Cryptococcal Meningitis and Extraneural Cryptococcosis
Also known as: Cryptococcal Meningoencephalitis, Cryptococcosis, Cryptococcal Meningitis
Cryptococcal meningitis is a subacute or chronic meningoencephalitis caused by Cryptococcus neoformans or the Cryptococcus gattii species complex. It is the commonest form of cryptococcosis in advanced HIV infection and the usual route of death. Extraneural cryptococcosis is infection of any other organ, either as part of dissemination from the lung or, less often, as a primary skin infection after inoculation.
Mortality depends on setting and treatment.
In well resourced trials, 10 week mortality with modern induction regimens is about 20 to 30 percent. In routine care in low income settings it is 40 to 60 percent or higher, because patients present late and amphotericin B, flucytosine, and measurement of cerebrospinal fluid pressure are not available.
Death in the first 2 weeks usually results from raised intracranial pressure, high fungal burden, and drug toxicity, and death later results from relapse, immune reconstitution, and other opportunistic infection.
Yeasts circulate after pulmonary infection and cross the blood brain barrier by transcytosis through endothelial cells, by paracellular passage, and inside infected phagocytes. Within the subarachnoid space, cerebrospinal fluid has little complement and no effective phagocytic cell population, so yeasts multiply and shed capsular polysaccharide.
The polysaccharide obstructs arachnoid granulations and raises cerebrospinal fluid outflow resistance, which causes raised intracranial pressure without hydrocephalus in most patients. Yeasts also enter perivascular spaces (Virchow Robin spaces), forming mucoid "soap bubble" pseudocysts in the basal ganglia, and form cryptococcomas in parenchyma.
The inflammatory response is weak in advanced HIV and exaggerated in people with normal immunity (including Cryptococcus gattii infection), in non HIV patients after withdrawal of immunosuppression, and after antiretroviral therapy begins. Excess inflammation causes the post infectious inflammatory response syndrome and immune reconstitution inflammatory syndrome.
Onset is subacute over 1 to 4 weeks (sometimes days in advanced HIV), with:
- Headache, often severe and progressive.
- Fever, which is absent in about one third of patients.
- Nausea and vomiting, and neck stiffness in fewer than half of patients with HIV.
- Altered mental state, from confusion to coma, and personality change.
- Visual blurring, diplopia, and loss of vision, from papilloedema, optic nerve damage, or cranial nerve palsies (the sixth and eighth nerves most often).
- Seizures and focal deficits, from cryptococcomas or stroke.
- Raised intracranial pressure: papilloedema, falling consciousness, and, with severe elevation, herniation.
Cerebrospinal fluid opening pressure is above 20 cm of cerebrospinal fluid in about half to three quarters of patients with HIV, and above 25 cm in about one third to one half.
Cerebrospinal fluid cell counts are low in HIV (often fewer than 20 cells per microlitre, mostly lymphocytes), with normal or slightly low glucose and a modest rise in protein. In non HIV patients, pleocytosis is higher and glucose is lower.
Imaging can be normal. Magnetic resonance imaging shows dilated perivascular spaces, gelatinous pseudocysts, cryptococcomas, hydrocephalus, and meningeal enhancement.
Cryptococcus gattii disease commonly presents with space occupying lesions, hydrocephalus, and neurological sequelae (visual loss, hearing loss, cognitive deficit), in patients who are often otherwise healthy.
| Condition | Points that separate it |
|---|---|
| Tuberculous meningitis | Acid fast bacilli or molecular detection in cerebrospinal fluid, higher cell count and protein, basal enhancement and infarcts; may coexist in HIV |
| Bacterial meningitis | Neutrophilic pleocytosis, high protein, low glucose, positive Gram stain and culture, acute course |
| Cerebral toxoplasmosis | Multiple ring enhancing lesions, positive toxoplasma serology; cryptococcal antigen negative |
| Progressive multifocal leukoencephalopathy | White matter lesions, JC virus detection |
| Primary central nervous system lymphoma | Enhancing periventricular mass, Epstein Barr virus in cerebrospinal fluid |
| Other fungal meningitis (histoplasmosis, coccidioidomycosis) | Geography, antigen, and culture |
| Neurosyphilis and viral encephalitis | Serology and polymerase chain reaction |
| Idiopathic intracranial hypertension | Normal cerebrospinal fluid, negative antigen |
| Investigation | Interpretation |
|---|---|
| Cerebrospinal fluid cryptococcal antigen by lateral flow assay | Sensitivity and specificity above 95 percent; first test at the bedside; positive in over 95 percent of HIV related meningitis |
| Serum cryptococcal antigen | Positive in over 95 percent of meningitis in HIV, so a negative serum result makes meningitis very unlikely; may be negative in non HIV disease |
| India ink | Positive in about 80 percent of HIV related meningitis; lower in non HIV |
| Quantitative cerebrospinal fluid culture | Colony forming units per mL measure fungal burden and early fungicidal activity of treatment; high burden above 100 000 colony forming units per mL predicts death |
| Opening pressure with manometer | Mandatory in every lumbar puncture; guides therapeutic drainage |
| Cerebrospinal fluid and serum antigen titres | A titre of 1 in 1024 or more indicates a high burden and poor prognosis |
| Blood culture | Positive in up to about 60 percent in HIV, a marker of high burden |
| Imaging | Computed tomography before lumbar puncture only when focal signs, papilloedema with focal deficit, or markedly depressed consciousness; magnetic resonance imaging for pseudocysts, cryptococcomas, hydrocephalus, and enhancement |
| Repeat lumbar puncture at 2 weeks | Documents sterilisation and guides step down in poor responders |
Treatment has three phases: induction (2 weeks or longer), consolidation (8 weeks), and maintenance (months to years), alongside management of raised pressure and of the underlying immune defect.
Induction in HIV
| Regimen | Doses | Notes |
|---|---|---|
| Single high dose liposomal amphotericin B with flucytosine and fluconazole | Liposomal amphotericin B 10 mg per kg intravenously once on day 1, flucytosine 25 mg per kg every 6 hours (100 mg per kg daily) for 14 days, and fluconazole 1200 mg once daily for 14 days | Preferred by recent World Health Organization guidance. In a randomised trial it was non inferior to 7 days of amphotericin B deoxycholate with flucytosine and caused fewer severe adverse events |
| Amphotericin B deoxycholate with flucytosine, 1 week | Amphotericin B deoxycholate 1 mg per kg intravenously daily for 7 days with flucytosine 100 mg per kg daily in 4 divided doses for 7 days, then fluconazole 1200 mg daily for days 8 to 14 | Alternative where single dose liposomal amphotericin B is unavailable; the best studied of the older regimens |
| Liposomal amphotericin B with flucytosine, 2 weeks | Liposomal amphotericin B 3 to 4 mg per kg daily with flucytosine 100 mg per kg daily in 4 divided doses, for 14 days | Used where lipid amphotericin B is available |
| Fluconazole with flucytosine | Fluconazole 1200 mg daily with flucytosine 100 mg per kg daily in 4 divided doses, for 14 days | Where no amphotericin B is available; in a randomised trial it was non inferior to 2 weeks of amphotericin B and fluconazole, though mortality was higher than with 1 week of amphotericin B and flucytosine |
| Amphotericin B with fluconazole | Amphotericin B deoxycholate 1 mg per kg daily with fluconazole 800 to 1200 mg daily for 14 days | Where flucytosine is unavailable; flucytosine adds fungicidal activity and is a priority drug |
| Fluconazole monotherapy | 1200 mg daily | Associated with high mortality and relapse; used only when nothing else is available |
Consolidation and maintenance
- Consolidation: fluconazole 800 mg once daily for 8 weeks (a common range is 400 to 800 mg).
- Maintenance (secondary prophylaxis): fluconazole 200 mg once daily. It is continued until the CD4 count exceeds 200 cells per microlitre on antiretroviral therapy with suppressed viral load for at least 6 months, and for a minimum of 1 year in total.
- Children and adolescents: amphotericin B deoxycholate 1 mg per kg daily with flucytosine 100 mg per kg daily in 4 divided doses for 2 weeks, then fluconazole 10 to 12 mg per kg daily (maximum 800 mg) for 8 weeks, then 6 mg per kg daily (maximum 200 mg) for maintenance.
- Pregnancy: amphotericin B is the preferred induction agent. Flucytosine and high dose fluconazole carry foetal risk in the first trimester, and the choice is individualised.
Induction, consolidation, and maintenance in transplant and other non HIV patients
| Group | Regimen |
|---|---|
| Solid organ transplant | Liposomal amphotericin B 3 to 4 mg per kg daily (or amphotericin B lipid complex 5 mg per kg daily) with flucytosine 100 mg per kg daily in 4 divided doses for at least 2 weeks; then fluconazole 400 to 800 mg daily for 8 weeks; then fluconazole 200 to 400 mg daily for 6 to 12 months. Immunosuppression is reduced where possible, with the risk of immune reconstitution inflammatory syndrome in mind |
| Non HIV, non transplant | Amphotericin B deoxycholate 0.7 to 1 mg per kg daily with flucytosine 100 mg per kg daily in 4 divided doses for at least 4 weeks (2 weeks if cerebrospinal fluid is sterile and there are no neurological complications or underlying immunosuppression); consolidation fluconazole 400 to 800 mg daily for 8 weeks; maintenance fluconazole 200 mg daily for 6 to 12 months |
| Cryptococcus gattii | Induction with liposomal amphotericin B 3 to 5 mg per kg daily (or amphotericin B deoxycholate 0.7 to 1 mg per kg daily) with flucytosine 100 mg per kg daily in 4 divided doses, often prolonged to 4 to 6 weeks or more when there are cryptococcomas or hydrocephalus, and consolidation and maintenance are longer, for 6 to 18 months, with fluconazole 400 to 800 mg daily; surgery or shunting is considered for mass lesions and hydrocephalus |
Management of raised intracranial pressure
Raised pressure is the main cause of early death, and control of pressure is as important as antifungal therapy.
- Measure the opening pressure at every lumbar puncture, with a manometer where possible.
- When the opening pressure is above 25 cm of cerebrospinal fluid, or when the pressure is above 20 cm with symptoms, drain cerebrospinal fluid by therapeutic lumbar puncture, removing 10 to 30 mL. Aim for a closing pressure of 50 percent of the opening pressure or below 20 cm of cerebrospinal fluid.
- Repeat the lumbar puncture daily until the pressure stays below 20 cm of cerebrospinal fluid and symptoms resolve, which usually takes several days.
- Persistent raised pressure despite repeated drainage, or the need for repeated daily punctures beyond 2 weeks. This is an indication for a lumbar drain or a ventriculoperitoneal or lumboperitoneal shunt. Shunting is safe once the culture is sterile or the patient is on effective therapy.
- Acetazolamide, mannitol, and corticosteroids are not recommended for pressure control. Acetazolamide increased adverse events in a trial, and dexamethasone increased disability and adverse events in a randomised trial, so corticosteroids are not used for routine treatment.
- Hydrocephalus with raised pressure not controlled by lumbar puncture needs neurosurgical cerebrospinal fluid diversion.
Supportive care and monitoring of toxicity
- Amphotericin B: pre hydration with 1 litre of normal saline over 2 to 4 hours before each dose of amphotericin B deoxycholate, with potassium chloride 20 mmol and magnesium sulphate (8 mmol) in the infusion, and oral potassium and magnesium supplements, to reduce nephrotoxicity. Creatinine, potassium, and magnesium are measured at baseline and at least twice weekly.
- Flucytosine: doses adjusted to renal function, with full blood count at baseline and twice weekly, and levels where available (peak 2 hours after the dose 30 to 80 micrograms per mL, trough under 25 to 50).
- Fluconazole: liver tests, QT interval with high dose, and interactions (rifampicin lowers levels, warfarin and phenytoin levels rise).
- Raised pressure and hyponatraemia: monitored and corrected; anaemia and hypokalaemia are corrected.
Response and relapse
Clinical improvement is expected in 1 to 2 weeks. Cerebrospinal fluid cultures are repeated at 2 weeks in patients who are not improving. Persistently positive cultures after 2 weeks of induction suggest drug failure, resistance, or an undrained focus, and induction is extended. Relapse (after 6 weeks of therapy, culture positive again) is caused by non adherence, inadequate induction, resistance, or a prostatic or other reservoir, and needs repeat induction therapy and testing of the isolate for fluconazole resistance.
Antiretroviral therapy timing and immune reconstitution
Antiretroviral therapy is delayed until 4 to 6 weeks after the start of antifungal therapy, because early initiation (within 2 weeks) increased mortality in a randomised trial. Immune reconstitution inflammatory syndrome occurs in 10 to 30 percent after antiretroviral therapy begins, typically 1 to 2 months later.
It presents as worsening headache, raised pressure, meningitis, lymphadenitis, or cryptococcomas, in patients who initially improved and have sterile cerebrospinal fluid cultures. Management is to continue antifungal therapy and antiretroviral therapy, to drain cerebrospinal fluid. Also exclude relapse and other infections, and give prednisolone 0.5 to 1 mg per kg daily for 2 to 6 weeks (with taper) in severe cases, with limited trial evidence. Unmasking disease refers to a first presentation of cryptococcosis soon after antiretroviral therapy begins.
Post infectious inflammatory response syndrome
Patients without HIV, including those with Cryptococcus gattii infection and healthy hosts, can worsen with a lymphocytic inflammatory response and sterile cultures after initial improvement. Corticosteroids (prednisolone 0.5 to 1 mg per kg daily with a slow taper) are used in carefully selected severe cases, with ongoing antifungal therapy.
| Site | Features | Diagnosis | Management |
|---|---|---|---|
| Lung | Nodules, masses, pneumonia, effusions | Antigen, culture, histology | Fluconazole 400 mg daily for mild disease; amphotericin B with flucytosine for severe disease |
| Blood | Cryptococcaemia indicates high burden and dissemination, with sepsis picture in advanced HIV | Blood culture, antigen | Induction with amphotericin B 0.7 to 1 mg per kg daily (or liposomal 3 to 5 mg per kg daily) with flucytosine 100 mg per kg daily in 4 divided doses for at least 2 weeks, then fluconazole 400 to 800 mg daily for 8 weeks, after lumbar puncture to exclude meningitis |
| Skin and soft tissue | Umbilicated papules resembling molluscum contagiosum, nodules, ulcers, cellulitis, necrotising lesions. Primary cutaneous disease follows inoculation (gardening, trauma) in immunosuppressed patients | Biopsy with mucicarmine, culture | Localised primary skin disease in a non disseminated host: fluconazole 400 mg daily for 3 to 6 months. Disseminated disease: induction with amphotericin B 0.7 to 1 mg per kg daily (or liposomal 3 to 5 mg per kg daily) with flucytosine 100 mg per kg daily in 4 divided doses for at least 2 weeks, then fluconazole 400 to 800 mg daily for 8 weeks |
| Bone and joint | Osteolytic lesions with little periosteal reaction, vertebral and joint infection, in about 5 to 10 percent of disseminated disease | Imaging, biopsy, culture | Induction with amphotericin B and flucytosine, then fluconazole 400 to 800 mg daily for 6 to 12 months or longer; surgical debridement for sequestra or abscess |
| Prostate | Silent reservoir; yeasts persist behind blood prostate barrier and cause relapse | Urine and semen culture after prostatic massage | Prolonged fluconazole 400 mg daily, sometimes for years; prostatectomy is rarely needed |
| Eye | Chorioretinitis, papilloedema, optic neuritis with rapid, permanent vision loss, endophthalmitis | Ophthalmological examination | Induction with amphotericin B 0.7 to 1 mg per kg daily (or liposomal 3 to 5 mg per kg daily) with flucytosine 100 mg per kg daily in 4 divided doses for at least 2 weeks, then fluconazole 400 to 800 mg daily for 8 weeks, with pressure control and ophthalmology; vision loss from raised pressure needs urgent lumbar drainage |
| Genitourinary tract | Renal abscess, pyelonephritis, epididymitis | Urine culture, imaging | Systemic therapy; drainage |
| Adrenal glands | Bilateral adrenal infiltration, adrenal insufficiency | Imaging, cortisol testing | Systemic therapy plus replacement hydrocortisone as indicated |
| Liver and peritoneum | Hepatitis, peritonitis in cirrhosis or peritoneal dialysis; ascitic fluid antigen | Fluid culture and antigen | Systemic therapy; remove dialysis catheter in peritoneal dialysis |
| Lymph nodes | Lymphadenitis, a common feature of immune reconstitution inflammatory syndrome | Aspirate, culture | Antifungal therapy; drainage if suppurative |
| Heart | Endocarditis, myocarditis, pericarditis (rare) | Blood culture, echocardiography | Amphotericin B and flucytosine with surgery for endocarditis |
Maintenance fluconazole (200 mg daily) continues in HIV until immune recovery (CD4 count above 200 cells per microlitre on antiretroviral therapy for at least 6 months with viral suppression, and at least 12 months of antifungal therapy). Interruption without immune recovery leads to relapse in a large proportion of patients.
Screening of serum cryptococcal antigen in adults with CD4 count below 200 cells per microlitre, with pre-emptive fluconazole in antigenaemic patients (after lumbar puncture excludes meningitis), prevents most deaths from cryptococcal meningitis in antigen positive patients in programmes. Timely antiretroviral therapy, adherence, and viral load monitoring complement screening.
