High Burden of Cryptococcal Meningitis Among ART-Experienced HIV-infected Patients in Northern Uganda in the era of “Test and Treat”: Implications for Cryptococcal Screening Programs

Background The impact of the "test-and-treat" program for HIV treatment in rural areas of Uganda on cryptococcal antigen (CrAg) screening or cryptococcal meningitis (CM) is poorly understood. Methods We retrospectively evaluated clinical factors in 212 HIV-infected patients diagnosed with CM from February of 2017 to November of 2019 at Lira Regional Referral Hospital (LRRH) in northern Uganda. Results Among 212 patients diagnosed with CM, 58.5% were male. Median age, CD4 count, and HIV viral load were 35 years, 86 cells/μL, and 9,463 copies/mL respectively. Only 10% of patients had a previous history of CM. We found that 190 of 209 (90.9%) patients were ART-experienced, and 19 (9.1%) were ART-naïve. Overall, 90 of 212 (42.5%) patients died while hospitalized with a median time to death of 14 days. Increased risk of death was associated with altered mental status (HR 6.6, 95% CI 2.411-18.219, p =<0.0001), and seizures (HR 5.23, 95% CI 1.245-21.991, p=0.024). Conclusion Current guidelines recommend CrAg screening based on low CD4 counts for ART-naïve patients and VL or clinical failure for ART-experienced patients. Using current guidelines for CrAg screening, some ART- experienced patients miss CrAg screening in resource limited settings, when CD4 or VL tests are unavailable. We found that the majority of HIV- infected patients with CM were ART- experienced (90.9%) at presentation. The high burden of CM in ART-experienced patients supports a need for improved CrAg screening of ART-exposed patients.

Nanopore sequencing of cerebrospinal fluid of three patients with cryptococcal meningitis

Background Cryptococcal meningitis (CM) has a high morbidity and mortality due to the low detection of Cryptococcus in cerebrospinal fluid (CSF) during the early stage of the disease with traditional methods. Case presentation In addition to the traditional methods of India ink staining and cryptococcal antigen (CrAg), we used nanopore sequencing and next-generation sequencing (NGS) to detect pathogenic DNA in CSF samples of three patients with CM. The CSF samples of all three patients were positive by India ink staining and CrAg. NGS also detected Cryptococcus in all three CSF samples. Nanopore sequencing detected Cryptococcus in two CSF samples. Conclusion Nanopore sequencing may be useful in assisting with the clinical diagnosis of CM. Further research is needed to determine the sensitivity and specificity of nanopore sequencing of CSF.

Clinical Profile of 24 AIDS Patients with Cryptococcal Meningitis in the HAART Era: A Report from an Infectious Diseases Tertiary Hospital in Western Romania

Management of cryptococcal infections among patients suffering from acquired immunodeficiency syndrome (AIDS) represents a medical challenge. This retrospective study aims to describe the disease management and outcomes among 24 AIDS patients who suffered from Cryptococcus neoformans meningitis. The parameters evaluated from our patients’ database records include epidemiological data, clinical manifestations, biochemical and microbiological analysis of patients’ cerebrospinal fluid (CSF), treatment profiles, and disease outcomes. All patients included in the study had a lymphocyte count of less than 200 CD4/mm3. Of the 24 patients included in this study, five had been diagnosed with HIV infection since childhood, after receiving HIV-infected blood transfusions. The most prominent symptom was fatigue in 62.5% of patients, followed by nausea/vomiting and headache. Seven patients had liver cirrhosis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, while Kaposi sarcoma and cerebral toxoplasmosis were found in two patients. Six out of 24 patients died due to bacterial sepsis and acute respiratory distress syndrome (ARDS). High intracranial pressure was the strongest predictive factor for mortality (OR = 2.9), followed by ARDS (OR = 1.8), seizures at disease onset (OR = 1.4), and diabetes mellitus (OR = 1.2). Interestingly, patients younger than 40 years old had a significantly lower survival rate than that of the older patients. Before developing Cryptococcal meningitis, all patients had low adherence to the early ART treatment scheme and skipped the follow-up visits. All patients received a combination of amphotericin B and flucytosine as induction therapy, adding fluconazole for maintenance. Simultaneously, AIDS HAART was initiated at diagnosis of the cryptococcal infection. A combined regimen of antifungals and highly active antiretroviral therapy showed improved patient recovery with minor side effects.

Combination Therapy for HIV-Associated Cryptococcal Meningitis—A Success Story

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far.

Case Report of SLE Patients with Cryptococcosis in Nongkhai Hospital

Background: Cryptococcal infection, especially cryptococcal meningitis, is the most common cause of central nervous system (CNS) infection with a high mortality rate in patients with systemic lupus erythematosus (SLE). The clinical features of cryptococcal meningitis may be non-specific, which may lead to miss or delay diagnosis and treatment. Objective: To collect the case series of SLE patients with cryptococcosis treated in Nongkhai Hospital between 2013 and 2021 and compared it with other studies. Materials and Methods: The medical records of SLE patients (ICD-10 M320-M329) with cryptococcal infection (ICD-10 B450-B459) treated in Nongkhai Hospital between 2013 and 2021 were reviewed and collected onto a medical record form. The following information were obtained, gender, occupation, age at SLE diagnosis, age of onset, duration of disease, comorbid or risks, previous infection, SLE disease activity, glucocorticoids, and immunosuppressors administered before or at infection diagnosis, cryptococcosis clinical manifestations, laboratory data, Cerebrospinal fluid (CSF) findings, antifungal agents used, and outcomes. Results: Six hundred thirty-six patients with SLE were identified and six patients developed cryptococcosis. Five patients had cryptococcal meningitis and one patient had cryptococcocemia. Fever and headache were the symptoms of all patients. CSF cryptococcal antigen was positive in five patients. Antifungal therapy was initiated as soon as the diagnosis was confirmed in all patients. Five patients (83.3%) recovered completely, and one patient was against the advice. Conclusion: The present study suggested that SLE patients presenting with fever and headache along with a history of moderate to high dose steroids and immunosuppressants administration should always be suspected of cryptococcal infection and cryptococcal meningitis. Meanwhile, CSF cryptococcal antigens are the effective screening tools to establish an early diagnosis. Accordingly, early appropriate treatment is crucial for a favorable outcome. Keywords: Cryptococcal infection; Cryptococcosis; Cryptococcal meningitis; SLE; Lupus

Prediction of hospital discharge outcome from changes in cerebrospinal fluid/serum albumin quotient and cerebrospinal fluid lactate dehydrogenase in patients with cryptococcal meningitis

Aim: This study aims to provide reliable prognostic factors for patients with cryptococcal meningitis (CM). Patients & methods: Clinical characteristics and laboratory findings of CM patients were retrospectively reviewed. Results: Sixty-three patients with CM were enrolled and 38/63 were confirmed to be HIV serology positive. Among clinical characteristics, headache, nausea and/or vomiting, and fever were the most common symptoms. Among cerebrospinal fluid (CSF) parameters, changes in leukocyte count, lactate dehydrogenase and chloride were significantly associated with the outcome. An increased CSF/serum albumin quotient (QAlb) was indicative of an unfavorable outcome in HIV-negative patients. Conclusion: CSF lactate dehydrogenase and QAlb may improve the prediction of outcomes in patients with CM.

The Effect of Early vs. Deferred Antiretroviral Therapy Initiation in HIV-Infected Patients With Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Analysis in China

Background: The optimal timing for initiation of antiretroviral therapy (ART) in HIV-positive patients with cryptococcal meningitis (CM) has not, as yet, been compellingly elucidated, as research data concerning mortality risk and the occurrence of immune reconstitution inflammatory syndrome (IRIS) in this population remains inconsistent and controversial.Method: The present multicenter randomized clinical trial was conducted in China in patients who presented with confirmed HIV/CM, and who were ART-naïve. Subjects were randomized and stratified into either an early-ART group (ART initiated 2–5 weeks after initiation of antifungal therapy), or a deferred-ART group (ART initiated 5 weeks after initiation of antifungal therapy). Intention-to-treat, and per-protocol analyses of data for these groups were conducted for this study.Result: The probability of survival was found to not be statistically different between patients who started ART between 2–5 weeks of CM therapy initiation (14/47, 29.8%) vs. those initiating ART until 5 weeks after CM therapy initiation (10/55, 18.2%) (p = 0.144). However, initiating ART within 4 weeks after the diagnosis and antifungal treatment of CM resulted in a higher mortality compared with deferring ART initiation until 6 weeks (p = 0.042). The incidence of IRIS did not differ significantly between the early-ART group and the deferred-ART group (6.4 and 7.3%, respectively; p = 0.872). The percentage of patients with severe (grade 3 or 4) adverse events was high in both treatment arms (55.3% in the early-ART group and 41.8% in the deferred-ART group; p=0.183), and there were significantly more grade 4 adverse events in the early-ART group (20 vs. 13; p = 0.042).Conclusion: Although ART initiation from 2 to 5 weeks after initiation of antifungal therapy was not significantly associated with high cumulative mortality or IRIS event rates in HIV/CM patients compared with ART initiation 5 weeks after initiation of antifungal therapy, we found that initiating ART within 4 weeks after CM antifungal treatment resulted in a higher mortality compared with deferring ART initiation until 6 weeks. In addition, we observed that there were significantly more grade 4 adverse events in the early-ART group. Our results support the deferred initiation of ART in HIV-associated CM.Clinical Trials Registration:www.ClinicalTrials.gov, identifier: ChiCTR1900021195.