CRYPTOCOCCAL CRYPTOCOCCAL MENINGITISMENINGITIS

IN HIV INFECTIONIN HIV INFECTION

Presentation and ManagementPresentation and Management

December 2012

Dr. Mutabazi Sharif MBchB (MUST)Dr. Mutabazi Sharif MBchB (MUST)

EPIDEMOLOGY OF EPIDEMOLOGY OF CRYPTOCOCCOSISCRYPTOCOCCOSIS

Cryptococcus neoformans - fungus ubiquitousCryptococcus neoformans - fungus ubiquitous

Two distinct varieties: Var Neoformans and Gatti.Two distinct varieties: Var Neoformans and Gatti. C. neoformans C. neoformans can be classified into 4 serotypes:can be classified into 4 serotypes: Serotype A. Serotype A. C. neoformansC. neoformans var grubbi.var grubbi. Serotype B. Serotype B. C. neoformansC. neoformans var gatti.var gatti. Serotype C. Serotype C. C. neoformans var gatti.C. neoformans var gatti. Serotype D. Serotype D. C. neoformansC. neoformans var neoformansvar neoformans

MICROBIOLOGY OF MICROBIOLOGY OF CRYPTOCOCCUSCRYPTOCOCCUS

Fungus 4 to 8 um, encapsulated budding yeastFungus 4 to 8 um, encapsulated budding yeast

CSF - India Ink shows clear large polysaccharide CSF - India Ink shows clear large polysaccharide capsule around the fungus with budding daughter capsule around the fungus with budding daughter cells connected to the mother cell with a thin pole cells connected to the mother cell with a thin pole of capsuleof capsule

Grows at 37Grows at 3700C on Sabouraud’s media, 1-4 weeksC on Sabouraud’s media, 1-4 weeks

EPIDEMIOLOGY OF EPIDEMIOLOGY OF CRYPTOCOCCOSIS CRYPTOCOCCOSIS

Cryptococcal meningitis rare before AIDS Cryptococcal meningitis rare before AIDS epidemic.epidemic.

Most common fungal meningitis, 10 to 30% of Most common fungal meningitis, 10 to 30% of AIDS patients; AIDS patients;

When present - AIDS defining diagnosis in When present - AIDS defining diagnosis in 90% in Africa.90% in Africa.

EPIDEMIOLOGY OF EPIDEMIOLOGY OF CRYPTOCOCCOSIS CRYPTOCOCCOSIS

3 X more common than all other types of 3 X more common than all other types of meningitis in AIDS patients combined meningitis in AIDS patients combined (meningococcal, pneumococcal, TB, etc). (meningococcal, pneumococcal, TB, etc).

Variety neoformans exclusively causes Variety neoformans exclusively causes meningitis in AIDS patients even in Africa meningitis in AIDS patients even in Africa where gattii once was most commonwhere gattii once was most common

PATHOPHYSIOLOGY OF CCMPATHOPHYSIOLOGY OF CCM

Fungus inhaled - soil to alveoli Fungus inhaled - soil to alveoli focal focal asymptomatic pneumoniaasymptomatic pneumonia

In immunosuppression (including CD4 In immunosuppression (including CD4 <100/mm3).<100/mm3).

Wide early dissemination throughout the body. Wide early dissemination throughout the body.

PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF CRYPTOCOCCAL MENINGITISCRYPTOCOCCAL MENINGITIS

Poorly understood tropism for central Poorly understood tropism for central nervous system. nervous system.

In subarachnoid space, large In subarachnoid space, large polysaccharide capsule defends polysaccharide capsule defends against phagocytosis by PMNs.against phagocytosis by PMNs.

CLINICAL PRESENTATION CLINICAL PRESENTATION OF CMOF CM

Typically insidious onset of a severe headache Typically insidious onset of a severe headache (87 to 99%).(87 to 99%).

Fever (75%), malaise (70%), nausea and Fever (75%), malaise (70%), nausea and vomiting (50 -60%) and altered mental status-vomiting (50 -60%) and altered mental status-drowsy to coma (25%). drowsy to coma (25%).

A stiff neck is reported in 30-60%.A stiff neck is reported in 30-60%.

CLINICAL PRESENTATION CLINICAL PRESENTATION OF CMOF CM

Visual disturbances in 30%, photophobia in up Visual disturbances in 30%, photophobia in up to 2/3, but cranial nerve palsies, papilledema, to 2/3, but cranial nerve palsies, papilledema, ataxia, seizures (inc in children 1/3), and ataxia, seizures (inc in children 1/3), and aphasia each in <10%.aphasia each in <10%.

In sub-Saharan Africa most (65%) are given a In sub-Saharan Africa most (65%) are given a course of antimalarial rx before diagnosis of course of antimalarial rx before diagnosis of cryptococcal meningitis suspectedcryptococcal meningitis suspected

PHYSICAL FINDINGS IN PHYSICAL FINDINGS IN C.MENINGITISC.MENINGITIS Generally non-specificGenerally non-specific

Papilledema <10% even though increased Papilledema <10% even though increased intracranial pressure >200 mmHintracranial pressure >200 mmH220 in 2/30 in 2/3

Stiff neck or other meningeal signs 40%Stiff neck or other meningeal signs 40%

Skin lesions - in 3-10% - scrappings show Skin lesions - in 3-10% - scrappings show encapsulated cryptococcus with India ink.encapsulated cryptococcus with India ink.

DIFFERENTIAL DIAGNOSIS DIFFERENTIAL DIAGNOSIS OF CMOF CM

Toxoplasmic encephalitisToxoplasmic encephalitis

TB Meningitis, bacterial meningitis, other fungal meningitis, TB Meningitis, bacterial meningitis, other fungal meningitis, aseptic meningitis (HIV or others), meningovascular luesaseptic meningitis (HIV or others), meningovascular lues

Primary CNS lymphomaPrimary CNS lymphoma

CMV or VZ encephalitisCMV or VZ encephalitis

Brain abscess (bacterial, aspergillus, nocardia)Brain abscess (bacterial, aspergillus, nocardia)

LABORATORY DIAGNOSIS OF C. LABORATORY DIAGNOSIS OF C. MENINGITISMENINGITIS

Blood:Blood: Serum CRAG positive in 99%. But not Serum CRAG positive in 99%. But not

diagnostic.diagnostic.

C Neoformans blood cultures positive in 75%C Neoformans blood cultures positive in 75%

LUMBAR PUNCTURE

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CSF NORMAL VALUES

Pressure: 70 - 180 mm H20 Pressure: 70 - 180 mm H20 Appearance: clear, colorless Appearance: clear, colorless CSF total protein: 15 - 45 mg/dL : 15 - 45 mg/dL Gamma globulin: 3 - 12% of the Gamma globulin: 3 - 12% of the total protein CSF glucose: 50 - 80 mg/100 mL (or greater : 50 - 80 mg/100 mL (or greater

than 2/3 of blood sugar level) than 2/3 of blood sugar level) CSF cell count: 0 - 5 white blood cells (all : 0 - 5 white blood cells (all

mononuclear), and no red blood cellsmononuclear), and no red blood cells

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FORMATION OF CSF

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FORMATION OF CSF

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LABORATORY DIAGNOSIS OF LABORATORY DIAGNOSIS OF CRYPTOCOCCAL MENINGITISCRYPTOCOCCAL MENINGITIS

CSF: CSF: Only 25% have >20 cells/mm3 Only 25% have >20 cells/mm3

(lymphocytes), median 4 cells/mm(lymphocytes), median 4 cells/mmGlucose <60% of serum in 30%Glucose <60% of serum in 30%Protein >45 mg/dl in 50%Protein >45 mg/dl in 50%India ink positive in 75-95%India ink positive in 75-95%CSF CRAG + >90%, high titers >1:2048 CSF CRAG + >90%, high titers >1:2048

a bad prognostic sign.a bad prognostic sign.

CSF Opening Measurement Pressure

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CSF PARAMETRS

Test Bacterial Viral Fungal TubercularOpening pressure Elevated Usually normal Variable Variable

White blood cell count≥1,000 per mm3 <100 per mm3 Variable Variable

Cell differential Predominance of PMNs*

Predominance of lymphocytes†

Predominance of lymphocytes

Predominance of lymphocytes

Protein Mild to marked elevation

Normal to elevated

Elevated Elevated

CSF-to-serum glucose ratio

Normal to marked decrease

Usually normal Low Low

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WHO 2011 GUIDELINES ON DIAGNOSIS In settings with ready access to and no In settings with ready access to and no

contraindication to LP.contraindication to LP. If both access to CrAg assay (either LA or If both access to CrAg assay (either LA or

LFA), and rapid results (i.e. <24 hours) are LFA), and rapid results (i.e. <24 hours) are assured: LP + rapid CSF CrAg assay.assured: LP + rapid CSF CrAg assay.

[Strong recommendation, moderate quality of [Strong recommendation, moderate quality of evidence]evidence]

b. of evidence]b. of evidence]April 8, 2023 21

LAB DIAGNOSIS

If access to CrAg assay either not available If access to CrAg assay either not available and/or rapid results not assured: LP + CSF and/or rapid results not assured: LP + CSF India ink test examination.India ink test examination.

[[Strong recommendation, moderate quality of Strong recommendation, moderate quality of evidenceevidence].].

In settings without immediate access to LP, In settings without immediate access to LP, or when it is clinically contraindicatedor when it is clinically contraindicated

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DIAGNOSIS

If access to rapid to CrAg assay assured: Do If access to rapid to CrAg assay assured: Do serum CrAg, if positive, initiate treatment, serum CrAg, if positive, initiate treatment, then reffer for appropriate investigation & then reffer for appropriate investigation & treatment.[Strong recommendation,moderate treatment.[Strong recommendation,moderate quality evidence].quality evidence].

If serum CrAg assay not available, rapidly If serum CrAg assay not available, rapidly refer for appropriate investigation [Strong refer for appropriate investigation [Strong recommendation] recommendation]

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DIAGNOSIS

CSF CrAg is more sensitive than India ink and CSF CrAg is more sensitive than India ink and preferred. Indian ink test requires more skill.preferred. Indian ink test requires more skill.

NB: No patient should be treated for CCM on NB: No patient should be treated for CCM on basis of serum CrAg without involving the basis of serum CrAg without involving the entire clinical team at BMC.entire clinical team at BMC.

Serum CrAg should cease to be a routine test Serum CrAg should cease to be a routine test in investigation of CMM. Only used in when in investigation of CMM. Only used in when LP contraindicated.LP contraindicated.

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Extraneural Manifestations Extraneural Manifestations of Cryptococcosisof Cryptococcosis

Pulmonary involvement –25% of cases; Pulmonary involvement –25% of cases; most asymptomatic most asymptomatic dry hacking cough, low grade fever, sputum dry hacking cough, low grade fever, sputum

production and pleuritic chest pain. production and pleuritic chest pain. Pleural effusions unusual but focal nodular or Pleural effusions unusual but focal nodular or

diffuse disseminated infiltrates can be seen on diffuse disseminated infiltrates can be seen on chest x-ray. chest x-ray.

Dx dependent on isolation of CM from pulmonary Dx dependent on isolation of CM from pulmonary secretions.secretions.

Extraneural Manifestations Extraneural Manifestations of Cryptococcosisof Cryptococcosis

Other sites – Other sites – skeletal system with focal osteomyelitis especially skeletal system with focal osteomyelitis especially

vertebrae and long bones, vertebrae and long bones, eyes, eyes, adrenal cortex, adrenal cortex, genital-urinary system (especially prostate which genital-urinary system (especially prostate which

may be site of relapse). may be site of relapse).

Treatment of Cryptococcal MeningitisTreatment of Cryptococcal Meningitis Induction phase: Two weeksInduction phase: Two weeks

Amphotericin B, 0.7 to 1 mg/kg IV for 5-7 Days with Amphotericin B, 0.7 to 1 mg/kg IV for 5-7 Days with high dose Fluconazole 1200mg PO/day. high dose Fluconazole 1200mg PO/day.

High dose Fluconazole when Amphotericin is not High dose Fluconazole when Amphotericin is not available.(Conditional recommendation).available.(Conditional recommendation).

If cost is not a limitation,IV AmphoB + Flucytosine is the If cost is not a limitation,IV AmphoB + Flucytosine is the preferred regimen.preferred regimen.

Consolidation phase:8 weeksConsolidation phase:8 weeks Fluconazole 800 mg/d po for 8 weeksFluconazole 800 mg/d po for 8 weeks

Minimum package for prevention of AmphoB toxicity Pre-emptive hydration& electrolyte Pre-emptive hydration& electrolyte

supplementation.supplementation.• 1L of NS 0.9% with 1 ampoule KCL over 2-1L of NS 0.9% with 1 ampoule KCL over 2-

4 hrs for each dose of AmphoB with 1-2 8 4 hrs for each dose of AmphoB with 1-2 8 mEq tablets of KCl BD and 250mg mEq tablets of KCl BD and 250mg Magnesium trisillicate BD.Magnesium trisillicate BD.

Monitoring. Twice weekly Serum Monitoring. Twice weekly Serum creatinine& K+,Mg+2,Daily U/O and weight.creatinine& K+,Mg+2,Daily U/O and weight.

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Management of toxicity

If K+ <3.3 mmol/L, increase KCL If K+ <3.3 mmol/L, increase KCL supplementation to 2 ampoules, if it remains supplementation to 2 ampoules, if it remains uncorrected, double the dose of Mg.uncorrected, double the dose of Mg.

If creatinine>2 fold from baseline, increase If creatinine>2 fold from baseline, increase NS to 1L 8qrly,once improved give AmphoB NS to 1L 8qrly,once improved give AmphoB & consider alternate days. If remains & consider alternate days. If remains uncorrected, discontinue& give High dose uncorrected, discontinue& give High dose Fluconazole.Monitor creatinine daily.Fluconazole.Monitor creatinine daily.

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ART INITIATION TIMING

Evidence is conflicting. Can be started 4-6 Evidence is conflicting. Can be started 4-6 weeks after induction phase. Avoid early weeks after induction phase. Avoid early initiation, as this is associated with initiation, as this is associated with increased mortality.increased mortality.

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WHEN TO DISCONTINUE Rx

If viral load monitoring is possible: Patients on If viral load monitoring is possible: Patients on antifungal maintanance for 1 year, adherent to antifungal maintanance for 1 year, adherent to ART, stable,CD4>100 (Two measurements ART, stable,CD4>100 (Two measurements 6months apart) and virolgically suppressed.6months apart) and virolgically suppressed.

Viral load monitoring not available: : Patients Viral load monitoring not available: : Patients on antifungal maintanance for 1 year, adherent on antifungal maintanance for 1 year, adherent to ART, stable,CD4>200 (Two measurements to ART, stable,CD4>200 (Two measurements 6months apar.6months apar.

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DISCONTINUATION IN CHILDREN 2-5 years if on ART for 1 year, adherent 2-5 years if on ART for 1 year, adherent

CD4 >25% OR >750 cells/mm3(two CD4 >25% OR >750 cells/mm3(two measurements 6 months apart).measurements 6 months apart).

No discontinuation in children under 2 yearsNo discontinuation in children under 2 years Maintenance should be re-started if CD4 Maintenance should be re-started if CD4

drops below 100(Adults)/750(Children)2-drops below 100(Adults)/750(Children)2-5years or WHO Stage IV event occurs 5years or WHO Stage IV event occurs irrespective of age.irrespective of age.

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TREATMENT

Maintenance:Maintenance: Fluconazole 200 mg/d Or 6mg/Kg/day is Fluconazole 200 mg/d Or 6mg/Kg/day is

less than 19 years upto 200mg/day. less than 19 years upto 200mg/day. [Strong recommendation].[Strong recommendation].

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Toxicity of therapies for CMToxicity of therapies for CM

Amphotericin B - renal in ¼ of all patients Amphotericin B - renal in ¼ of all patients

dose –dependent; dose –dependent;

Risk factors:Risk factors: include dose >35 mg/d, male sex, weight >90 kg, include dose >35 mg/d, male sex, weight >90 kg,

chronic renal failure, use of other nephrotoxic drugs chronic renal failure, use of other nephrotoxic drugs (amakacin, cyclosporin etc). ((amakacin, cyclosporin etc). (AJM 111:528, 2001AJM 111:528, 2001))

Toxicity of therapies for CMToxicity of therapies for CM

Flucytosine (5-FC): Up to 50% bone marrow Flucytosine (5-FC): Up to 50% bone marrow toxicity if 150 mg/kg/d used and serum levels toxicity if 150 mg/kg/d used and serum levels not kept below 100 ugm/ml. not kept below 100 ugm/ml.

Fluconazole: relatively non-toxic, occ. nausea, Fluconazole: relatively non-toxic, occ. nausea, vomiting,diarrhea, elevation transaminasesvomiting,diarrhea, elevation transaminases

Outcome of therapy of CMOutcome of therapy of CM

Ampho. B (0.5 mg/k/d)followed by flu: By 2 wks Ampho. B (0.5 mg/k/d)followed by flu: By 2 wks 10% mortality and 14% by 10 wks vs. Flu. alone; 10% mortality and 14% by 10 wks vs. Flu. alone; 15% mortality by 2 wks and 18% by 10 wks in 194 15% mortality by 2 wks and 18% by 10 wks in 194 patients.(patients.(NEJM 326:83, 1992NEJM 326:83, 1992).).

Ampho. B + 5FC followed by fluconazole: By 2 Ampho. B + 5FC followed by fluconazole: By 2 weeks 12.5% mortality, 26% by 10 wk in 236 weeks 12.5% mortality, 26% by 10 wk in 236 patients(patients(CID 28:82,1999CID 28:82,1999).).

Outcome of therapy of CMOutcome of therapy of CM

Flu. (400 or 800mg/d): 50% mortality at 10 wks Flu. (400 or 800mg/d): 50% mortality at 10 wks in 130 patients at Mulago Hospital-a trend for inc in 130 patients at Mulago Hospital-a trend for inc mortality in higher dose. (mortality in higher dose. (Grant et alGrant et al).).

Flu. (400 mg/d); 100% of 230 Zambians had Flu. (400 mg/d); 100% of 230 Zambians had died by 6 months. None had received HAART died by 6 months. None had received HAART ((Post grad med J 77:769, 2001Post grad med J 77:769, 2001))

Management of Increased Management of Increased Intracranial Pressure in CMIntracranial Pressure in CM

Increased ICP (>250 mm HIncreased ICP (>250 mm H220) - associated with increased 0) - associated with increased

mortality and morbidity. (mortality and morbidity. (CID 31:1309, 2000CID 31:1309, 2000).).

Treatment - remove 10 to 30 mls of CSF via LP as often as Treatment - remove 10 to 30 mls of CSF via LP as often as needed: symptoms often immediately dramatically needed: symptoms often immediately dramatically improve (return of vision, relief of headache etc).improve (return of vision, relief of headache etc).

Steroids or other measures of questionable value. Steroids or other measures of questionable value.

Primary and Secondary Primary and Secondary Prophylaxis (suppression) of CMProphylaxis (suppression) of CM

Primary prophylaxis:Primary prophylaxis: Fluconazole prophylaxis should be avoided unless there Fluconazole prophylaxis should be avoided unless there

is a likely delay for ART initiation.is a likely delay for ART initiation.

Secondary prophylaxis: (maintenance therapy)Secondary prophylaxis: (maintenance therapy) As alluded to earlier.As alluded to earlier.