Dr.Jayakumar S A

Prof.Dr.A.Gowrishankar unit

FEVER IN IMMUNOCOMPROMISED

PATIENT

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

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

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

Personal history mixed diet RMP 3/30

Family history husband died due to HIV six yrs

back two children

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

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 ;

Impression :

Retroviral disease with

CNS infection cause to be evaluated

INVESTIGATONS 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

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

ink

CT BRAIN : Normal ;

MRI BRAIN : 1.2 × 0.8cm T 2 hyperintensity

noted in left parietal region suggestive of arachnoid cyst

DATE CD4

18.06.2010 – 75 cells/ųl

03.08.2010 -174 cells/ųl

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

Final diagnosis : RETROVIRAL DISEASE CDC

STAGE C 3 WITH OPPORTUNISTIC INFECTION -CRYPTOCOCCAL MENINGITIS POSSIBLE

unmasking type of cryptococcal IRIS

CRYPTOCOCCOSIS C.neoformans , C.gattii

Encapsulated fungus ;

inhalation

infection

immunocompromise

disease

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

System Manifestation

CNS MENINGITIS ;DEMENTIAABSCESS ,GRANULOMA

LUNG NODULES ,CAVITIES ,ARDS , PLEURAL EFFUSION PNEUMOTHORAX

SKIN PAPULES ,VESICLES , PURPURACRYPTOCOCCOMAS

EYE KERATITIS ,ENDOPHTHALMITIS ,OPTIC NERVE ATROPHY

CVS PANCARDITIS ,MYCOTIC ANEURYSM

GIT HEPATITIS ,ESOPHAGEAL NODULES

OTHERS BREAST ABSCESS ,THYROIDITIS

CRYPTOCOCCAL MENINGITIS & HIV 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

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

DIAGNOSIS 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

IMAGING 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

TREATMENT Acute phase : amphotericin B + flucytosine – 2

weeks Consolidation phase : fluconazole -10 weeks

Maintenance fluconazole –lifelong

Drug Dose Side effect

AMPHOTERICIN B 0.7 – 1.0 MG/KG/DAY HYPOKALEMIA HYPOTENSION ARRHYTHMIASNAUSEA ,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 HEPATOTOXICITYALOPECIA MUSCLE WEAKNESS METALLIC TASTE

PROGNOSIS 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

IMMUNE RECONSTITUTION ART

RAPID INCREASE IN CD 4 & DEPLETION OF VIRAL LOAD

IMPROVED /EXAGGERATED IMMUNE RESPONSE

Is immune reconstitution

always beneficial?

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROMES (IRIS): 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.

IRIS CASE DEFINITION 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 failureSide effects of ART.Complete ART non-compliance

34

PRACTICAL DEFINITION: NACO “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

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.

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).

PATHOGENS ASSOCIATED WITH IRIS 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)

RISK FACTORS 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

IRIS ASSOCIATED WITH CRYTOCOCCAL MENINGITIS 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.

IRIS MANAGEMENT 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).

CARRY HOME POINTS

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 ;

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

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