Summary Background Cryptococcus is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated cryptococcal disease. Methods We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per μL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for cryptococcal infection, specifically those with CD4 less than 100 cells/μL not on ART, and those with CD4 less than 100 cells per μL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from cryptococcal meningitis. Findings We estimated an average global cryptococcal antigenaemia prevalence of 6·0% (95% CI 5·8–6·2) among people with a CD4 cell count of less than 100 cells per μL, with 278 000 (95% CI 195 500–340 600) people positive for cryptococcal antigen globally and 223 100 (95% CI 150 600–282 400) incident cases of cryptococcal meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014 (162 500 cases [95% CI 113 600–193 900]). Annual global deaths from cryptococcal meningitis were estimated at 181 100 (95% CI 119 400–234 300), with 135 900 (75%; [95% CI 93 900–163 900]) deaths in sub-Saharan Africa. Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10–19). Interpretation Our analysis highlights the substantial ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa. Cryptococcal meningitis is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority. Funding None.

/pdf/global-burden-of-disease-of-hiv-associated-cryptococcal-4l7b2xsk1g.pdf

Global burden of disease of HIV-associated cryptococcal meningitis: An updated analysis

Cryptococcosis has been one of the most common opportunistic infections and causes of mortality among HIV-infected patients, especially in resource-limited countries. Cryptococcal meningitis is the most common form of cryptococcosis. Laboratory diagnosis of cryptococcosis includes direct microscopic examination, isolation of Cryptococcus from a clinical specimen, and detection of cryptococcal antigen. Without appropriate treatment, cryptococcosis is fatal. Early diagnosis and treatment is the key to treatment success. Treatment of cryptococcosis consists of three main aspects: antifungal therapy, intracranial pressure management for cryptococcal meningitis, and restoration of immune function with antiretroviral therapy (ART). Optimal integration of these three aspects is crucial to achieving successful treatment and reducing the mortality. Antifungal therapy consists of three phases: induction, consolidation, and maintenance. A combination of two drugs, i.e. amphotericin B plus flucytosine or fluconazole, is preferred in the induction phase. Fluconazole monotherapy is recommended during consolidation and maintenance phases. In cryptococcal meningitis, intracranial pressure rises along with CSF fungal burden and is associated with morbidity and mortality. Aggressive control of intracranial pressure should be done. Management options include therapeutic lumbar puncture, lumbar drain insertion, ventriculostomy, or ventriculoperitoneal shunt. Medical treatment such as corticosteroids, mannitol, and acetazolamide are ineffective and should not be used. ART has proven to have a great impact on survival rates among HIV-infected patients with cryptococcosis. The time to start ART in HIV-infected patients with cryptococcosis has to be deferred until 5 weeks after the start of antifungal therapy. In general, any effective ART regimen is acceptable. Potential drug interactions between antiretroviral agents and amphotericin B, flucytosine, and fluconazole are minimal. Of most potential clinical relevance is the concomitant use of fluconazole and nevirapine. Concomitant use of these two drugs should be cautious, and patients should be monitored closely for nevirapine-associated adverse events, including hepatotoxicity. Overlapping toxicities of antifungal and antiretroviral drugs and immune reconstitution inflammatory syndrome are not uncommon. Early recognition and appropriate management of these consequences can reinforce the successful integrated therapy in HIV-infected patients with cryptococcosis.

https://link.springer.com/content/pdf/10.1186%2Fs12981-016-0126-7.pdf

Integrated therapy for HIV and cryptococcosis.

OBJECT Patients with cryptococcal meningitis often develop symptomatic intracranial hypertension. The need for permanent CSF diversion in these cases remains unclear. METHODS Cases of cryptococcal meningitis over a 5-year period were reviewed from a single, large teaching hospital. Sources of identification included ICD-9 codes, operative logs, and microscopy laboratory records. RESULTS Fifty cases of cryptococcal meningitis were identified. Ninety-eight percent (49/50) of patients were HIV positive. Opening pressure on initial lumbar puncture diagnosing cryptococcal meningitis was elevated (> 25 cm H2O) in 33 cases and normal (≤ 25 cm H2O) in 17 cases. Thirty-eight patients ultimately developed elevated opening pressure over a follow-up period ranging from weeks to years. Serial lumbar punctures for relief of intracranial hypertension were performed in 29 cases. Thirteen of these patients ultimately had shunting procedures performed after failing to improve clinically. Two factors were significantly associated with the need for shunting: patients undergoing shunt placement were more likely to be women (5/13 vs 0/16; p = 0.01) and to have a pattern of increasing CSF cryptococcal antigen (10/13 vs 3/16 cases; p = 0.003). All patients re-presenting with mycological relapse either underwent or were offered shunt placement. CONCLUSIONS Neurosurgeons are often asked to consider CSF diversion in cases of cryptococcal meningitis complicated by intracranial hypertension. Most patients do well with serial lumbar punctures combined with antifungal therapy. When required, shunting generally provided sustained relief from intracranial hypertension symptoms. Ventriculoperitoneal shunts are the favored method of diversion. To the authors' knowledge, the present study is the largest series on diversionary shunts in primarily HIV-positive patients with this problem.

https://thejns.org/downloadpdf/journals/j-neurosurg/125/1/article-p177.pdf

Shunting in cryptococcal meningitis

Cryptococcal antigen (CrAg) screening and targeted pre-emptive fluconazole in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL seems promising to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg-positivity (31 studies; 35,644 participants) and asymptomatic CM in CrAg-positives, incidence of CM and all-cause mortality in screened participants. Pooled prevalence of blood CrAg-positivity was 6% (95%CI: 5 - 7) and asymptomatic CM in CrAg-positives was 33% (95%CI: 21 - 45). Incidence of CM without pre-emptive fluconazole was 21.4% (95%CI: 11.6 - 34.4) and 5.7% (95%CI: 3.0 - 9.7) with pre-emptive fluconazole initiated at 800 mg/day. In CrAg-positives, post-screening lumbar puncture prior to initiating pre-emptive fluconazole at 800 mg/day further reduced incidence of CM to null and showed some survival benefits. However, all-cause mortality remained significantly higher in CrAg-positives than CrAg-negatives: RR: 2.2 (95%CI: 1.7 - 2.9, p<0.001).

/pdf/impact-of-routine-cryptococcal-antigen-screening-and-3nbrgd4t43.pdf

Impact of Routine Cryptococcal Antigen Screening and Targeted Preemptive Fluconazole Therapy in Antiretroviral-naive Human Immunodeficiency Virus-infected Adults With CD4 Cell Counts <100/μL: A Systematic Review and Meta-analysis.

Cryptococcal meningoencephalitis was first described over a century ago. This fungal infection is preventable and treatable yet continues to be associated with excessive morbidity and mortality. The largest burden of disease resides in people living with HIV in low-income and middle-income countries. In this group, mortality with the best antifungal induction regimen (7 days of amphotericin B deoxycholate [1·0 mg/kg per day] and flucytosine [100·0 mg/kg per day]) in a clinical trial setting was 24% at 10 weeks. The world is now at an inflection point in terms of recognition, research, and action to address the burden of morbidity and mortality from cryptococcal meningoencephalitis. However, the scope of interventional programmes needs to increase, with particular attention to implementation science that is specific to individual countries. This Review summarises causes of excessive mortality, interventions with proven survival benefit, and gaps in knowledge and practice that contribute to the ongoing high death toll from cryptococcal meningoencephalitis. TRANSLATIONS: For the Vietnamese and Chichewa translations of the abstract see Supplementary Materials section.

/pdf/cryptococcal-meningoencephalitis-time-for-action-4uku1ve2ca.pdf

Cryptococcal meningoencephalitis: time for action

Objectives: To determine the prevalence, clinical features, risk factors and outcomes associated with cryptococcal meningitis (CM) in human immunodeficiency virus (HIV) positive patients at two referral hospitals in Nairobi, Kenya. Design: Prospective, observational study. Setting: Kenyatta National Hospital (KNH) and Mbagathi District Hospital (MDH), Nairobi, Kenya Subjects: Three hundred and forty HIV patients presenting with suspected CM. Results: Of three hundred and forty suspected CM patients, 111 (33%) were diagnosed with CM by CrAg. Among CM patients, in-hospital mortality was 36% (38/106), median age was 35 years (range, 19-60 years) and median CD4 count was 41 cells/μL (n=89, range 2-720 cells/μL). Common clinical manifestations among CM patients included headache 103 (93%), neck stiffness 76 (69%) and weight loss 53 (48%). Factors independently associated with CM were male sex, headache, blurred vision and previous antifungal drug use. Night sweats and current use of anti-retroviral therapy were associated with reduced risk for CM. Conclusions: There is a high prevalence of CM and CM-associated mortality in HIV patients at KNH and MDH despite treatment with antifungal and anti-retroviral drugs. This study demonstrates the need to address the existing inadequacies of CM patient outcomes in Kenya.

/pdf/the-prevalence-clinical-features-risk-factors-and-outcome-wz967wawvs.pdf

The prevalence, clinical features, risk factors and outcome associated with cryptococcal meningitis in HIV positive patients in Kenya.

Background : Cryptococcal meningitis (CM) is an increasingly prevalent  infection among HIV/AIDS patients and is becoming a leading cause of  morbidity and mortality in Africa. The short-term prognosis and  management of patients with CM may be improved by identifying factors leading to mortality in patients with CM. Objective : To assess the clinical management and mortality associated with cryptococcal meningitis (CM) in patients with acquired  immunodeficiency syndrome (AIDS) in Kenya. Design : A retrospective study. Setting : Kenyatta National Hospital and Mbagathi District Hospital, between August 2008 and March 2009. Subjects : Seventy six HIV-infected patients confirmed to be CM positive. Results : Results show that 30 (40%) of 76 patients diagnosed with CM died during hospitalisation after a median hospital stay of ten days (range, 2-73 days). Significant predictors of mortality in the univariate model were Mycobacterium tuberculosis (TB) co-infection (P = 0.04), having been diagnosed with a co-morbid condition such as diabetes mellitus, oral candidiasis and hypertension (P = 0.01), and a low median CD4+ T lymphocyte count (P < 0.001). The multivariable model revealed that male sex, previous or current anti-retroviral therapy (ART) at admission and CD4+ T lymphocyte count less than 50 were significant predictors of mortality. Conversely, a minimum of two weeks of amphotericin B treatment (P < 0.001), initiation of ART (P = 0.007) and monitoring of creatinine and electrolyte levels (P = 0.02) were significantly associated with survival in the univariate model. Conclusions : CM-associated mortality in Kenya is high; there is an  opportunity to improve the management and the short-term outcomes of hospitalised HIV positive patients with CM in Kenya.

/pdf/mortality-after-clinical-management-of-aids-associated-4oubvcv0un.pdf

Mortality After Clinical Management of Aids-Associated Cryptococcal Meningitis in Kenya

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The prevalence, clinical features, risk factors and outcome associated with cryptococcal meningitis in HIV positive patients in Kenya.

Mortality After Clinical Management of Aids-Associated Cryptococcal Meningitis in Kenya