1. Dr.Jayakumar S A
Prof.Dr.A.Gowrishankar
unit

2.  34 year old Mrs.Hajara ,came with
c/o –fever
headache 2 weeks
lethargy
 HOPI:-
Fever – intermittent ,low grade
not associated with chills or rigor
headache – diffuse ;
- constant dull ache
- progressively increasing
severity

3.  h/o increasing tiredness and inability to do
daily activities
 h/o nausea
 No h/o rash/vomiting ,loose stools
 No h/o dysuria
 No h/o cough with expectoration
 No h/o weakness of limbs
 No h/o altered sensorium
 No h/o seizures
 No history suggestive of jaundice
 No h/o bleeding manifestations

4.  Past history:-
not a known DM/HT/TB/IHD/BA/EPILEPTIC
patient
 Treatment history :
1 ½ months back
evaluated for unexplained fever ,loss of
weight and diarrhea;
diagnosed HIV positive ;
HAART initiated on 24.06.2010
zidovudine 300mg
lamivudune 150 mg
nevirapine 200 mg

5.  Personal history
mixed diet
RMP 3/30
 Family history
husband died due to HIV six yrs back
two children

6.  o/e:
conscious
oriented
febrile
anemic
no cyanosis/clubbing /pedal edema
/icterus/ lymphadenopathy
 Vitals :
Pulse – 96/mt,regular ,normal volume ,felt
in all peripheral pulses
BP -130/80 mmhg

7.  CVS : S1, S2 heard
no murmurs
 RS : normal vesicular breath sounds
no crepitations / wheeze
 P/a : soft
Bs+
no organomegaly
 CNS :
Higher functions normal
bilateral lateral rectus weakness
no weakness of limbs
bilateral plantar flexor
minimal neck stiffness present
 Fundus : mild disc blurring seen ;

8. Impression :
Retroviral disease with
CNS infection
cause to be evaluated

9.  CBC:- CXR –normal;
 Hb -8.5 g/dl ECG –normal;
 Tc -6ooo
 P 55 L 42 E 3
 ESR -6/15
 Plt – 1.7 lac
 PCV -28%
 Random blood sugar – 110mg/dl
 urea -18 mg/dl
 creatinine – 0.8mg/dl

14.  CSF analysis :
sugar – 87 mg/dl
protein – 27 mg/dl
cytology –acellular
AFB -negative
culture and sensitivity – negative
cryptococcus –positive in india ink

16.  CT BRAIN : Normal ;
 MRI BRAIN :
1.2 × 0.8cm T 2 hyperintensity noted in
left parietal region suggestive of
arachnoid cyst

17. DATE CD4
18.06.2010 – 75 cells/ųl
03.08.2010 -174 cells/ųl

18.  Neurologist opinion:
headache ,fever ,
bilateral gaze restriction ;
neckstiffness
suggested :
ophthalmologist opinion
CT brain
CSF analysis
 Ophthalmologist opinion
bilateral lateral rectus weakness
fundus-mild blurring of disc margins

19.  Final diagnosis :
RETROVIRAL DISEASE CDC STAGE C 3
WITH
OPPORTUNISTIC INFECTION
-CRYPTOCOCCAL MENINGITIS
POSSIBLE
unmasking type of cryptococcal IRIS

20.  C.neoformans , C.gattii
 Encapsulated fungus ;
inhalation
infection
immunocompromise
disease

21.  Virulence factors
--polysaccharide capsule
--antiphagocytic ,diminish
complement,enhances HIV replication
--melanin
--protects from antifungal agents
-- ability to grow at high temperature
--production of phospholipase ,urease

22. System Manifestation
CNS MENINGITIS ;DEMENTIA
ABSCESS ,GRANULOMA
LUNG NODULES ,CAVITIES ,ARDS ,
PLEURAL EFFUSION
PNEUMOTHORAX
SKIN PAPULES ,VESICLES , PURPURA
CRYPTOCOCCOMAS
EYE KERATITIS ,ENDOPHTHALMITIS ,
OPTIC NERVE ATROPHY
CVS PANCARDITIS ,MYCOTIC
ANEURYSM
GIT HEPATITIS ,ESOPHAGEAL
NODULES
OTHERS BREAST ABSCESS ,THYROIDITIS

23.  Leading infectious cause of meningitis in HIV
patients -7 % HIV patients (Adam’s neurology)
 Usually in CD4 < 100 cells /ųl;
 Presentation :
subacute course with
Fever ,nausea ,vomiting ,altered mental
status ,headache ,meningeal signs
Cranial nerve palsies & cryptococcomas
 Seizures and focal neurologic deficits is rare

24.  In HIV patients
burden of yeast is higher
higher antigen titres ,
slower CSF sterilization
 Greater likelihood of second CNS event
 Immune reconstitution syndrome in patients
on ART

25.  CSF : Normal or modest elevations in protein
 Microscopy :
Indian ink stain
mucicarmine stain
fontana mason stain
gomori methanamine silver stain
 Culture :
saboraud’s agar – 3 to 12 days
staib’s birdseed ,dopa ,caffeic acid media
 Serology:
polysaccharide Ag testing in serum CSF
latex agglutination test /EIA

26.  CT Brain :
normal /hydrocephalus /gyral
enhancement /cortical atrophy
 MRI Brain :
no pathognomonic feature
hydrocephalus /cryptococcomas
lesions may’nt decrease in size for a
year despite treatment

27.  Acute phase :
amphotericin B + flucytosine – 2 weeks
 Consolidation phase :
fluconazole -10 weeks
 Maintenance
fluconazole –lifelong

28. 
Drug Dose Side
effect
AMPHOTERICIN B 0.7 – 1.0 MG/KG/DAY HYPOKALEMIA
HYPOTENSION
ARRHYTHMIAS
NAUSEA ,VOMITING
RARE HEPATIC DAMAGE
FLUCYTOSINE 100 MG /KG /DAY ANEMIA ,LEUKOPENIA
THROMBOCYTOPENIA
RENAL ,GI TOXICITY
FLUCONAZOLE 400 MG /DAY –
CONSOLIDATION
PHASE
200 MG /DAY-
MAINTENANCE
REVERSIBLE
HEPATOTOXICITY
ALOPECIA
MUSCLE WEAKNESS
METALLIC TASTE

29.  High CSF pressure
 Low CSF glucose
 Low CSF pleocytosis ( < 2 /ųl)
 CSF /serum antigen level > 1: 32
 Absence of antibody to C.neoformans
 Recovery of yeast cells from extraneural sites
 Positive CSF assay by India ink
itself is a poor prognostic factor

30. ART
RAPID INCREASE IN CD 4
&
DEPLETION OF VIRAL LOAD
IMPROVED /EXAGGERATED IMMUNE
RESPONSE

31. Is immune reconstitution
always
beneficial?

32.  Immune Reconstitution Paradox:
inflammatory reaction to antigens that were
previously not recognized by the immune
system.
 can sometimes lead to worsening of a current
or latent opportunistic infection.
 The onset of IRIS often occurs 2-8 weeks after
initiation of ARV therapy but can occur earlier
or later.

33.  Evidence of clinical response to ART with:
 On ART
 >1 log10 copies/mL decrease in HIV RNA (if
available)
 Infectious or Inflammatory condition within 6
months of ART initiation
 Symptoms can not be explained by either:
 Expected clinical course of a previously
recognized and successfully treated infectious
agent
 Treatment failure
 Side effects of ART.
 Complete ART non-compliance

34. 34
“Occurrence or manifestations of
new OIs within six weeks to six
months after initiating ART; with
increase in CD4 count”
India’s National AIDS Control Organization, Antiretroviral
Therapy Guidelines for HIV-infected Adults and Adolescents
Including Post-exposure Prophylaxis. May 2007

35.  Paradoxical IRIS :
the clinical worsening of an infection that
was previously successfully treated and is
caused by exaggerated activation of the
immune system against persisting antigens
present as dead organisms or debris
following the initiation of ART.

36.  Unmasking IRIS:
patients with advanced immune
suppression prior to ART are unable to
mount an effective immune response
against the viable pathogenic organisms
that are present, but improving
immunity after ART allows previously
unrecognized pathogens to evoke an
inflammatory response (unmasking).

37.  Mycobacterium
avium
 Mycobacterium
tuberculosis
 Mycobacterium
leprae
 Cryptococcus
neoformans
 Pneumocystis jiroveci
 Histoplasma
capsulatum
 Hepatitis B virus
 Hepatitis C virus
 Varicella-zoster virus
 Cytomegalovirus
 BK Virus
 Parvovirus B19
 JC virus
 Papilloma virus
 HHV-8 (KS)

38.  Risk factors at base line:
 Lower CD4 count prior to start of ART
 Higher HIV-1 RNA levels at base line
 Initiating ART in close proximity to starting
therapy for an OI
 Response to therapy & the development of
IRIS:
 Rapid fall in HIV-1 RNA level during the first 3
months of therapy
Source: Journal of Antimicrobial Chemotherapy (2006) 57, 167-
170;Samuel A. Shelburne, Martin Montes and Richard J.Hamill

39.  Up to 30% develop IRIS after initiation of ART
 Increases in headache,
 Increase intracranial pressure,
 In ≈25%, serious complications like
loss of vision,
cranial nerve palsies,
reduced cognition
death.

40.  Evidence-based treatment recommendations are
lacking.
 Identify the inciting pathogen and treat it.
 Most cases of IRIS are managed without stopping
ARVs.
 In severe cases, treatment options include
stopping ARVs, steroids, NSAIDS, and surgical
treatment (for example drainage of abscesses).

41.  Cryptococcus infection is common ;
disease is rare
 Entry route is nasal ;
 Treatment in HIV patients is for lifelong;
 Carefully watch for IRIS ;
 Clinical worsening after HAART doesn’t mean
failure of haart;
 Don’t stop HAART for IRIS ;

42.  National Institutes of Health Clinical Center
(CC) ClinicalTrials.gov Identifier:
NCT00286767
 JAIDS Journal of Acquired Immune Deficiency Syndromes:
15 August 2007 - Volume 45 - Issue 5 - pp 595-596
Timing of Cryptococcal Immune Reconstitution Inflammatory
Syndrome After Antiretroviral Therapy in Patients With AIDS and
Cryptococcal Meningitis
 Journal of Immune Based Therapies and Vaccines 2005,
3:7doi:10.1186/1476-8518-3-7
 HARRISON’S PRINCIPLES OF INTERNAL MEDICINE -17TH EDITION
 MANSON’S TROPICAL DISEASES -22ND EDITION
 MANDELL,DOUGLAS & BENNETT INFECTIOUS DISEASES -7 TH EDITION