
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.

163. 163
Contd.
 Vector:
 Culex fatigans mosquitoes-urban
 Anapheline or aedean in rural
 W. bancrofti is nocturnally periodic. (Nocturnally periodic forms of
microfilariae are scarce in peripheral blood by day and increase at night,
whereas subperiodic forms are present in peripheral blood at all times and
reach maximal levels in the afternoon.)
 B. malayi found in China, India, Indonessia, Korea, Japan, Malaysia, Phillipin.

164. 164
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

165. 165
Clinical presentation
 The most common manifestation:
 Asymptomatic microfilaremia, hydrocele,
acuteadenolymphangitis(ADL) and chronic
lymphatic disease.
 Early manifestations
 Microscopic hematuria or proteinuria
 Dilated, totuous lymphatics – by imaging
 Scrotal lymphangiectasia by ultrasound

166. 166
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

167. 167
Cont.
 Both involves the upper and lower
extremities
 Genital involvement is exclusively with
W. bancrofti infection
 Epididmitis
 Scrotal pain and tenderness

168. 168
Cont.
 Dermatolymphangioadenities (DLA)-another
type of acute disease other than ADL.
 High grade fever, chills, myalgia and head
ache
 Edematous inflammatory plaques
 Vesicles, ulcers, hyper pigmentation
 History of trauma precedes
 Mimics cellulites

169. 169
Cotnd.
 Chronic changes
 Brawny edema follows early pitting edema, and thickening
of the subcutaneous tissues and hyperkeratosis occur.
 Early pitting
 Thickening of SC tissue and hyperkeratosis
 Fissuring and hyperplastic changes with super infection
 Hydrocele- scrotal elephantiasis
 Furthermore, if there is obstruction of the retroperitoneal
lymphatics, the increased renal lymphatic pressure leads to
rupture of the renal lymphatics and the development of
chyluria, which is usually intermittent and most prominent in
the morning.

170. 170
Dx.
 Demonstration of micrifilaria in blood, body fluids, hydrocele
 Direct staining
 by the centrifugation of fluid fixed in 2% formalin (knott’s technique)
 Adult worms are not accessible
 Serology- Ag of W. bancrofti
 ELISA
 rapid-format immunochromatographic card test
 Sensitivity =96-100%
 Specificity= 100%
 PCR for DNA
 High frequency U/S with Doppler
 Visualizes worms in the scrotum or female breast. Worms may be visualized
in the lymphatics of the spermatic cord in up to 80% of infected men. Live
adult worms have a distinctive pattern of movement within the lymphatic
vessels (termed the filaria dance sign).
 Eosinophilia
 Increased IgE and antifilarial anti body They only
support
the dx

171. 171
Microfilaria of W. bancrofti in a
peripheral blood

172. 172
Contd.
 Difference from bacterial lymphangitis
 Assending infection
 Filarial infection a retrograde extension.
 Active disease
 Microfilaremia
 Antigen positivity
 Detection of adult worms on ultrasound

173. 173
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
 An 8-week course of daily doxycycline (targeting the intracellular
Wolbachia endosymbiont) has significant macrofilaricidal activity
 Adult worm carriers without microfilaria- need
 DEC
 Chronic complication
 Surgical correction of hydrocele
 It recurs

174.  Side effects of DEC treatment include fever, chills, arthralgias, headaches,
nausea, and vomiting.
 Both the development and the severity of these reactions are directly related to
the number of microfilariae circulating in the bloodstream.
 The adverse reactions may represent either an acute hypersensitivity reaction to
the antigens being released by dead and dying parasites or an inflammatory
reaction induced by lipopolysaccharides from the intracellular Wolbachia
endosymbionts freed from their intracellular niche.
 Ivermectin has a side effect profile similar to that of DEC when used in
lymphatic filariasis.
 In patients infected with L. loa, who have high levels of Loa microfilaremia,
DEC—like ivermectin —can elicit severe encephalopathic complications.
 When used in single-dose regimens for the treatment of lymphatic filariasis,
albendazole is associated with relatively few side effects
174

175. 175
Prevention
 Impregnated bed nets.
 DEC – prophylaxis
 Mass distribution of chemotherapy
annually
 Albendazole + DEC/Ivermectine

176. 176
Filarial abscess scar in a young
male with W. bancrofti infection

177. 177
Limb lymph edema , inguinal
lymphadenopathy and hydrocele

178. 178
Unilateral left lower leg elephantiasis

179. 179
Lymphedema and typical skin appearance
of depigmentation and warty changes-
verrucosities

180. 180

181. 181

182. 182
Bilateral hydrocele, testicular enlargement
and inguinal LAP

183. Onchocericasis ( River blindness)
 Transmitted by blackfly vector that breeds along free-flowing
rivers and streams (particularly in rapids)
 Onchocerciasis primarily affects the skin, eyes, and lymph
nodes.
 In contrast to the pathology in lymphatic filariasis, the damage
in onchocerciasis is elicited by microfilariae and not by adult
parasites.
 In the eye, neovascularization and corneal scarring lead to
corneal opacities and blindness. Inflammation in the anterior
and posterior chambers frequently results in anterior uveitis,
chorioretinitis, and optic atrophy.
183

184. Clinical feature:
 Skin- Pruritus and rash are the most frequent manifestations of
onchocerciasis.
 Onchocercomata– These are subcutaneous nodules, which can be
palpable and/or visible, contain the adult worm. In African patients, they
are common over the coccyx and sacrum, the trochanter of the femur,
the lateral anterior crest, and other bony prominences.
 Ocular tissue-Lesions may develop in all parts of the eye. The most
common early finding is conjunctivitis with photophobia. Punctate
keratitis—acute inflammatory reactions surrounding dying microfilariae
and manifested as "snowflake" opacities—is common among younger
patients and resolves without apparent complications. Anterior uveitis
and iridocyclitis develop in ~5% of infected persons in Africa
184

185.  Lymph node-- Mild to moderate lymphadenopathy is common,
particularly in the inguinal and femoral areas, where the enlarged
nodes may hang down in response to gravity ("hanging groin")
 DX detection of an adult worm in an excised nodule or, more
commonly, of microfilariae in a skin snip.
 Eosinophilia and elevated serum IgE levels are common .
 The Mazzotti test is a provocative technique that can be used in cases
where the diagnosis of onchocerciasis is still in doubt (i.e., when skin
snips and ocular examination reveal no microfilariae). A small dose of
DEC (0.5–1.0 mg/kg) is given orally; the ensuing death of any dermal
microfilariae elicits the development or exacerbation of pruritus or
dermatitis within hours—an event that strongly suggests onchocerciasis
185

186.  DEC (300 mg weekly) is an effective
prophylactic regimen for loiasis. But no
drug has proved successful prophylaxis
for onchocerciasis.
186

187. 187
Trypanosomiasis
 Trypanosoma Cruzi Chagas desease
 In America
 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

188. 188
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.

189. 189
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.

190. 190
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

191. 191
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

192. 192
Contd.
 West African- Insidious course
 East African- Acute course
 Symptoms appear early-persistent
tachycardia which is unrelated with fever
 Death could be due to: arrhythmias & CHF
before CNS disease occurs
 Takes weeks to months

193. Table 206-1 Comparison of West African and East African
Trypanosomiases
Point of Comparison West African
(Gambiense)
East African
(Rhodesiense)
Organism T. b. gambiense T. b. rhodesiense
Vectors Tsetse flies (palpalis
group)
Tsetse flies (morsitans
group)
Primary reservoir Humans Antelope and cattle
Human illness Chronic (late CNS
disease)
Acute (early CNS
disease)
Duration of illness Months to years <9 months
Lymphadenopathy Prominent Minimal
Parasitemia Low High
Diagnosis by rodent
inoculation
No Yes
Epidemiology Rural populations Workers in wild areas,
rural populations,
tourists in game parks
193

194. 194
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

195. 195
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

196. 196
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
 Melarsoprol cures both stages of the disease and therefore is also
indicated for the treatment of stage I disease in patients who fail to
respond to or cannot tolerate suramin or pentamidine. However,
because of its relatively high toxicity, melarsoprol is never the first
choice for the treatment of stage I disease

197.  Melarsoprol is highly toxic and should be administered with great care.
 To reduce the likelihood of drug-induced encephalopathy, all patients receiving
melarsoprol should be given prednisolone at a dose of 1 mg/kg (up to 40 mg) per
day, beginning 1–2 days before the first dose of melarsoprol and continuing
through the last dose.
 Without prednisolone prophylaxis, the incidence of reactive encephalopathy has
been reported to be as high as 18% in some series.
 Clinical manifestations of reactive encephalopathy include high fever, headache,
tremor, impaired speech, seizures, and even coma and death.
 Treatment with melarsoprol should be discontinued at the first sign of
encephalopathy but may be restarted cautiously at lower doses a few days after
signs have resolved.
 Extravasation of the drug results in intense local reactions. Vomiting, abdominal
pain, nephrotoxicity, and myocardial damage can occur
197

198. 198
Prevention
 Avoid insect bite
 Protective clothing
 Insect repellent
 Vaccine not available
 Chemoprophylaxis not recommended

199. 199
Intestinal nematodes
(Round worms)
 Associated with
 Poor fecal sanitation
 Contribute to malnutrition
 Decreases work capacity

200. 200
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

201. 201
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

202. 202
Transmission
 Fecaly contaminated soil
 Poor sanitation
 Affects young children
 Transported vegetables as means of
transmission outside endemic areas

203. 203
Clinical presentation
 Lung Phase
 Irritating cough – dry
 Burning substernal discomfort
 Fever (38.5oC)
 Eosinophilia
 Complication– Eosinophilic pneumonitis
(Loffler’s syndrome) => Round/oval
pulmonary infiltrations.

204. 204
Contd.
Intestinal Phase -> Heavy load
 Predispose to intestinal obstruction
 Perforation, intussusception or volvulus
 Biliary colick, cholecystits, cholangitis,
pancreatits, intrahepatic obscess

205. 205
Diagnosis
 Demonstration of ova in stool
 Identification of adult worm
 ERCP

206. 206
Treatment
 The aim is to prevent complications
 Albendazole 400mg stat
 Mebendazole 500mg stat
 Pyrantel pamoate 11mg/kg stat maximum
1gm. Safe in pregnancy.

207. 207
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

208. 208
Clinical Presentation
 Pruritic maculopapular dermatitis => ground itching at the site of skin
penetration as well as serpiginous tracks of subcutaneous migration
 Pneumonitis – milder degree than that of Ascaris
 Epigastric pain – post prandial accentuation
 Diarrhea
 Iron def. anemia, hypoprotenemia
 Risk factor for diseases development:
 Worm burden
 Prolonged duration of infection
 Inadequate iron intake

209. 209
Diagnosis
 Ova in the stool
 Hypochromic microcytic anemia
 Hypoalbuminemia

210. 210
Rx
 Albensdazole
 Mebendazale
 Pyrantel pamoate x 3 days
 Iron supplementation
 Nutritional support

211. 211
Strongyloidiasis
 Etiology: S. Stercoralis
 S. stercoralis is distinguished by its ability—
unusual among helminths—to replicate in the
human host
 Replicates with in the human host =>
autoinfection
 In immuno-compromized host => become
invasive => Disseminate widely
 Can be fatal

212. 212
Transmission
 Fecal contaminated soil
 Larva penetrates the skin--- lung---
sputum---ingested again to repeat the
cycle
 Common in hot humid regions

213. 213
Clinical Presentation
 Recurrent urticaria – buttocks & wrists
 Migration –”Larva currens” – Running larva
 Abdominal or epigastric pain which resembles
peptic ulcer pain except that it is aggravated
by food ingestion.
 Nausea, diarrhea, Gl bleeding, mild chronic
colitis and weight loss
 Pulmonary symptoms – rare
 Eosinophilia - common

214. 214
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.

215. 215
Diagnosis
 Stool for larva
 Eggs are not detectable in stool
 Rx. Even in the asymptomatic state, strongyloidiasis must be treated because of
the potential for subsequent fatal hyperinfection. Ivermectin (200 g/kg daily for
2 days) is more effective than albendazole (400 mg daily for 3 days). For
disseminated strongyloidiasis, treatment with ivermectin should be extended for
at least 5–7 days or until the parasites are eradicated.
 Tinidazole

216. 216
Giardiasis
 Intestinal protozoa
 Infection occurs following ingestion of
hard cyst which excyst in the SI to
fagellated trophozoites.
 Inhabits the proximal SI.
 As few as 10 cysts sufficient to cause
infection in humans.

217. 217
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 occur as an epidemic or endemic
 The greater susceptibility of the young than of the old and of
newly exposed persons than of chronically exposed populations
suggests that at least partial protective immunity may develop.

218. 218
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
 A number of extraintestinal manifestations have been described, such as
urticaria, anterior uveitis, and arthritis
 Course and treatment response is the same with HIV.

219. 219
Diagnosis
 Cysts in feces or trophozoites
 Ag detection in feces
Treatment:
 Metronidazole (250 mg thrice daily for 5 days) usually >90%-----
cure rate.
 Tinidazole (2 g once by mouth) is reportedly more effective than
metronidazole)
 If refractory: prolonged therapy with metronidazole(750mg tid x 21
days)

220. 220
Rhabiditiform larva of strongyloides
stercoralis in slool specimen

221. 221
Strongloides eggs from feces of a new
borne

222. 222
Ascaris lumbricoides egg in feces

223. 223
Ova of trichuris trichiura

224. 224
Reading assignment
 Amaebiasis---Rx for acute colitis is
metronidazole 750mgPO or IV tid for 5–
10 days plus luminal agents (iodoquinol
and paromomycin) eradicate the cyst.
 Cestodes
 Taeniasis
 Cysticercosis
 Echinococosis

225. 225
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.

226. 226
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

227. 227
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

228. 228
Three forms
 Generalized
 Localized
 Cephalic
 Neonatal

229. 229
Clinical presentation
 Incubation period: 1 day-2 month
 Period of onset: 1-7 days
 Increased tone in the masseter 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

230. 230

231. 231
Complications
 Fracture
 DVT, PTE
 Muscle rupture
 Aspiration pneumonia
 Bed sore
 Rhabdomyolysis

232. 232
DDX
 Poisonong
 Hypocalcemic tetany
 Alveolar abcess
 Drug dystonia
 Meningitis
 Rabies
 Peritonitis

233. 233
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

234. 234
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

235. 235
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

236. 236

237. 237
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

238. 238
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

239. 239
Pathogenesis
 Multiply in the blood stream
 Produces toxins and cytokines causes
edema, inhibition of PMN leads to shock
and death

240. 240
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

241. 241

242. 242
Inhalational anthrax
(wool sorters disease)
 IP: 3 days
 Fever, malaise, dyspnea, stridor
 Mediastinal widening, pleural effusion,
 Death in 24 hours
 Non contagious

243. 243

244. 244
GI anthrax
 Nausea, vomiting, abdominal pain,
bloody diarrhea and fever
 Ascites

245. 245
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

246. 246
HIV
(Human Immunodeficiency virus)
Virology
Immunology
Pathogenesis
Opportunistic infection
HAART

247. 247
HIV
 Virology
 Immunology
 Pathogenesis and Natural Course of the
Disease

248. 248
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

249. 249
HIV Epidemic
 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

250. 250
HIV Virology

251. 251
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

252. 252
Virology continued…..
 Retroviridae
 Onchoviridae
 HTLV 1 and HTLV 2
 Spumaviridae
 Lentiviridae
 HIV 1 and HIV 2

253. 253
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

254. 254
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 to severe
immunosuppression
 HIV-1 – median time to AIDS = 10 years
 HIV-2 – median time to AIDS = longer, but ?

255. 255
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

256. 256
Classification of HIV
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
McCutchenn F, et al. XIII IAC, 2000. Abstract 165
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
HIV-1

257. 257
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)

258. 258
Geographic Distribution

259. 259

260. 260
p17
p24
P7, P6
9.7 kb
Matrix – p17

261. 261

262. 262
Life Cycle of HIV.

263. 263
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

264. 264
HIV Receptors
HIV Receptors
HIV and Cellular Receptors
Copyright © 1996 Massachusetts Medical Society. All rights reserved.

265. 265
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

266. 266
HIV Immunology

267. 267
Intracellular
infection
Naïve
B-Cell
Naïve
T8 cell
Naïve T4
helper cell
MHC I presentation
of endogenous
antigen MHC II
presentation of
exogenous antigen
Cell-mediated
(CTLs)
Humoral
(plasma cells /
antibodies)
Free antigen
Th1 Th2
Overview of Adaptive Immune
Response Extracellular
infection
APC
Diagram courtesy of Dr. Samuel Anderson

268. 268
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

269. 269
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

270. 270
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

271. 271
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

272. 272
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

273. 273
Pathogenesis of HIV

274. 274
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

275. 275
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

276. 276
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

277. 277
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

278. 278
EM of supernatant
of HIV infected
tissue culture
Budding of HIV from
Infected Tissue
Culture Cell

279. 279
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.

280. 280
Apoptosis
Courtesy of CDC

281. 281
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

282. 282
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)

283. 283
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

284. 284
Natural History of
HIV Infection

285. 285
Years
Weeks
CD4
Viral Load
Time after infection
AIDS

286. 286
Natural History of HIV-1
Fauci As, 1996

287. 287
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

288. 288
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)

289. 289
Spread of HIV in Host Tissues
Copyright © 1998 Massachusetts Medical Society. All
rights reserved.

290. 290
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”

291. 291
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

292. 292
Patterns of HIV Disease
Progression
HIV
Infection
Long-term
Non-progressors
Rapid Progressors
Typical Progressors
<3 years
7-10 years
>10-20 yr
Normal, Stable CD4
85-90 %
<5 %
<10 %

293. 293
Pathogenesis of HIV Infection:
No Progression with Low-level
Viremia
CD4
RNA
Primary HIV Chronic Non-progressive HIV Infection
RNA Set Point ~ 103

294. 294
Pathogenesis: Average
Progression with Median-Level
Viremia
RNA
CD4
5
Primary HIV Slowly Progressive HIV AIDS
Years
1 10
RNA Set Point ~104

295. 295
Pathogenesis: Rapid
Progression with High-Level
Viremia
RNA
CD4
3
2
Primary HIV AIDS
Years
RNA Set Point ~ 106

296. 296
HIV RNA Levels Predict
Progression to AIDS

297. 297
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

298. 298
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

299. 299
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

300. 300
OPPORTUNISTIC INFECTIONS

301. 301
PCP
 A fungal exists in two forms
 Trophs-smaller
 Cysts-larger
 Transmission
 Reactivation of latent infection
 Person to person
 Environmental source

302. 302
PCP cont…
 Effective inflammatory response
 Neutrophilic lung inflammation
 Promotes lung injury
 Diffuse alveolar damage
 Impairing lung exchange
 Respiratory failure

303. 303
PCP cont….
 PCP in AIDS characterized by
 High organism burden
 Fewer neutrophilis
 High diagnostic yield following induced
sputum or BAL
 Better oxygenation and survival

304. 304
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)

305. 305
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

306. 306

307. 307
PCP Diagnosis …
 Sputum induction with saline
 Yield: 50-90%
 BAL: >95%
 Staining
 For Trophic forms: papanicolaou,wright-Giemsa,
or Gram-weigert
 For cysts: Gomori methylamine silver, cresyl echt
violet, toluidine blue o, or calcofluor white.
 Monoclonal antibodies-can stain both trophs
and cysts. Has high sensitivity and specificity.
 PCR

308. 308
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

309. 309
Benefit of Corticosteroids in
Pneumocystis Therapy

310. TUBERCULOSIS
 Leading cause of death in HIV patients
accounting for one third of cases.
 Clinical presentation depends on the
degree of immunosupression
 Ethiopia is among the high TB burden
countries in the world
310

311. 311
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

312. 312
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”

313. 313
Tuberculosis in HIV+
Host
Latent TB Infection
Active TB Disease
Majority
Increased to
10% per year
Death

314. 314
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

315. 315
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

316. 316
ART, IPT and TB Incidence
 N=6391
 Cluster
randomized trial
 IPT in Brazil
Incidence
(per
100py)
No IPT, No ART 7.4
No IPT, ART 1.5
IPT, No ART 1.0
IPT, ART 0.6
Golub, IAS 2006; # MOPE0395
P<.0001 for all

317. 317
Concerns
 Safety
 INH resistance
 Adherence
 Duration of effectiveness

318. 318
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

319. 319
Effect of INH Resistance on
Treatment Outcomes
 Retrospective cohort
study
 1148 new TB cases
 First-line therapy
 HRZE or HRZS x 2m
 HR x 4m
Success
Rate
Failure
rate
Drug
susceptible
85% 2%
INH-
resistant
82% 4%
Espinal, JAMA 2000; 283:2537-45.

320. CNS Toxoplasmosis
 Is caused by the intracellular protozoan
parasite, Toxoplasma gondii.
 The parasite can reactivate and cause
disease, usually when the CD4
lymphocyte count falls below 100
cells/mm 3.
320

321.  Patients with cerebral toxoplasmosis
typically present with headache,
confusion, and fever.
 Focal neurologic deficits or seizures are
also common
321

322. Diagnosis
Definitive
Stereotactic brain biopsy
Presumptive
If the patient has a CD4 cell count <100/mm 3 and:
 Is seropositive for T. gondii IgG antibody
 Has not been receiving effective prophylaxis for
toxoplasma
 Brain imaging demonstrates a typical radiographic
appearance (eg, multiple ring-enhancing lesions)
322

323. 323

324. 324
Toxoplasmosis Treatment
 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

325. 325
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

326. 326
Suppressive Therapy
 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

327. 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
327

328. 328
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

329. 329
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

330. 330
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

331. 331
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
CNS
 CMV encephalitis

332. 332

333. 333
Diarrhea
 Enteropathogenic
bacteria
 Shigella
 Salmonella
 E. coli
 Mycobacteria
 M. tuberculosis
 M. bovis
 CMV
 Parasites
 E. histolytica
 G. lamblia
 Cryptosporidiu
m parvum
 Isospora belli
 Strongyloides
stercoralis,
others

334. 334
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)

335. 335
Case 1 Chronic Diarrhoea
 Stage 4 HIV (+) patient
 Watery diarrhea, 10 x a day,
cramping abdominal pain, severe
dehydration
 Trial of cotrimolxazole ineffective
 Diagnosis?

336. 336
Cryptosporidiosis
 Treatment
 Palliative
 No effective
specific treatment
 ART is very
effective!!!!!
Modified acid
fast stain

337. 337
Case 2 Chronic Diarrhoea
 42-year old man, new patient
 No cotrimoxazole prophylaxis
 Persistent diarrhea, watery stools,
cramping
 Diagnosis?

338. 338
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

339. 339
Case 3: Chronic Diarrhoea
 Profuse watery diarrhea, no
response to co-trimoxazole and
metronidazole empiric therapy
 Stool exam is negative for
cryptosporidiosis, Isospora belli
 Diagnosis ???

340. 340
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
weeks or CD4> 200
 E. bienuesi – Rx w/
fumagillin 60mg/day
x 14 d
Empiric therapy with ??
Albendazole? HAART!

341. 341
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

342. 342
Clostridium difficile
 Underestimated
 Associated with significant
mortality
 Usually in patients who have been
hospitalized
 Treatment: metronidazole 500 mg
3x/day x 7 days

343. 343
Diagnosis and Treatment of Common
Causes of Diarrhea in AIDS Patients
Agent CD4 Symptom Diagnosis Rx
E. histolytica any
bloody stool,
colitis
Stool
microscopy
Metronidazol
e
Giardia any Watery diarrhea “ “
Cryptosporidium <150 Watery diarrhea Modified AFB HAART
Isospora belli <100 Watery diarrhea Modified AFB TMP-SMX
Microsporidium <50 Watery diarrhea Giemsa stain
Albendazole
(20% respond
CMV <50
Watery to Bloody
stool, colitis
Biopsy,
barium study
Ganciclovir

344. 344
Oral Thrush 60% of patients
per year with CD4
< 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
Candida albicans is an
endogenous yeast

345. 345
Clinical presentations:
 Thrush:
 Pseudomembranous (classical) >
80%,
 Atrophic,
 Erythematous
 Angular cheilitis (perleche)
 Median rhomboid glossitis

346. 346
Pseudomembranous thrush

347. 347
Erythematous thrush

348. 348
Atrophic thrush

349. 349
Angular cheilitis

350. 350
Median Rhomboid Glossitis

351. 351
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

352. 352
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

353. 353
T0 = lesions confined to the skin
and/or lymph nodes/ and or minimal
oral disease*
T1 = tumour-associated oedema or
ulceration
S0 = No B symptoms, no history for
OI, no oral thrush
S1 = history of OI and/or oral thrush,
B symptoms present
ART alone for T0S0 or
T0S1
ART
And chemotherapy
for others
Staging of Kaposi's Sarcoma

354. 354
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

355. 355
WHO Staging System for
HIV/AIDS in Resource Limiting
Settings

356. 356
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

357. 357
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

358. 358
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

359. 359
WHO Staging of HIV/AIDS
With confirmed HIV infection
 Stage I - asymptomatic
 Stage II - mild disease
 Stage III - moderate disease
 Stage IV - advanced
immunocompromise

360. 360
WHO Stage I
 Asymptomatic or
 Persistent generalized
lymphadenopathy (PGL)

361. 361
Persistent Generalized
Lymphadenopathy (PGL)
Courtesy of Charles Seinberg MD

362. 362
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

363. 363
Pruritic Papular Eruption
Courtesy of Charles Steinberg MD

364. 364
Pruritic Papular Eruption
Courtesy of Charles Steinberg MD

365. 365
Apthous Ulcer
Source: www.HIVdent.org. Copyright © 1996-2000 David Reznik, D.D.S.

366. 366
Herpes Zoster
Courtesy of Tom Thacher, MD Courtesy of the Public Health Image Library/CDC

367. 367
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

368. 368
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

369. 369
Oral Candidiasis
Courtesy of Samuel Anderson, MD Courtesy of Dr. R. Ojoh

370. 370
Oral Candidiasis (2)
Source: http://members.xoom.virgilio.it/Aidsimaging

371. 371
Oral Hairy leukoplakia
Courtesy of Dr. R. Ojoh