Cryptococcal Meningitis In HIV-infected Patients Research Articles

Nanopore targeted sequencing-based diagnosis of central nervous system infections in HIV-infected patients

BackgroundEarly and accurate etiological diagnosis is very important for improving the prognosis of central nervous system (CNS) infections in human immunodeficiency virus (HIV)-infected patients. The goal is not easily achieved by conventional microbiological tests. We developed a nanopore targeted sequencing (NTS) platform and evaluated the diagnostic performance for CNS infections in HIV-infected patients, with special focus on cryptococcal meningitis (CM). We compared the CM diagnostic performance of NTS with conventional methods and cryptococcal polymerase chain reaction (PCR).MethodsThis study included 57 hospitalized HIV-infected patients with suspected CNS infections from September 2018 to March 2022. The diagnosis established during hospitalization includes 27 cases of CM, 13 CNS tuberculosis, 5 toxoplasma encephalitis, 2 cytomegalovirus (CMV) encephalitis and 1 Varicella-zoster virus (VZV) encephalitis. The 2 cases of CMV encephalitis also have co-existing CM. Target-specific PCR amplification was used to enrich pathogen sequences before nanopore sequencing. NTS was performed on stored cerebrospinal fluid (CSF) samples and the results were compared with the diagnosis during hospitalization.Results53 (93.0%) of the patients were male. The median CD4 cell count was 25.0 (IQR: 14.0–63.0) cells/uL. The sensitivities of CSF culture, India ink staining, cryptococcal PCR and NTS for CM were 70.4% (95%CI: 51.5 − 84.1%), 76.0% (95%CI: 56.6 − 88.5%), 77.8% (59.2 − 89.4%) and 85.2% (95%CI: 67.5 − 94.1%), respectively. All those methods had 100% specificity for CM. Our NTS platform could identify Cryptococcus at species level. Moreover, NTS was also able to identify all the 5 cases of toxoplasma encephalitis, 2 cases of CMV encephalitis and 1 VZV encephalitis. However, only 1 of 13 CNS tuberculosis cases was diagnosed by NTS, and so did Xpert MTB/RIF assay.ConclusionsNTS has a good diagnostic performance for CM in HIV-infected patients and may have the ability of simultaneously detecting other pathogens, including mixed infections. With continuing improving of the NTS platform, it may be a promising alterative microbiological test for assisting with the diagnosis of CNS infections.

Is it possible to differentiate tuberculous and cryptococcal meningitis in HIV-infected patients using only clinical and basic cerebrospinal fluid characteristics?

Tuberculous and cryptococcal meningitis (TBM and CM) are the most common causes of opportunistic meningitis in HIVinfectedpatients from resource-limited settings, and the differential diagnosis is challenging. To compare clinical and basic cerebrospinal fluid (CSF) characteristics between TBM and CM in HIV-infected patients. A retrospective analysis was conducted of clinical, radiological and laboratory records of 108 and 98 HIV-infected patients withculture-proven diagnosis of TBM and CM, respectively. The patients were admitted at a tertiary centre in São Paulo, Brazil. A logisticregression model was used to distinguish TBM from CM and derive a diagnostic index based on the adjusted odds ratio (OR) to differentiatethese two diseases. In multivariate analysis, TBM was independently associated with: CSF with neutrophil predominance (odds ratio (OR) 35.81, 95%confidence interval (CI) 3.80 - 341.30, p=0.002), CSF pleocytosis (OR 9.43, 95% CI 1.30 - 68.70, p=0.027), CSF protein >1.0 g/L (OR 5.13,95% CI 1.38 - 19.04, p=0.032) and Glasgow Coma Scale <15 (OR 3.10, 95% CI 1.03 - 9.34, p=0.044). Nausea and vomiting (OR 0.27, 95% CI0.08 - 0.90, p=0.033) were associated with CM. Algorithm-related area under the receiver operating characteristics curve was 0.815 (95% CI0.758 - 0.873, p<0.0001), but an accurate cut-off was not derived. Although some clinical and basic CSF characteristics appear useful in the differential diagnosis of TBM and CM in HIVinfectedpatients, an accurate algorithm was not identified. Optimised access to rapid, sensitive and specific laboratory tests is essential.

Rapid Clinical Score for the Diagnosis of Tuberculous Meningitis: A Retrospective Cohort Study.

Objective:The aim of our study was to retrospectively validate a previously described rapid clinical score (RCS) in distinguishing tuberculous meningitis (TBM) from viral meningitis (VM) in people who are at increased risk of tuberculosis, as well as from cryptococcal meningitis (CM) in HIV-infected patients.Methods:We performed a retrospective study of patients admitted with a diagnosis of aseptic meningitis between January 2012 and December 2015, to a referral hospital for infectious diseases. The variables included in RCS were duration of symptoms before admission, neurological stage, cerebrospinal fluid (CSF) to blood glucose ratio, and CSF protein. We included in this retrospective study 31 patients with definite or probable TBM including 14 HIV-infected patients, 62 HIV-noninfected patients with VM, and 18 HIV-infected patients with CM.Results:The sensitivity of RCS to distinguish TBM from VM was 96.7%, with a specificity of 81.1% and the area under the receiver operating characteristic (ROC) curve was 0.949 (0.90–0.99). When all four criteria from the RCS were present, the specificity increased at 100%. In HIV-infected patients, the sensitivity and specificity of RCS in differentiating TBM from CM were 86.6% and 27.7%, respectively, and the area under the ROC curve was 0.669 (0.48–0.85).Conclusion:This easy-to-use RCS was found to be helpful in differentiating TBM from VM, with a better sensitivity than molecular amplification techniques and a relatively good specificity. However, the RCS was not useful to differentiate between TBM and CM in HIV-infected patients.

Predictors of poor clinical outcome of cryptococcal meningitis in HIV-infected patients

The aim of this study was to identify baseline prognostic factors for poor clinical outcome of HIV-associated cryptococcal meningitis. We conducted a trial in Thailand and the USA comparing low- and high-dose concomitant use of amphotericin B and fluconazole for HIV-associated cryptococcal meningitis to amphotericin B followed by fluconazole. Subjects who were either alive and cerebrospinal fluid (CSF) culture-positive or dead were considered to have a poor outcome. At day 14, baseline characteristics associated with poor outcome included: low weight, high CSF cryptococcal antigen (CrAg) titre and low CSF white blood cell (WBC) count. At day 70, the associated baseline characteristics included: CSF CrAg titre >1:1024 and low Karnofsky performance status. Overall, consistent with published findings, low weight, high CSF CrAg titre and low CSF WBC counts at baseline were predictors for poor clinical outcome. In addition, we found that low Karnofsky performance status was predictive of poor outcome. Prompt management with appropriate antifungal therapy for this particular group of patients may improve the outcomes.

Cryptococcal meningitis in HIV-infected patients: a longitudinal study in Cambodia

To describe the frequency of diagnosis of cryptococcosis among HIV-infected patients in Phnom Penh, Cambodia, at programme entry, to investigate associated risk factors, and to determine the incidence of cryptococcal meningitis. We analysed individual monitoring data from 11,970 HIV-infected adults enrolled between 1999 and 2008. We used Kaplan-Meier naïve methods to estimate survival and retention in care and multiple logistic regression to investigate associations with individual-level factors. Cryptococcal meningitis was diagnosed in 12.0% of the patients: 1066 at inclusion and 374 during follow-up. Incidence was 20.3 per 1000 person-years and decreased over time. At diagnosis, median age was 33 years, median CD4 cell count was 8 cells/μl, and 2.4% of patients were receiving combined antiretroviral therapy; 38.7% died and 34.6% were lost to follow-up. Of 750 patients alive and in care after 3 months of diagnosis, 85.9% received secondary cryptococcal meningitis prophylaxis and 13.7% relapsed in median 5.7 months [interquartile range 4.1-8.8] after cryptococcal meningitis diagnosis (relapse incidence=5.7 per 100 person-years; 95%CI 4.7-6.9). Cryptococcal meningitis was more common in men at programme entry (adjusted OR=2.24, 95% CI 1.67-3.00) and fell with higher levels of CD4 cell counts (P<0.0001). Cryptococcal meningitis remains an important cause of morbidity and mortality in Cambodian HIV-infected patients. Our findings highlight the importance of increasing early access to HIV care and cryptococcal meningitis prophylaxis and of improving its diagnosis in resource-limited settings.

Management of cryptococcal meningitis in HIV-infected patients: Experience from western India

Cryptococcal meningitis is one of the acquired immunodeficiency syndrome defining infections with high mortality. Amphotericin B is the preferred drug for induction therapy. Despite advances in human immunodeficiency virus (HIV) treatment, Antiretroviral Treatment (ART) roll-out programs and availability of amphotericin B, cryptococcal meningitis remains an important cause of mortality in the African and other developing countries. We carried out a prospective observational study to determine the treatment response rate, tolerability and outcome of patients with cryptococcal meningitis in HIV treated with amphotericin B. Descriptive statistic was used to analyze the data. A total of 27 patients were diagnosed with cryptococcal meningitis during the study period. Headache (96.29%) was the single most common presenting symptom of cryptococcal meningitis in HIV-infected patients, followed by vomiting (77.77%) and fever (66.66%). Cerebrospinal fluid (CSF) routine and microscopic examination was within normal limits in six patients. CSF became sterile on the 12th day of Amphotericin B in 55.55% of the patients while 33.33% had positive CSF cultures. Patients were started with ART after achieving sterile CSF and tolerated at least 2 weeks of fluconazole consolidation treatment and were free from symptoms. Median time for antiretroviral treatment initiation was 35 (14-90) days after completion of Amphotericin B treatment. One patient developed immune reconstitution inflammatory syndrome (IRIS) after ART. We found that the recommended 2 weeks induction treatment with Amphotericin B monotherapy for HIV patients with cryptococcal meningitis in resource-limited settings may be suboptimal for at least one-third of the patients. Extending the therapy to 3 weeks is likely to result in sterilization of the CSF in a majority of these patients. This finding requires confirmation by a larger sample size in appropriately powered studies. Delaying ART initiation by at least 2 weeks after amphotericin B treatment may decrease the incidence of IRIS.

Management of cryptococcal meningitis in HIV-infected patients: Experience from western India

Introduction:Cryptococcal meningitis is one of the acquired immunodeficiency syndrome defining infections with high mortality. Amphotericin B is the preferred drug for induction therapy. Despite advances in human immunodeficiency virus (HIV) treatment, Antiretroviral Treatment (ART) roll-out programs and availability of amphotericin B, cryptococcal meningitis remains an important cause of mortality in the African and other developing countries.Materials and Methods:We carried out a prospective observational study to determine the treatment response rate, tolerability and outcome of patients with cryptococcal meningitis in HIV treated with amphotericin B. Descriptive statistic was used to analyze the data.Results:A total of 27 patients were diagnosed with cryptococcal meningitis during the study period. Headache (96.29%) was the single most common presenting symptom of cryptococcal meningitis in HIV-infected patients, followed by vomiting (77.77%) and fever (66.66%). Cerebrospinal fluid (CSF) routine and microscopic examination was within normal limits in six patients. CSF became sterile on the 12th day of Amphotericin B in 55.55% of the patients while 33.33% had positive CSF cultures. Patients were started with ART after achieving sterile CSF and tolerated at least 2 weeks of fluconazole consolidation treatment and were free from symptoms. Median time for antiretroviral treatment initiation was 35 (14–90) days after completion of Amphotericin B treatment. One patient developed immune reconstitution inflammatory syndrome (IRIS) after ART.Conclusions:We found that the recommended 2 weeks induction treatment with Amphotericin B monotherapy for HIV patients with cryptococcal meningitis in resource-limited settings may be suboptimal for at least one-third of the patients. Extending the therapy to 3 weeks is likely to result in sterilization of the CSF in a majority of these patients. This finding requires confirmation by a larger sample size in appropriately powered studies. Delaying ART initiation by at least 2 weeks after amphotericin B treatment may decrease the incidence of IRIS.

Recurrence of cryptococcal meningitis in HIV-infected patients following immune reconstitution

Two HIV-infected patients had recurrent cryptococcal meningitis (CM) despite treatment with fluconazole and immune reconstitution with combination antiretroviral therapy (CART). Following treatment of CM with fluconazole, lumbar puncture should be performed either after completion of induction treatment for CM or before starting CART, in order to confirm cerebrospinal fluid sterility.

Cryptococcal meningitis in HIV infected: Experience from a North Indian tertiary center

Cryptococcal meningitis is a common opportunistic infection in Human Immunodeficiency Virus (HIV)-infected individuals. There is little information specifically addressing cryptococcal meningitis in HIV-infected patients from North India. To determine clinical presentation, hospital course, response to treatment, complications developed, in-hospital mortality, any recurrence of cryptococcal meningitis and reasons of recurrence during follow-up. A retrospective observational study undertaken in a large tertiary care center. Patient's demographic data, presenting clinical symptomatology, physical findings, laboratory parameters, cerebrospinal fluid (CSF) examination findings, side-effects of treatment, development of any complications and hospital outcome were analyzed. During follow-up any recurrence of cryptococcal meningitis, possible reasons of recurrence, type of treatment received, complications developed and outcome was recorded as well. Forty patients diagnosed to have cryptococcal meningitis were analyzed. Twenty-two (55%) patients had acute/ subacute presentation. Thirty-six (90%) patients presented with headache and 18 (45%) had altered sensorium. Twenty (50%) patients had no cells in the CSF. Hypoglycorrhchia was seen in 30 (75%) patients. Cryptococcal meningitis was the first acquired immune deficiency syndrome (AIDS)-defining illness in 30 (75%) patients. Thirty-five patients developed some adverse effects to amphotericin-B. Thirty-three patients improved with treatment while three patients died. Four patients had recurrence of cryptococcal meningitis within six months of first episode. Non-compliance of fluconazole therapy was the reason for recurrence in all of these patients. Cryptococcal meningitis is a common initial AIDS-defining illness. Acute and/or subacute presentation of cryptococcal meningitis is not uncommon in HIV-infected individuals. An early diagnosis of HIV infection might reduce the incidence of this infection.

High-Dose Amphotericin B with Flucytosine for the Treatment of Cryptococcal Meningitis in HIV-Infected Patients: A Randomized Trial

High-Dose Amphotericin B with Flucytosine for the Treatment of Cryptococcal Meningitis in HIV-Infected Patients: A Randomized Trial

O171 A comparative study of treatment outcome in cryptococcal meningitis in HIV-infected patients during period before versus after implementation of treatment guidelines for management of increased intracranial pressure

O171 A comparative study of treatment outcome in cryptococcal meningitis in HIV-infected patients during period before versus after implementation of treatment guidelines for management of increased intracranial pressure

Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy.

Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy.

Cryptococcal Meningitis in HIV-Infected Patients.

Cryptococcosis is a fungal infection that is potentially deadly for and common among AIDS patients, in the United States and worldwide. Subacute meningitis and meningoencephalitis are typical, clinically. This article will review relevant aspects of cryptococcal meningitis in AIDS, focusing on the most recent information pertaining to pathogenesis, epidemiology, clinical syndromes, and treatment of this devastating disease.

Risk factors for cryptococcal meningitis in HIV-infected patients.

To identify the risk factors for cryptococcal meningitis in patients with HIV disease we conducted a nested case-control study of 37 incident cases of cryptococcal meningitis and 74 controls, identified from a cohort of more than 2000 HIV-infected patients. Conditional logistic regression was used to study demographic and AIDS-related variables in addition to fluconazole and steroid use. No difference in demographic variables, HIV risk factors, or stage of AIDS was detected between cases and controls. Exposure to fluconazole for more than 90 days reduced the risk of cryptococcal meningitis by 82% (OR=0.18; 95% CI=0.04-0.85; p=0.03). We did not find a difference in steroid use between cases and controls for either the length or amount of steroid exposure (p=0.41). No difference in survival during follow-up in the clinic was observed by the log-rank test (p=0.74). Among the cases, a cryptococcal antigen was positive in more than 97% of the CSF or blood samples. CSF and blood cultures were positive in 81 and 44% of the samples, respectively. We conclude that demographic factors did not affect the risk of cryptococcal meningitis in an inner city United States population. While fluconazole use has a protective effect, steroid use was not associated with an increased risk of cryptococcal meningitis in HIV-infected patients.

High‐dose therapy with fluconazole ≥ 800 mg day‐1

Fluconazole dosages greater than 800 mg day-1 have been reported in about 900 patients treated for candidemia, oropharyngeal candidiasis and cryptococcal meningitis in HIV-infected patients, and for initial therapy of endemic mycoses. In patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, results of a limited number of dose-finding trials with non-neutropenic and HIV-infected patients show dose-dependent responses. These study results indicate that higher daily doses of fluconazole than are currently approved for these indications are well tolerated and tend to provide better clinical efficacy in selected patient populations. An excellent safety profile of dosages up to 2000 mg day-1 and linear predictable pharmacokinetics up to 1600 mg day-1 appear to justify further clinical investigations to better determine the optimum dosage and duration of treatment.

High-dose therapy with fluconazole > or = 800 mg/day. Review

The clinical use of fluconazole in dosages > or = 800 mg/day has been reported in about 900 patients against candidemia, oropharyngeal candidiasis and cryptococcal meningitis in HIV-infected patients as well as for initial therapy of endemic mycoses. Especially in patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, the results of a limited number of dose-finding trials with non-neutropenic and HIV-infected patients show dose-dependent response rates. These findings strongly advocate the application of high dose-fluconazole; their evaluation, however, still awaits final clarification. The good safety profile for dosages up to 2000 mg/day and the linear, predictable pharmacokinetics up to 1600 mg/day indicate the excellent tolerability of fluconazole in the clinical situation which justifies prospective, randomized clinical trials with treatment groups as homogeneous as possible for further evaluation of the optimum dosage and duration of treatment.

Primary prevention of cryptococcal meningitis by fluconazole in HIV-infected patients

To evaluate whether oral fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients, we conducted a case-control study of patients cared for in a university teaching hospital and two urban HIV-outpatient clinics. Cases consisted of HIV-infected patients with CD4 cell counts less than 250/μL who developed a first episode of cryptococcal meningitis between July 1, 1990, and June 30, 1993. For each case (n=18), 4 control subjects were chosen from HIV-infected patients (CD4 count < 250/μL) whose cerebrospinal fluid was negative for cryptococcal antigen and culture, and who were matched by age, sex, and time of lumbar puncture. There were no significant differences between cases and controls in age, sex, insurance status, mean CD4 count, history of oral candidosis, presence of a previous AIDS-defining illness, the number of visits to the HIV-outpatient clinic, or use of antiretroviral therapy. In the 6 months before lumbar puncture, 2 of 18 cases (11%) and 26 of 72 controls (36%) were exposed to fluconazole, a finding that gives a matched odds ratio (adjusted for race, route of HIV infection, and CD4 count) of 0·08 (95% Cl 0·01-0·84; p=0·035) and indicates a 92% protective efficacy. We conclude that fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients with a CD4 count less than 250/uL. Although the optimum dose and duration of fluconazole could not be determined, our results suggest that less than daily use was effective in the prevention of cryptococcal meningitis.

Cryptococcal meningitis in HIV-infected patients

Cryptococcal meningitis in HIV-infected patients

The value of cryptococcal serum antigen screening among HIV-positive/AIDS patients in Kinshasa, Zaire

Cryptococcal meningitis is a frequently observed opportunistic infection in AIDS patients in Zaire and other countries in Central Africa. The prognosis in those patients is very poor because of the advanced stage of their cryptococcal disease at presentation. To improve the prognosis of cryptococcal meningitis in HIV-infected patients through earlier diagnosis, a routine serum cryptococcal antigen screening was performed on 450 HIV-positive/AIDS patients seen at the Cliniques Universitaires de Kinshasa between 1 January 1988 and 31 August 1988. Cryptococcal antigen was detected in the sera of 55 (12.2%) of them. Cerebrospinal fluid was obtained from 44 of these 55 patients and the presence of Cryptococcus neoformans was demonstrated by direct microscopy and culture in 29 (66%) of them.