Differences in Immunologic Factors Among Patients Presenting with Altered Mental Status During Cryptococcal Meningitis.
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ABSTRACT:
SUBMITTER: Lofgren S
PROVIDER: S-EPMC5388270 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
Differences in Immunologic Factors Among Patients Presenting with Altered Mental Status During Cryptococcal Meningitis.
Lofgren Sarah S Hullsiek Kathy H KH Morawski Bozena M BM Nabeta Henry W HW Kiggundu Reuben R Taseera Kabanda K Musubire Abdu A Schutz Charlotte C Abassi Mahsa M Bahr Nathan C NC Tugume Lillian L Muzoora Conrad C Williams Darlisha A DA Rolfes Melissa A MA Velamakanni Sruti S SS Rajasingham Radha R Meintjes Graeme G Rhein Joshua J Meya David B DB Boulware David R DR
The Journal of infectious diseases 20170301 5
Altered mental status in cryptococcal meningitis results in poorer survival, but underlying causes of altered mentation are poorly understood. Within two clinical trials, we assessed risk factors for altered mental status (GCS score<15) considering baseline clinical characteristics, CSF cytokines/chemokines, and antiretroviral therapy. Among 326 enrolled participants, 97 (30%) had GCS<15 and these patients had lower median CSF cryptococcal antigen titers (P = .042) and CCL2 (P = .005) but higher ...[more]
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Project description:UnlabelledIn sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th(2) response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality.ImportanceCryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response.
| S-EPMC3448160 | biostudies-literature
Project description:BACKGROUND:Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. METHODS:We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. RESULTS:We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ?5 white cells/?L) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91). CONCLUSIONS:Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. CLINICAL TRIALS REGISTRATION:NCT01802385.
| S-EPMC6541705 | biostudies-literature
Project description:Cryptococcus neoformans, an encapsulated basidiomycete fungus of medical importance, is capable of crossing the blood-brain barrier and causing meningitis in both immunocompetent and immunocompromised individuals. To gain insight into the adaptation of the fungus to the host central nervous system (CNS), serial analysis of gene expression (SAGE) was used to characterize the gene expression profile of C. neoformans cells recovered from the CNS of infected rabbits. A SAGE library was constructed, and 49,048 tags were sequenced; 16,207 of these tags were found to represent unique sequences or tag families. Of the 304 most-abundant tags, 164 were assigned to a putative gene for subsequent functional grouping. The results (as determined according to the number of tags that identified genes encoding proteins required for these functions) indicated that the C. neoformans cells were actively engaged in protein synthesis, protein degradation, stress response, small-molecule transport, and signaling. In addition, a high level of energy requirement of the fungal cells was suggested by a large number of tags that matched putative genes for energy production. Taken together, these findings provide the first insight into the transcriptional adaptation of C. neoformans to the host environment and identify the set of fungal genes most highly expressed during cerebrospinal fluid infection.
| S-EPMC326655 | biostudies-literature
Project description:Definitive diagnosis of nonconvulsive seizures (NCS) can be made only by electroencephalography, and delay in diagnosis can increase morbidity, resource utilization, and length of hospitalization. We performed an evidence-based literature review to estimate the prevalence of NCS in patients with altered mental status (AMS) of unknown cause. PUBMED, EMBASE, the Cochrane Library, and other resources were searched for studies that included AMS and seizure as topics. The resulting 276 articles were screened for predetermined inclusion and exclusion criteria, leaving 5 studies enrolling 478 patients for review. The prevalence of NCS in patients with AMS ranged from 8 to 30% (overall prevalence of 21.5%, 95% CI: 18-25%), suggesting that the prevalence of NCS is sufficiently high to consider routine use of urgent electroencephalography in such patients. However, methodological weaknesses limit the generalizability of the results. A large, prospective study enrolling and screening for NCS in all patients who present with acute AMS is needed.
| S-EPMC3185184 | biostudies-literature
Project description:BackgroundCryptococcal meningitis is an uncommon but severe complication of sarcoidosis.MethodsWe present 2 patients with cryptococcal meningitis complicating sarcoidosis and compared findings with 38 cases reported in the literature.ResultsWhen analyzing our patients and 38 cases reported in the literature, we found that median age of sarcoidosis patients with cryptococcal meningitis was 39 years (range 30-48); 27 of 33 reported cases (82%) had a history of sarcoidosis. Only 16 of 40 patients (40%) received immunomodulating therapy at the time of diagnosis of cryptococcal meningitis. The diagnosis of cryptococcal meningitis was delayed in 17 of 40 patients (43%), mainly because of the initial suspicion of neurosarcoidosis. Cerebrospinal fluid (CSF) examination showed mildly elevated white blood cell count (range 23-129/mm). Twenty-nine of 32 cases (91%) had a positive CSF culture for Cryptococcus neoformans and 25 of 27 cases (93%) had a positive CSF C neoformans antigen test. CD4 counts were low in all patients in whom counts were performed (84-228/mL). Twelve patients had an unfavorable outcome (32%), of which 7 died (19%) and 24 patients (65%) had a favorable outcome. The rate of unfavorable outcome in patients with a delayed diagnosis was 7 of 17 (41%) compared to 5 of 28 (21%) in patients in whom diagnosis was not delayed.ConclusionCryptococcal meningitis is a rare but life-threatening complication of sarcoidosis. Patients were often initially misdiagnosed as neurosarcoidosis, which resulted in considerable treatment delay and worse outcome. CSF cryptococcal antigen tests are advised in patients with sarcoidosis and meningitis.
| S-EPMC5008555 | biostudies-literature
Project description:Single-end reads of serial isolates from cryptococcal meningitis cases
| PRJEB28390 | ENA
Project description:ObjectivesTo determine whether altered mental status (AMS) as a presenting symptom in older adults with COVID-19 is independently associated with adverse outcomes.MethodsA retrospective single center observational study of admitted patients (n = 421) age greater than 60 and a positive COVID-19 test. Outcomes included mortality, intubation, acute respiratory distress syndrome, acute kidney injury, and acute cardiac injury. Multivariate regression analysis was used to determine if presenting with AMS was associated with adverse outcomes.ResultsThere was an increased risk of mortality (RR 1.29, 95% CI 1.05-1.57), intubation (RR 1.52, 95% CI 1.09-2.12) and AKI (RR 1.42, 95% CI 1.13-1.78) in patients that presented with AMS.ConclusionsDuring a global pandemic, prognostic indicators are vital to help guide the clinical course of patients, reduce healthcare cost, and preserve life. Our study suggests that AMS can play a major role in diagnostic algorithms in older adults with COVID-19.
| S-EPMC8196474 | biostudies-literature
Project description:IntroductionThe first-line combination therapy for HIV-associated cryptococcal meningitis (CM), a condition of high mortality particularly in the first two weeks of treatment, consists of amphotericin B plus flucytosine (5-FC). Given that 5-FC remains unavailable in many countries, the knowledge of factors influencing mycological clearance in patients treated with second-line therapy could contribute to effective management.ObjectivesTo determine the factors associated with the clearance of Cryptococcus sp. from the cerebrospinal fluid by the second week of effective antifungal therapy (early mycological clearance) in HIV-associated CM.MethodsRetrospective cohort study based on secondary data corresponding to HIV-associated CM cases hospitalized at a tertiary health care center in Lima, Peru where 5-FC remains unavailable. Risk factors associated with early mycological clearance were analyzed by generalized linear regression models.ResultsFrom January 2000 to December 2013, 234 individuals were discharged with a diagnosis of HIV-associated CM; in 215 we retrieved the required data. The inpatient mortality was 20% (43/215), 15 of them in the first two weeks of treatment. In the final model (157 cases), adjusted for age, previous episode of CM, ART use, type of antifungal treatment, raised intracranial pressure, frequency of therapeutic lumbar punctures, baseline fungal burden and treatment period, the factors associated with early mycological clearance were: Amphotericin B deoxycholate plus fluconazole as combination therapy (RR, 1.56; 95% CI, 1.14-2.14); severe baseline intracranial pressure (≥35 cm H2O) (RR, 0.57; 95% CI, 0.33-0.99); and baseline fungal burden over 4.5 log10 CFU/mL (RR, 0.61 95% CI: 0.39-0.95).ConclusionsIn a setting without access to first-line therapy for CM, the combination therapy with amphotericin B deoxycholate plus fluconazole was positively associated with early mycological clearance, while high fungal burden and severe baseline intracranial pressure were negatively associated, and thus related to failure.
| S-EPMC5371305 | biostudies-literature
Project description:BackgroundCombination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.MethodsWe conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks.ResultsA total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy.ConclusionsAmphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).
| S-EPMC3978204 | biostudies-literature
Project description:ObjectiveMycobacterium tuberculosis and Cryptococcus neoformans are major causes of meningitis in HIV-1-infected patients. Identifying differences in the inflammatory profiles of HIV-1-associated tuberculous meningitis (TBM) and cryptococcal meningitis may inform differences in immunopathogenic mechanisms in these diseases. In this study we compared the clinical and inflammatory features of HIV-1-associated TBM, and cryptococcal meningitis.MethodsA prospective study of HIV-1-infected adults who presented with either TBM [antiretroviral therapy (ART)-naive] or cryptococcal meningitis (regardless of ART prescription). Clinical and laboratory findings and concentrations of 40 inflammatory mediators measured in cerebrospinal fluid (CSF, 33 paired with blood) were compared between TBM and cryptococcal meningitis patients regardless of ART prescription and between TBM and cryptococcal meningitis patients not receiving ART.ResultsClinical and laboratory findings were similar in TBM (n=34) and cryptococcal meningitis (n?=?19; ART prescribed: n?=?10, no ART prescribed: n?=?9). Exceptions included a higher median CD4 cell count [interquartile: 113 (69-199) vs. 25 (8-49) cells/?l, P?=?0.0001] and higher HIV-1 median viral load [plasma: 5.46 (4.82-5.89) vs. 4.87 (4.36-5.17) log10copies/ml, P?=?0.037; CSF: 6.05 (5.43-6.56) vs. 5.56 (4.52-5.80) log10copies/ml, P?=?0.03] in TBM vs. cryptococcal meningitis patients not receiving ART. CSF interleukin (IL)-17A was lower in TBM compared with cryptococcal meningitis [1.00 (0.25-2.35) vs. 9.31 (1.24-23.36) pg/ml, P-adjusted?=?0.03].ConclusionDespite presenting with higher peripheral CD4 cell counts, TBM patients also presented with higher HIV-1 viral loads compared with cryptococcal meningitis patients, suggesting a greater propensity of M. tuberculosis compared with C. neoformans to increase HIV-1 replication in vivo. CSF IL-17A was lower in TBM; its role in the immunopathogenesis of TBM and cryptococcal meningitis deserves further research.
| S-EPMC4711381 | biostudies-literature