D21 Cryptococcosis

Introduction

Cryptococcus neoformans is an encapsulated yeast found ubiquitously in soil worldwide. It causes the majority of HIV-associated cryptococcal infections. The yeast spreads haematogenously from the lung to the central nervous system (CNS). Other possible disseminated sites include skin, bone, and the genitourinary tract, but meninges appear to be the preferred site. The reasons are not yet clear but there are several postulations. Firstly, cryptococcal capsular antigens may have limited ability to induce inflammatory response in the cerebrospinal fluid (CSF). On the other hand, the alternative pathway of complement is absent in the CSF. Besides, CSF is a good growth medium for the fungus, possibly because of trophic properties of dopamine and other neurotransmitters in the CSF and the absence of cryptococcus-toxic proteins. Cryptococcal disease usually develops when CD4 counts drop below 100/μL.

In pre-HAART (highly active antiretroviral therapy) era, approximately 5%-8% of HIV-infected patients in developed countries acquired disseminated cryptococcosis. Although the widespread use of HAART has reduced the incidence of cryptococcosis in developed countries, its incidence and mortality are still high in resource limited countries with limited access to HAART and health care. It is estimated that the incidence of HIV-associated cryptococcal meningitis is as high as 223,100 cases per year worldwide, and that it is responsible for 15% of AIDS-related deaths.[1]

Clinical manifestations of cyptococcosis

Cryptococcal meningitis

CNS is the most common site of disseminated cryptococcal infection. Cryptococcaemia often precedes CNS invasion. Cryptococcal meningitis typically presents with subacute onset of headache, fever, altered mental status; although either acute or chronic meningitis can occur. Classical meningeal symptoms and signs such as neck stiffness and photophobia occur in only one third or less of patients. Cranial nerve palsies and papilloedema may occur. Complications of CNS infection include hydrocephalus, motor or sensory deficits, cerebellar dysfunction, seizures, and dementia. Intracerebral granulomata known as cryptococcomas are uncommon. Approximately one-half of HIV-infected patients with cryptococcal meningitis have elevated baseline intracranial pressures (ICP) >25 cm H₂O. In the 4-arm, 2-step clinical trial conducted by the National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group (MSG/ACTG study), majority of deaths were associated with increased ICP.[2]

CT (computerised tomography) brain is not sensitive or specific for the diagnosis of cryptococcal meningitis, but has a value in the exclusion of cryptococcal meningitis-associated hydrocephalus or mass lesion that may suggest alternative diagnoses like toxoplasmosis or lymphoma. About 20-30% of patients show meningeal enhancement, parenchymal solid mass lesion without haemorrhage (granuloma), atrophy, cerebral oedema, or hydrocephalus. MRI brain performs better, which may reveal low-intensity lesions in the basal ganglia on T1-weighted images, which are hyperintense on T2-weighted images and may enhance with gadolinium.

Other cryptococcal manifestations

Lung is the most likely portal of entry. Given the relatively nonspecific clinical features and variable radiographic findings, it is likely that pulmonary cryptococcosis is under diagnosed and not recognised until dissemination. Patients may present with cough, fever, malaise, shortness of breath, and pleuritic chest pain. Physical examination may reveal lymphadenopathy, tachypnoea, or crackles on chest auscultation. Chest radiographs often show focal or diffuse infiltrates. Less common chest radiographic findings include solitary subpleural nodules, mass-like infiltrates with consolidation, hilar and mediastinal adenopathy, or pleural effusions. The fungus is less likely to be isolated from sputum for microbiological confirmation.

Cutaneous cryptococcosis is present in approximately 10% of disseminated cases. Skin lesions mimicking molluscum contagiosum are frequently observed. Other morphology includes papules, vesicles, plaques, abscesses, cellulitis, purpura, draining sinus, ulcers, bullae, or subcutaneous swelling. Cryptococcal myocarditis, arthritis, and gastroenteritis may also occur. Fungal invasion of the adrenal glands may result in adrenal insufficiency.

Laboratory diagnosis

Serum cryptococcal antigen (CrAg)

Cryptococcus neoformans possesses a capsule consisting of high-molecular weight polysaccharide, which has slow clearance from the serum and CSF. It can be detected in both serum and CSF. Cryptococcal antigen (CrAg) detected in the serum is usually indicative of systemic disease and correlates with fungal burden. Serum CrAg is almost always positive in cases of CNS disease and in other forms of disseminated infection. As such, testing for serum CrAg is a useful screening tool for the diagnosis of cryptococcosis in HIV-infected patients.[3] Patients with asymptomatic antigenaemia should also undergo lumbar puncture to rule out cryptococcal meningitis.

The time course of CrAg levels during treatment of cryptococcosis is poorly characterised. There is generally no correlation between outcome and changes in serum titers of CrAg. Therefore, serum CrAg is a valuable tool for initial diagnosis of cryptococcal disease but the utility of serial measurements for disease monitoring is less clear.[3]

CSF analysis

Lumbar puncture is important in the diagnosis of cryptococcal meningitis. The CSF often demonstrates a low white cell count (e.g. less than 50 cells/μL) with a mononuclear cell predominance. CSF protein may be slightly elevated while glucose level is commonly low. However, 20-30% of patients with culture-proven cryptocccal meningitis had normal CSF profile,[4] therefore findings of an apparently normal CSF do not exclude a diagnosis of cryptococcal meningitis. In addition, CSF opening pressure should be measured to rule out raised ICP.

CSF should be sent for Indian ink staining, CrAg detection and cryptococcal culture. Microscopy by India ink staining is positive in 70-90% of infected patients, and nearly 100% of CSF culture results are positive for Cryptococcus neoformans.

Other cultures

Depending on the clinical presentation, specimens from suspected sites of infection (e.g. blood, urine, sputum etc.) should be sent for cryptococcal cultures. Around 70% of blood cultures are positive in patients suffering from cryptococcal meningitis.

Treatment of cryptococcal meningitis [Algorithm 21] and extra-pulmonary cryptococcosis

Antifungal treatment of invasive cryptococcosis consists of three phases: induction, consolidation, and maintenance therapy.

Induction and consolidation anti-fungal therapy

A combination of amphotericin B and flucytosine is recommended for the induction treatment of invasive cryptococcosis, which has been shown to have survival benefit as well as a more rapid CSF sterilisation.[5][6] Either IV amphotericin B deoxycholate (AmBd) 0.7 – 1.0 mg/kg per day or IV liposomal amphotericin B 3 – 4 mg/kg per day can be used in the combination therapy, as evidenced by a randomised clinical trial showing comparable efficacy between the two, while nephrotoxicity was less in the arm using liposomal amphotericin B.[7] Flucytosine should be given orally at 100mg/kg per day in four divided doses.

When there is toxicity or availability issue so that either amphotericin B or flucytosine cannot be used, the following alternative regimens may be considered:[8] amphotericin B plus fluconazole 800mg daily, amphotericin B alone, or fluconazole 400 – 800mg daily plus flucytosine.

A repeat lumbar puncture should be performed after the initial 2 weeks of induction therapy to ensure that the cryptococcus organism has been cleared from CSF. Positive CSF cultures after 2 weeks of therapy are predictive of less favourable clinical outcomes and future relapse.

After at least 2 weeks of successful induction therapy, with substantial clinical improvement and a negative CSF culture on follow-up lumbar puncture, amphotericin B and flucytosine can be discontinued and switched to fluconazole 400 mg daily as consolidation therapy. This therapy should continue for at least 8 weeks. Itraconazole 200 mg twice daily is an acceptable though less effective alternative. Only limited data are available for the newer triazoles (voriconazole and posaconazole) as either primary or follow-up therapy for patients with cryptococcosis.

Patients treated with amphotericin B should be monitored for dose-dependent nephrotoxicity and electrolyte disturbances. Pre-infusion administration of 500 mL of normal saline appears to reduce the risk for nephrotoxicity. Common adverse events associated with flucytosine include gastrointestinal toxicity, bone marrow suppression and hepatic dysfunction. Persons treated with fluconazole should be monitored for hepatotoxicity.

Maintenance anti-fungal therapy

Patients who have completed the initial 10 weeks of antifungal therapy for cryptococcal meningitis should be administered chronic maintenance therapy with fluconazole 200mg daily for at least 12 months to prevent relapse, after which maintenance therapy can be discontinued in patients whose CD4 cell counts are ≥100/μL, and who have undetectable viral loads for more than three months after HAART. Itraconazole is inferior to fluconazole for preventing relapse. On the other hand, reinstitution of maintenance therapy should be considered if the CD4 cell count falls below <100/μL.

Non-CNS extra-pulmonary cryptococcosis, and diffuse pulmonary disease should be treated similarly to CNS disease. For focal pulmonary disease, treatment with fluconazole (400 mg daily for 12 months) combined with effective HAART is appropriate.

Initiation of HAART

The optimal timing of HAART initiation in HIV-infected patients with cryptococcal meningitis remains uncertain, which should be based on balancing potential advantage of early immune recovery against the risk of developing immune reconstitution inflammatory syndrome (IRIS). A randomised clinical trial showed that patients with cryptococcal meningitis who were started on HAART within 1 – 2 weeks after fungal diagnosis had a significant increase in 6-month mortality, as compared with patients in whom HAART was deferred until 5 weeks after diagnosis (45% vs 30%, p=0.03).[9] Some guidelines suggest initiating HAART 2 – 10 weeks after commencement of initial antifungal treatment (i.e. after completion of antifungal induction therapy, and in certain circumstances until the total induction/consolidation phase has been completed).[10] Deferring initiation of HAART may be particularly important in those with raised ICP or in those having a low CSF white cell counts.

Management of raised intracranial pressure (ICP)

Majority of deaths associated with cryptococcal meningitis in the MSG/ACTG study were associated with increased ICP.[2] Patients with raised ICP should have daily lumbar puncture to remove a volume of CSF that at least halves the opening pressure, which can be discontinued once the pressure is normal for several days. Temporary percutaneous lumbar drains or ventriculostomy may be considered in patients with opening CSF pressure >40 cm H₂O necessitating frequent lumbar punctures. Permanent ventriculoperitoneal (VP) shunts should be placed only if a patient receiving appropriate antifungal therapy and conservative measures to control increased ICP has failed. VP shunts can be placed before CNS sterilisation provided that the patient is receiving appropriate antifungal therapy.

Mannitol and acetazolamide have no proven benefit and are not routinely recommended. Corticosteroids should be avoided to control increased ICP unless it is indicated for the treatment of IRIS. In one study, corticosteroids were strongly associated with mycologic failure, clinical failure, and early death, but this may just reflect the severity of the disease in patients non-randomly selected to receive steroids.[2]

IRIS [Chapter C17]

About 30% HIV-infected patients with cryptococcal meningitis experience IRIS after initiation or reinitiation of ART. Severe cryptococcal disease, very low CD4 cell counts, lack of previous ART, failed CSF sterilisation at week 2, introduction of HAART during early part of induction therapy, and rapid initial decrease in HIV RNA in response to HAART have all been recognised as risk factors for IRIS. Elevated ICP is common in cryptococcal IRIS and high mortality rates have been reported. In patients with severely symptomatic IRIS, short-course corticosteroids are recommended. Delaying the initiation of HAART might be prudent, at least until the completion of first 2-week induction therapy for severe cryptococcal meningitis, especially if patients have elevated ICP.

Treatment failure and relapse

Treatment failure is defined as either the lack of clinical improvement after 2 weeks of appropriate therapy, or relapse after an initial clinical response, defined as a positive CSF culture and/or a rising CSF CrAg titer with an associated compatible clinical picture after ≥4 weeks of treatment.[10] Isolates collected for the evaluation of persistence or relapse should be checked for fluconazole susceptibility and compared with the original isolate.

Optimal therapy for treatment failure has not been established. Induction phase of primary therapy for longer course (4-10 weeks) should be reinstituted until a clinical response occurs. In general combination therapy is recommended. Dose increase can be considered if the initial dosage of induction therapy is ≤0.7 mg/kg/day for AmBd. Liposomal amphotericin B may be better tolerated in this setting. Higher doses of fluconazole (≥800 mg per day orally) plus flucytosine (100 mg/kg per day orally in 4 divided doses) may also be considered.

Isolates having a minimum inhibitory concentration (MIC) ≥16 mg/mL for fluconazole or ≥32 mg/mL for flucytosine may suggest resistance, and alternative agents should be considered. After induction therapy, salvage consolidation therapy is considered with either fluconazole (800-1200 mg per day orally), voriconazole (200-400 mg twice per day orally), or posaconazole (200 mg orally 4 times per day or 400 mg twice per day orally) for 10-12 weeks. In the event of any compliance issues and a susceptible isolate, prior suppressive doses of fluconazole may be reinstituted.

References