GUIDELINE FOR THE MANAGEMENT OF CRYPTOCOCCAL MENINGITIS Full title of guideline Guideline for the management of cryptococcal meningitis Author Dr P Venkatesan (ID consultant) Division and specialty Medicine, Infectious Diseases Scope (Target audience, Trustwide (adults) state if Trustwide) Review date 18.03.2021 Explicit definition of patient Any adult patient with suspected or confirmed cryptococcal group to which it applies meningitis (e.g. inclusion and exclusion criteria, diagnosis) Changes from previous version (not applicable if this is a new guideline) Summary of evidence base this guideline has been created from Updated with reference to international guidance, with main alterations concerning 5-flucytosine 1. UK BHIVA Opportunistic Infection Guidelines https://www.bhiva.org/oi-guidelines.aspx 2. US Opportunistic Infection Guidelines available at https://aidsinfo.nih.gov/guidelines
GUIDELINE FOR THE MANAGEMENT OF CRYPTOCOCCAL MENINGITIS A. INTRODUCTION Cryptococcal meningitis is caused by an encapsulated fungus (mostly Cryptococcus neoformans, sometimes C. gattii). It is seen primarily amongst HIV infected individuals although can affect other immunocompromised individuals e.g. transplant recipients. Worldwide there are an estimated 1 million cases per annum, with ~60% mortality. This condition usually affects patients with CD4 lymphocyte counts <100 cells/mm 3 and although antiretroviral therapy has led to a decreased incidence of cryptococcal meningitis, it may still be encountered as the first presentation of HIV infection. It is characterised pathologically by chronic non-exudative meningitis. Median survival without antifungal therapy is 14 days but effective antifungal chemotherapy has improved survival. However, deaths still occur and many may be related to raised intracranial pressure (ICP). Guidelines from national societies exist in the UK and USA. 1,2,3 B. ASSESSMENT AND DIAGNOSIS Risk groups Cryptococcal meningitis is encountered mainly amongst individuals with CD4 lymphocyte counts <100 cells/mm 3 but should be considered in any HIV-infected individual with neurological symptoms or signs. It may also be considered in any individual not known to be infected with HIV but with a meningitis-type illness. Clinical features Clinical presentation is often non-specific and therefore a high index of suspicion is required. There is commonly insidious onset of headache and fever. Other symptoms include nausea/vomiting, confusion, behavioural change, and fits. Some patients may report recent respiratory symptoms (cough, dyspnoea), which may represent cryptococcal pneumonia.
Clinical signs are similarly not always present. Meningism with neck stiffness is present in only 20-30%. Focal neurological signs, reduced conscious level, and other signs of raised intracranial pressure (bradycardia, hypertension, papilloedema) may be present and should always be actively sought. Manifestations outside the CNS are seen less commonly and include pulmonary disease, skin lesions, PUO and bone lesions. In males Cryptococcus may persist in the prostate. Investigations Imaging Imaging of the CNS (CT or MRI) is essential prior to lumbar puncture due to the possibility of an intracranial space-occupying lesion. CT/MRI may be normal or may show nonspecific abnormalities including cerebral atrophy. Diffuse meningeal enhancement may be seen. Cryptococcomas usually appear as multiple cortical lesions. Lumbar puncture Lumbar puncture should follow imaging, and measurement and documentation of opening pressure (OP) is essential (~70% have CSF OP >20 cm H 2 O). Routine CSF analysis may be normal or may show pleocytosis (predominantly lymphocytes), raised protein, and low glucose. The inflammatory response is usually less marked than that seen in other infections. The diagnosis may be made by CSF India ink stain in 60-80% (see picture above), fungal culture (~95% positive within 7 days), or cryptococcal antigen (CRAG) testing. Cryptococcal antigen (CRAG) Both CSF and serum should be tested for CRAG and the serum test has 99% sensitivity for cryptococcal meningitis. If a CRAG is performed initially and found to be positive a lumbar puncture still needs to be performed to determine whether there is CNS involvement. False positive CRAGs may be seen in patients who are Rheumatoid Factor positive or have heterophile antibodies from glandular fever. Other Other tests should include CXR (may show concurrent pneumonia), ECG, blood cultures and blood tests should provide a baseline prior to antifungal therapy (FBC, U&Es, LFTs, Ca, PO 4, Mg, Glucose, CRP). C. MANAGEMENT (Evidence grade - 1b) 1,2 Antifungal chemotherapy The details of antifungal therapy are displayed in figure 1. Initial therapy consists of amphotericin B +/- flucytosine. Conventional amphotericin B has been withdrawn from NUH and AmBisome is recommended in its place.
AmBisome + / - Flucytosine - 3-4 mg /kg daily iv - 25mg/kg qds iv The above treatment is given for two weeks and then followed by oral Fluconazole - 400mg daily for a further 8 weeks then maintenance therapy at 200mg od - on the basis of in vitro sensitivity data and CNS penetration the second line choice for an azole is voriconazole 4 (see BNF for dosing by weight) Some suggest that concomitant use of amphotericin B and fluconazole can be antagonistic. 6 AmBisome A 1 mg test dose should be administered prior to full dosage of AmBisome. BHIVA guidelines quote a dose of 4 mg/kg from a trial by Leenders et al (1997) involving 15 patients on AmBisome. 1,6 Hamill et al (2010) compared AmBisome doses of 3 mg/kg (86 patients) and 6 mg/kg (94 patients) and found that they were equi-effective and therefore the lower dose is sufficient with less risk of side-effects. 7 The main adverse effects from amphotericin B and flucytosine are shown in table 1. Febrile reactions are primarily due to prostaglandin E 2 release and may be prevented with paracetamol, ibuprofen or hydrocortisone pre-medication. Reducing the rate of infusion may also reduce the adverse effects, but infusions should not take longer than 2 hours to maintain drug stability. There is a risk of infusion site reactions and where possible a central IV line should be used. Renal toxicity is more likely in dehydrated patients and adequate hydration is important. FBC, U&Es, Ca, Mg, LFTs should be monitored at least 2-3 times per week in all patients. AmBisome is usually switched to fluconazole after 2 weeks. A repeat LP at 2 weeks may determine longer durations of AmBisome, if CSF cultures remain positive. Flucytosine (5FC) In US trials flucytosine has a demonstrated additive benefit to non-lipid associated amphotericin B (AmB) when the latter is given at a dose of 0.4 mg/kg, but when the dose of the latter is 0.7 mg/kg the additive benefit is less and seen in the severely ill, with increased mycological sterilisation but no difference in mortality. 8 After 2 weeks of treatment CSF respectively became sterile in 60 or 51% in those treated with AmB+5FC versus AmB alone (P=0.06), and there were 11/202(5.4%) and 10/179(5.6%) deaths (P=0.65) in each arm. 8 In a study from Vietnam (using AmB at a dose of 1 mg/kg) flucytosine was also associated with more rapid, early reduction of CSF cryptococcal burden, with 74% mycological sterilisation at day 70 with AmB+5FC and 52% with AmB alone, with 26/92(28.3%) and 37/87( 42.5%) deaths in each arm (P=0.04). 9 When balancing risks and benefits there is a clear place for flucytosine in the very ill and in those
patients in whom side-effects limit the dose of amphotericin B. 10 In murine models there is synergy between amphotericin B and flucytosine, even in the presence of flucytosine mono-resistance. Flucytosine levels should be determined (blood taken immediately prior to infusion optimum levels 25-50mg/l), after a day or two when steady state has been reached. However levels are sent away to a regional laboratory and one hopes that results return before 14 days of treatment have finished. In the past most toxicity is observed when flucytosine is used longer than 14 days. Side-effects from flucytosine are more common in renal impairment, but are seen less with the current dosage of 25 mg/kg qds. Renal function should be monitored closely and the flucytosine dose adjusted accordingly for patients with renal impairment. The dose of flucytosine should be reduced by 50% for every 50% decline in creatinine clearance. Table 1. Important adverse effects from antifungal therapy Amphotericin B Nausea/vomiting/diarrhoea Rash Alterations in LFTs Blood disorders (anaemia, leucopenia, thrombocytopenia) Infusion site reactions Febrile reactions Anaphylaxis Renal impairment Electrolyte disturbance ( K, Mg) Arrhythmias Flucytosine Nausea/vomiting/diarrhoea Rash Alterations in LFTs Blood disorders (anaemia, leucopenia, thrombocytopenia) Mucositis CNS effects (confusion, hallucinations, convulsions) Fluconazole Fluconazole is the first line azole for Cryptococcus. If amphotericin B cannot be given induction therapy requires a combination of fluconazole 400 mg od plus flucytosine. This regime is associated with a higher mortality than induction with amphotericin B and the dose of flucytosine used may be slightly higher (totalling 100 150 mg/kg/day). Fluconazole is usually used after induction with AmBisome at the doses shown above. If there are problems with fluconazole, itraconazole is not preferred, and instead voriconazole is the second line azole, and posaconazole third line. 4 Echinocandins are ineffective against Cryptococcus.
Management of raised intracranial pressure Optimal management of raised intracranial pressure is crucial to the success of therapy. Close collaboration with neurosurgeons and ICU are important. The management is summarised in figure 2. Persistently raised pressure compromises blood flow into the retinal and retinal ischaemia can lead to blindness. 11 There is no evidence to support the use of mannitol, steroids, or acetazolamide. Raised intracranial pressure (> 25 cm H 2 O) should be managed aggressively with repeated, daily lumbar puncture and CSF removal. If this is inadequate then the case should be discussed with the neurosurgical team as a lumbar drain or even a lumbar-peritoneal shunt or ventriculo-peritoneal shunt may be appropriate. n-cns cryptococcosis and special groups n-cns cryptococcosis may not require Ambisome induction and may be treated initially with fluconazole. Treatment recommendations for such sites and special patient groups e.g. pregnant women, is provided in the 2010 IDSA guideline. 3 Initiation of antiretroviral therapy In many patients cryptococcal meningitis may be the first presentation of HIV infection and antiretroviral therapy will be indicated. There is no clear evidence to guide the timing of initiation of HAART, although US guidelines suggest starting between 2-10 weeks, and especially later if there is raised intracranial pressure. 2 In a small Zimbabwean study involving 54 patients commencing HAART within 72 hours of starting cryptococcal treatment was associated with increased mortality. 12 A study from South Africa may not be comparable with our circumstances as AmB+fluconazole was used as induction. In this study 6 month mortality was higher when ART commenced within 1-2 weeks (40/88[45%] mortality), compared with at 5 weeks (27/89[30%] mortality) with P=0.03. 13 It is important to be aware of the possibility of worsening/relapse of cryptococcal meningitis with HAART as a feature of the immune reconstitution inflammatory syndrome (IRIS). The need for antiretroviral therapy must be balanced against the risks of drug interactions and overlapping toxicities. Follow-up All patients should be closely followed up on hospital discharge. There is some evidence to support discontinuation of maintenance fluconazole therapy in those who have good immune reconstitution with antiretroviral therapy and have two CD4 counts above 100 over a 3 month period with an undetectable viral load. 14 Fluconazole should be reinstituted if the CD4 lymphocyte count falls below 100 cells/mm 3. Serum CRAG may be monitored, but deterioration due to cryptococcal disease may occur at the time of a stable or falling CRAG level. 15 E. NURSING ISSUES Isolation / precautions
Patients do not require isolation and standard precautions for HIV should be observed. Observations Weight on admission Neuro-obs (pulse/bp/temp/rr/oxygen saturation/pupils/gcs) - frequency depends on clinical condition [warning signs are falling pulse, rising BP, falling GCS, pupillary changes] Fluid balance Early Warning Scores as usual Infusions / reactions Febrile reactions are common with amphotericin B. These can usually be managed with pre-medication with paracetamol or ibuprofen but may require hydrocortisone if more severe. Slowing the rate of infusion may reduce these adverse effects. The dosing schedule for amphotericin B is noted in section D. Infusion site reactions are also common and so the infusion site must be monitored closely. Disturbed patient Some patients may exhibit disturbed behaviour. This may be a consequence of raised ICP and so patients should be reviewed by medical staff before any sedation or other medication is administered. Patients may require special nursing. References 1. UK BHIVA Opportunistic Infection Guideline - https://www.bhiva.org/oi-guidelines.aspx 2. US Opportunistic Infection Guidelines available at https://aidsinfo.nih.gov/guidelines 3. Perfect JR et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases 2010;50:291-322. 4. Pfaller MA et al. In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans from the United States and Africa. Antimicrobial Agents and Chemotherapy 1999;43:169-171. 5. Brouwer AE et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004;363:1764-1767. 6. Leenders ACAP et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDSassociated crytpococcal meningitis. AIDS 1997;11:1463-71. 7. Hamill RJ, Soble JD, El-Sadr W et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of
AIDS-associated acute cryptococcal meningitis: a randomised, double-blind clinical trial of efficacy and safety. Clinical Infectious Diseases 2010:51:225-32. 8. van der Horst CM et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. New England Journal of Medicine 1997;337:15-21. 9. Day JN et al. Combination antifungal therapy for cryptococcal meningitis. New England Journal of Medicine 2013;368:1291-302. 10. Dromer F et al. Major role for amphotericin B-flucytosine combination in severe cryptocococcosis. Plos One 2008;3:e2870 11. Seaton AR et al. Visual loss in immunocompetent patients with Cryptococcous neoformans var. gattii meningitis. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997;91:44-9. 12. Makadzange CE et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in Sub-Saharan Africa. Clinical Infectious Diseases 2010;50:1532-8. 13. Boulware DR et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. New England Journal of Medicine 2014;370:2487-98. 14. Mussini C et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clinical Infectious Diseases 2004;38:565-571. 15. Aberg JA et al. Clinical utility of monitoring serum cryptococcal antigen (scrag) titers in patients with AIDS-related cryptococcal disease. HIV Clinical Trials 2000;1:1-6. 16. Further recent references on www.medadvocates.org
FIGURE 1. Antifungal therapy for cryptococcal meningitis IV AmBisome 3-4 mg/kg daily + / - IV Flucytosine 25mg/kg qds (2 WEEKS) Oral Fluconazole 400mg daily (8 WEEKS) Oral Fluconazole 200mg daily (CONTINUOUS) Stable HAART VL <40 copies/ml CD4 >100 cells/mm 3 For > 3 months STOP FLUCONAZOLE
Lumbar puncture OP <25 cm H 2 O OP >25 cm H 2 O Repeat LP at 2 weeks or sooner if there is clinical deterioration Remove CSF pressure 50% Daily LP OP <25 cm H 2 O for 2 days Persistent raised OP STOP Consider lumbar drain or shunt FIGURE 2. Management of intracranial pressure in cryptococcal meningitis
AUDIT FORM Date : Please print off the protocol / guideline together with this audit form. Place the audit form on the front of the notes and complete the form at discharge or when dictating the discharge summary. On completion please return this audit form to Dr Venkatesan. Hospital number : Diagnosis : Cryptococcal meningitis / please state site if other form of cryptococcosis History and examination adequate Investigations as per guideline Management as per guideline Discharge and follow up as per guideline Outcomes (please tick) Full recovery Complications (please state) Death (please give details) Near misses / Serious incidents Could we have done better?