Cerebrospinal Fluid Cryptococcal Antigen Research Articles

Anti-GM-CSF autoantibodies predict outcome of cryptococcal meningitis in patients not infected with HIV: A cohort study

ObjectivesTo explore the seroprevalence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in non-HIV cryptococcal meningitis (CM) and assess its predictive value for survival. MethodsThis is a retrospective study of 12 years of non-HIV CM. We detected serum anti-GM-CSF autoantibodies, and evaluated the clinical features and outcomes, together with the exploration of prognostic factors for 2-week and 1-year survival. ResultsA total of 584 non-HIV CM cases were included. 301 of 584 patients (51.5%) were phenotypically healthy. 264 Cryptococcus isolates were obtained from cerebrospinal fluid (CSF) culture, of which 251 were identified as C. neoformans species complex and 13 as C. gattii species complex. Thirty-seven of 455 patients (8.1%) tested positive for serum anti-GM-CSF autoantibodies. Patients with anti-GM-CSF autoantibodies were more susceptible to C. gattii species complex infection (66.7% vs. 6.3%; p < 0.001) and more likely to develop pulmonary mass lesions with a diameter >3 centimetres (42.9% vs. 6.5%; p 0.001). Of 584 patients 16 (2.7%) died within 2 weeks, 77 of 563 patients (13.7%) died at 1 year, and 93 of 486 patients (19.1%) lived with disabilities at 1 year. Univariant Cox regression analysis found that anti-GM-CSF autoantibodies were associated with lower 1-year survival (HR, 2.66; 95% CI, 1.34–5.27; p 0.005). Multivariable Cox proportional hazards modelling revealed that CSF cryptococcal antigen titres ≥1:1280 were associated with both, reduced 2-week and 1-year survival rates (HR, 5.44; 95% CI, 1.23–24.10; p 0.026 and HR, 5.09; 95% CI, 1.95–13.26; p 0.001). DiscussionPresence of serum anti-GM-CSF autoantibodies is predictive of poor outcomes, regardless of host immune status and the causative Cryptococcus species complex.

Pitfalls in the diagnosis of Cryptococcal Meningoencephalitis. (P1-10.001)

<h3>Objective:</h3> We report a case of cryptococcal meningoencephalitis which challenges the prevailing theory of antigen detection being more sensitive for the diagnosis than CSF biofire. <h3>Background:</h3> 60 year old immunocompetent male was admitted with episodes of unsteady gait, staring and picking at his clothes. Examination revealed lethargy and constructional apraxia. MRI brain showed ventriculomegaly. CSF analysis showed opening pressure 34cm H2O, protein 134, WBC count 62 with 98% lymphocytes. CSF multiplex PCR panel and Cryptococcal antigen were negative. He was started on Topiramate and Acetazolamide. As he did not improve, repeat lumbar puncture was obtained six days after admission. Repeat CSF PCR panel was positive for cryptococcal DNA, however both serum and CSF cryptococcal antigen were negative. CD4 count was 977 cells/uL. He was started on induction therapy for Cryptococcal meningoencephalitis. A lumbar drain was placed for secondary hydrocephalus. He completed 12 months of maintenance therapy and is doing well on follow up. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> Detection of the capsular antigen by lateral flow assay has widely been believed to be the most reliable diagnostic method for Cryptococcal Meningoencephalitis. The cryptococcal antigen in the specimen diluent binds to gold conjugated anticryptococcal monoclonal antibodies on the test strip, producing a detection line. This test is based on an optimal antigen-antibody ratio, known as the zone of equivalence. A false negative result might be obtained in case of antigen levels greater than 0.14 mg/L (postzone phenomenon), as the excess antigen binds colloidal gold instead of immobilized antibody in the test area of the strip. Hospital laboratories do not routinely test for this occurrence, which can lead to a missed diagnosis. <h3>Conclusions:</h3> Using a greater dilution ratio of 1:5 (semi quantitative) or 1:9, instead of 1:2 (qualitative) can bring the antigen titer in the zone of equivalence. Using an alternate diagnostic method such as CSF biofire is another option. <b>Disclosure:</b> Dr. Nene has nothing to disclose. Dr. Mahapatra has nothing to disclose. Dr. Duleep has nothing to disclose.

Cryptococcal Meningoencephalitis and Immune Reconstitution Inflammatory Syndrome in a patient on Tocilizumab Therapy: A Case Report (P1-10.005)

<h3>Objective:</h3> To describe a case of cryptococcal meningoencephalitis complicated by immune reconstitution inflammatory syndrome (IRIS), vasculitis, ischemic strokes, and hydrocephalus. <h3>Background:</h3> Cryptococcus neoformans is the most common cause of fungal meningitis worldwide and typically affects individuals with defects in cell-mediated immunity. A 71-year-old female with giant cell arteritis on daily prednisone and monthly Tocilizumab infusions presented with worsening headaches for 2 weeks and new-onset confusion for 3 days. Initial workup revealed hyponatremia (sodium 125 mmol/L) and community acquired pneumonia. She was treated with antibiotics, but her mental status rapidly declined necessitating endotracheal intubation. MRI Brain demonstrated multifocal areas of diffusion restriction in the bilateral cerebral and cerebellar hemispheres, basal ganglia, and brainstem with diffuse leptomeningeal enhancement. Cerebrospinal fluid (CSF) studies revealed an elevated opening pressure of 28 cm H₂O, positive CSF cryptococcal antigen, and CSF fungal cultures grew cryptococcus neoformans. She was started on empiric liposomal amphotericin B and flucytosine before the cryptococcal antigen and cultures resulted. Despite treatment, her neurological status continued to decline with repeat MRI showing new ischemic infarctions, subarachnoid hemorrhages, and leptomeningeal and parenchymal enhancement. Digital subtraction angiography revealed cerebral vasospasm and possible vasculitis. Repeat lumbar puncture demonstrated persistently elevated opening pressure, continued pleocytosis, and increased protein. She was continued on antifungal therapy and received IV methylprednisolone for IRIS. She additionally underwent ventriculoperitoneal (VP) shunt placement. Despite these interventions, her clinical status continued to deteriorate and she was palliatively extubated. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> N/A <h3>Conclusions:</h3> This patient presented with cryptococcal meningoencephalitis in the setting of immune suppression from prednisone and tocilizumab, a monoclonal antibody that targets the IL-6 receptor. Despite early and appropriate treatment, she continued to worsen with multiple complications including IRIS, a dysfunctional inflammatory response to infection precipitated by immune recovery. In patients treated appropriately for cryptococcal meningoencephalitis, a failure to respond should raise concern for complicating conditions. <b>Disclosure:</b> Dr. Navalkar has nothing to disclose. Dr. Sui has nothing to disclose. The institution of Dr. Bashir has received research support from NIH. The institution of Dr. Bashir has received research support from PICORI. The institution of Dr. Bashir has received research support from Sanofi. Dr. Bashir has received research support from GWSP. The institution of Dr. Bashir has received research support from Roche. The institution of Dr. Bashir has received research support from Novartis. The institution of Dr. Bashir has received research support from Hoffmann-La Roche.

Lack of Association between YEASTONE Antifungal Susceptibility Tests and Clinical Outcomes of Cryptococcus Meningitis.

The relation between antifungal susceptibility and treatment outcomes is not well-characterized. There is paucity of surveillance data for cerebrospinal fluid (CSF) isolates of cryptococcus investigated with YEASTONE colorimetric broth microdilution susceptibility testing. A retrospective study of laboratory-confirmed cryptococcus meningitis (CM) patients was conducted. The antifungal susceptibility of CSF isolates was determined using YEASTONE colorimetric broth microdilution. Clinical parameters, CSF laboratory indices, and antifungal susceptibility results were analyzed to identify risk factors for mortality. High rates of resistance to fluconazole and flucytosine were observed in this cohort. Voriconazole had the lowest MIC (0.06 µg/mL) and lowest rate of resistance (3.8%). In a univariate analysis, hematological malignancy, concurrent cryptococcemia, high Sequential Organ Failure Assessment (SOFA) score, low Glasgow coma scale (GCS) score, low CSF glucose level, high CSF cryptococcal antigen titer, and high serum cryptococcal antigen burden were associated with mortality. In a multivariate analysis, meningitis with concurrent cryptococcemia, GCS score, and high CSF cryptococcus burden, were independent predictors of poor prognosis. Both early and late mortality rates were not significantly different between CM wild type and non-wild type species.

Sterile Cerebrospinal Fluid Culture at Cryptococcal Meningitis Diagnosis Is Associated with High Mortality.

Cryptococcus is the leading cause of AIDS-related meningitis in sub-Saharan Africa. The clinical implications of a sterile cerebrospinal fluid (CSF) culture among individuals diagnosed with cryptococcal meningitis using CSF cryptococcal antigen (CrAg) are unclear. We prospectively enrolled 765 HIV-positive Ugandans with first-episode cryptococcal meningitis from November 2010 to May 2017. All persons were treated with amphotericin-based induction therapy. We grouped participants by tertile of baseline CSF quantitative Cryptococcus culture burden and compared clinical characteristics, CSF immune profiles, and 18-week mortality. We found 55 (7%) CSF CrAg-positive participants with sterile CSF cultures. Compared to the non-sterile groups, participants with sterile CSF cultures had higher CD4 counts, lower CSF opening pressures, and were more frequently receiving ART. By 18 weeks, 47% [26/55] died in the sterile culture group versus 35% [83/235] in the low culture tertile, 46% [107/234] in the middle tertile, and 56% [135/241] in the high tertile (p < 0.001). The sterile group had higher levels of CSF interferon-gamma (IFN-γ), IFN-α, interleukin (IL)-6, IL-17, G-CSF, GM-CSF, and chemokine CXCL2 compared with non-sterile groups. Despite persons with sterile CSF cultures having higher CD4 counts, lower CSF opening pressures, and CSF cytokine profiles associated with better Cryptococcus control (e.g., IFN-γ predominant), mortality was similar to those with higher fungal burdens. This unexpected finding challenges the traditional paradigm that increasing CSF fungal burdens are associated with increased mortality but is consistent with a damage-response framework model.

869. Oral Encochleated Amphotericin B for Cryptococcal Meningitis: a Phase II Randomized Trial

Abstract Background Intravenous (IV) amphotericin B is the gold standard treatment of severe mycoses. A new orally absorbed, less-toxic formulation of amphotericin has been developed (Matinas Biopharma). We evaluated the efficacy of this novel anti-fungal agent amongst adults with cryptococcal meningitis. Methods We conducted a phase II randomized clinical trial testing oral encochleated amphotericin B (cAMB) versus IV amphotericin B for first episode cryptococcal meningitis in Kampala, Uganda from December 2020 to August 2021. Participants were HIV-positive, CSF cryptococcal antigen (CrAg) positive, and had the capacity to consent and take oral medications (GCS=15). Participants in the experimental arm received two loading doses of either IV deoxycholate amphotericin B 1.0 mg/kg/day or liposomal amphotericin 3 mg/kg/day, followed by 1.8g oral cAMB daily in 6 divided doses through 2 weeks with flucytosine (5FC) at 100mg/kg/day, and thereafter cAMB at 1.2g daily in 4 divided doses through 6 weeks. Participants in the control arm received 7 days of IV amphotericin B (deoxycholate or liposomal) with 5FC, then 7 days of fluconazole 1200mg/day. After 14 days, all participants received fluconazole 800mg/day through 10 weeks and thereafter a maintenance dose of 200mg/day. Results We randomized 40 participants to oral cAMB + 5FC and 30 control participants to IV amphotericin + 5FC. With cAMB the 30-day survival was 97.5% (39/40) and 18-week survival was 90% (36/40) compared with 87% (26/30) 18-week survival in IV amphotericin controls. The CSF Early Fungicidal Activity (EFA) was lower with oral cAMB (mean EFA = 0.42 log10Cryptococcus CFU/mL/day; 95%CI, 0.29 to 0.54) versus IV amphotericin (mean EFA = 0.52 log10 CFU/mL/day; 95%CI, 0.39 to 0.66). Among those CSF culture positive at baseline, CSF sterility was achieved by 2 weeks in 65% (24/37) of cAMB participants and 68% (17/25) of controls. Grade &amp;gt;=3 laboratory adverse events were more common with IV amphotericin. Grade 3–4 anaemia occurred in 10% (n=4) with cAMB versus 37% (n=11) with IV amphotericin. Grade 3 hypokalaemia (&amp;lt; 3mEq/L) occurred in 5% (n=2) with cAMB versus 27% (n=8) with IV amphotericin. Conclusion Novel oral cAMB appears to be a safe agent with promising efficacy for HIV-related cryptococcal meningitis. Disclosures All Authors: No reported disclosures.

2361. Timing of antiretroviral therapy prior to diagnosis of cryptococcal meningitis

Abstract Background Cryptococcal meningitis (CM) is the most common cause of meningitis in adults in Sub-Saharan Africa (SSA), causing significant morbidity and mortality in people living with HIV. Early initiation of antiretroviral therapy (ART) after cryptococcal diagnosis is associated with increased mortality. With increasing access to ART in SSA, an increasing proportion of CM patients are now presenting on ART, and outcomes remain unclear. Methods We performed a retrospective study of 724 participants with positive CSF cryptococcal antigen in four clinical trials performed in Uganda from June 2017 to February 2022. We compared survival outcomes based on ART experience at the time of CM diagnosis. We had implemented structured ART interruption when ART had recently been initiated (&amp;lt; 2weeks). Results Sixty-one percent (445/724) of participants were ART-naïve at the time of CM diagnosis. Compared to those receiving ART, those ART-naïve had lower CD4 counts and higher Cryptococcus colony forming units (CFUs)/mL on quantitative CSF culture (p&amp;lt; 0.001). However, the two-week mortality between ART-naïve and ART-experienced groups did not statistically differ (16.6% vs. 16.8%, Hazard Ratio = 0.97 (95%CI, 0.67–1.40) as well as for ten-week mortality (25.4% vs. 26.2%, Hazard Ratio = 0.98 (95%CI, 0.73–1.31)). Further stratification of ART-experienced participants by length of ART experience (&amp;lt; =2 weeks vs. &amp;gt;2 weeks prior to diagnosis) and ART continuation status (ART continued vs. discontinued if ART started &amp;lt; =2 weeks prior to diagnosis) demonstrated no statistically significant difference between the groups for two- or ten-week mortality. Conclusion Cryptococcal diagnosis after ART initiation is now increasingly common. In this study, we found no significant mortality differences between ART-naïve and ART-experienced participants at 2 weeks and 10 weeks. Accounting for length of ART experience did not change these short-term mortality outcomes. One potential limitation of our study is different CM treatment regimens were used across clinical trials. Disclosures All Authors: No reported disclosures.

PULMONARY CRYPTOCOCCUS: THE GREAT IMPERSONATOR

PULMONARY CRYPTOCOCCUS: THE GREAT IMPERSONATOR

Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study

Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38·7%) individuals received a flucytosine-containing regimen and 943 (61·3%) received another regimen. The median age was 36 years (IQR 32-43) and 906 (58·9%) participants were male and 633 (41·1%) were female. The crude in-hospital case-fatality ratio was 23·9% (95% CI 20·0-27·0; 143 of 596) in those treated with flucytosine-containing regimens and 37·2% (95% CI 34·0-40·0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1·95 [95% CI 1·53-2·48]; p<0·0001) and those who were antiretroviral treatment-experienced (aOR 1·30 [1·02-1·67]; p=0·033) were more likely to receive flucytosine. After adjusting for relevant confounders, flucytosine treatment was associated with a 53% reduction in mortality (aOR 0·47 [95% CI 0·35-0·64]; p<0·0001). Among survivors, the median length of hospital admission in the flucytosine group was 11 days (IQR 8-15) versus 17 days (13-21) in the comparison group (p=0·0010). In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. National Institute for Communicable Diseases, a Division of the National Health Laboratory Service. For the Zulu translation of the abstract see Supplementary Materials section.

Clinical and microbiologic outcomes of central nervous system cryptococcosis: Re-examining the need for a 2-week cerebrospinal fluid analysis.

Cryptococcus spp. infection involving the central nervous system (CNS) is associated with poor outcomes. Current guidelines recommend repeating a cerebrospinal fluid (CSF) fungal culture after 2 weeks of treatment to evaluate for clearance. However, this practice has not clearly been associated with outcomes. We sought to assess the relationship between CSF fungal clearance at 2 weeks and 12-month mortality in patients with CNS cryptococcosis. This is a retrospective cohort study from 2011 to 2020 of patients with CNS cryptococcosis. Factors associated with 12-month mortality were assessed with Fisher's exact test for categorical variables and Mann-Whitney test for continuous variables. Among 51 patients with CNS cryptococcosis, 42 (82.4%) were initially CSF culture positive. Among 27 patients with follow-up CSF culture at 2 weeks, 6 (22.2%) had a positive result. Factors associated with a positive CSF culture at 2 weeks were an initial CSF cryptococcal antigen titre ≥1:2560, fungaemia, and an elevated intracranial pressure requiring therapeutic lumbar punctures. The 12-month mortality rate was 33.3%, and this was significantly associated with baseline fungaemia, extra-CNS cryptococcal involvement and requirement of intensive care unit level of care. Lack of CSF culture clearance by 2 weeks was not associated with 12-month mortality. CNS cryptococcosis has a high mortality rate. A markedly elevated CSF cryptococcal antigen, and opening CSF pressure was associated with lack of CSF culture clearance at 2 weeks of treatment. Severe disseminated disease and cryptococcemia were associated with 12-month mortality.

Clinical Characteristics and Risk Factors for Mortality in Cryptococcal Meningitis: Evidence From a Cohort Study.

IntroductionDespite advances in the diagnosis and management, cryptococcal meningitis (CM) is still associated with high mortality due to insufficient knowledge about clinical characteristics and risk factors for poor outcomes. The aim of the present study is to provide additional evidence for regarding clinical characteristics, diagnosis, and factors associated with increased risk of mortality in CM patients.MethodsIn this cohort study, we included eligible patients consecutively admitted to West China Hospital between January 2009 and December 2018. The clinical characteristics and diagnosis method of cerebrospinal fluid culture and India ink stain were analyzed. Independent risk factors were identified by a multivariable logistic regression.ResultsA total of 186 CM patients were included in the analysis. After a 1-year follow-up, 63 patients had died. Headache is the most common presenting symptom (97.3%), followed by vomiting (72%), fever (71.5%), altered consciousness (45.7%), abnormal vision (32.8%), and seizure (15.1%). Older age, altered consciousness or seizures, lower white blood cell count or total protein in cerebrospinal fluid (CSF), and unidentified CSF cryptococcal antigen (CrAg) are all factors associated with increasing risk of death (P < 0.05). We also found a dose-dependent trend between the number of symptoms and risk of death (trend p < 0.001). Multivariate logistic regression revealed that age (P = 0.004, OR = 1.042, 95% CI 1.013–1.071), seizure (P = 0.025, OR = 3.105, 95% CI 1.152–8.369), altered consciousness (P < 0.001, OR=6.858, 95% CI 3.063–15.38), and unidentified CSF CrAg are the independent prognostic factors. In addition, we observed that diagnosis of 28.5% and 22.5% CM could not be established by a single testing of CSF India ink stain or culture, respectively. Use of multiple testing methods or combination of the two assays increases the detection rate.ConclusionOur data show that older age, seizures, altered consciousness, and an inability to detect CSF CrAg are the independent risk factors of death within 1 year in CM patients. Moreover, we recommend use of multiple testing methods with CSF culture and India ink stain. Combined testing with both assays should be considered for initial CM diagnosis.

Epidemiological and Clinical Characteristics, Antifungal Susceptibility, and MLST-Based Genetic Analysis of Cryptococcus Isolates in Southern Taiwan in 2013-2020.

Cryptococcal meningoencephalitis (CM) is a treatable condition, but it leads to excessive morbidity and mortality. We collected 115 non-duplicated Cryptococcus clinical isolates during 2013–2020 in southern Taiwan to perform antifungal susceptibility testing. Multi-locus sequence typing was performed on 96 strains from patients with CM (n = 47) or cryptococcemia (n = 49). In addition, the epidemiological and clinical characteristics of patients with CM during 2013–2020 (n = 47) were compared with those during 2000–2010 (n = 46). During 2013–2020, only one C. neoformans isolate (0.9%) had a fluconazole minimum inhibitory concentration of >8 μg/mL. Amphotericin B (AMB), flucytosine (5FC), and voriconazole were highly active against all C. neoformans/C. gattii isolates. The most common sequence type was ST5. Among these 47 patients with CM, cerebrospinal fluid cryptococcal antigen (CSF CrAg) titer >1024 was a significant predictor of death (odds ratio, 48.33; 95% CI, 5.17–452.06). A standard induction therapy regimen with AMB and 5FC was used for all patients during 2013–2020, but only for 2.2% of patients in 2000–2010. The in-hospital CM mortality rate declined from 39.1% during 2000–2010 to 25.5% during 2013–2020, despite there being significantly younger patients with less CSF CrAg >1024 during 2000–2010. The study provides insight into the genetic epidemiology and antifungal susceptibility of Cryptococcus strains in southern Taiwan. The recommended antifungal drugs, AMB, 5FC, and FCZ, remained active against most of the Cryptococcus strains. Early diagnosis of patients with CM and adherence to the clinical practice guidelines cannot be overemphasized to improve the outcomes of patients with CM.

A case report of a brain herniation secondary to cryptococcal meningitis with elevated intracranial pressure in a patient with Human Immunodeficiency Virus/Acquired immunodeficiency syndrome (HIV/AIDS)

BackgroundCryptococcal meningitis is a major opportunistic infection in individuals with HIV. The worldwide annual incidence is estimated to be approximately one million cases per year, with the most significant burden in sub-Saharan Africa. HIV-associated cryptococcal meningitis continues to have a high mortality rate despite widespread availability and use of HAART.Case36-year-old male with a past medical history of AIDS and a CD4 count of 35 cells/mm3 presented with altered mental status initially thought to be related to using crystalline methamphetamine as reported by EMS. However, a lumbar puncture performed in the emergency department showed elevated CSF opening pressure of 29 cmH2O and positive CSF and serum cryptococcal antigen. The patient was admitted and commenced treatment according to the current IDSA guideline but continued to have waxing and waning mental status. On the fourth day of admission, he complained of headache, had a witnessed seizure, and was taken emergently for a CT scan of the brain, which was negative for any acute intracranial process, but suffered a cardiac arrest before it could be done. He was intubated and transferred to the intensive care unit. CT brain follow-up showed anoxic encephalopathy, development of marked cerebral edema, and complete effacement of the basilar cisterns, suggestive of downward transtentorial herniation; he continued to deteriorate and expired on the seventh day of admission.Objectives1.Describe a case of brain death secondary to increased intracranial pressure due to cryptococcal meningitis in a patient with HIV/AIDS.2.Explain the mechanisms of elevation in intracranial pressure in patients with cryptococcal meningitis.3.Discuss the options for managing elevated intracranial pressure in patients with cryptococcal meningitis.4.Create awareness in the medical community about the importance of prompt and efficient management of increased intracranial pressure in patients with cryptococcal meningitis.ConclusionThis case highlights the importance of aggressive management of elevated intracranial pressure in cryptococcal meningitis. It reiterates the need for more data regarding the optimal timing and frequency of therapeutic lumbar puncture and the use of temporary lumbar drainage catheters and ventriculostomy to manage this potentially fatal complication.

Postrenal transplant disseminated cryptococcosis presenting as a syndrome of inappropriate antidiuretic hormone secretion - A case report

Cryptococcosis is the most common invasive fungal infection to involve the central nervous system in the posttransplant period. Cryptococcal meningitis, which constitutes disseminated cryptococcosis, can present with nonspecific signs and symptoms leading to a diagnostic challenge. There are case reports of cryptococcal meningitis presenting as a syndrome of inappropriate antidiuretic hormone secretion (SIADH). A 54-year-old male with autosomal dominant polycystic kidney disease was a live-related renal allograft recipient 1 year back and presented with complaints of generalized weakness and imbalance while walking. His serum sodium on admission was 117 mEq/L and investigations were suggestive of SIADH. He was given hypertonic saline and fluid restriction. However, he had a recurrence of symptomatic hyponatremia. He was evaluated for the cause of SIADH. Chest X-ray and computed tomography of the thorax revealed patchy consolidation. In view of persistent giddiness and imbalance, lumbar puncture was done and cerebrospinal fluid (CSF) analysis showed hypoglycorrhachia with elevated protein and cell counts. CSF cryptococcal antigen test was positive. He was thus diagnosed with disseminated cryptococcosis with meningitis and pulmonary involvement. He received amphotericin B deoxycholate for 4 weeks, followed by fluconazole. He improved symptomatically and serum sodium normalized thereafter. This is the first case of disseminated cryptococcosis presenting with SIADH in the postrenal transplant period with one prior case being reported after a liver transplant. This highlights the variable presentations of cryptococcosis and the need to evaluate the primary cause in posttransplant patients presenting with hyponatremia.

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

Evaluation of point of care serum cryptococcal antigen by lateral flow immunoassay for diagnosis of cryptococcosis and cryptococcal meningitis in HIV-positive patients.

Background:Cryptococcal meningitis (CM) is the initial acquired immunodeficiency syndrome (AIDS) defining illness in 2% of patients with CD4 levels <100/μL and a leading cause of mortality in AIDS in the developing world. It is the most common opportunistic infection of the central nervous system in AIDS in various Indian studies. Detection of serum cryptococcal antigen (SCRAG) is the most widely used diagnostic method for cryptococcosis. The presence of cerebrospinal fluid cryptococcal antigen (CSF CRAG) is diagnostic of CM. CRAG can be determined by latex agglutination (LAT), enzyme-linked immunosorbent assay and now, by lateral flow (LFA)immunoassay. LFA is a point of care test that rapidly detects CRAG.Aims and Objectives:This study compares LAT and LFA for the detection of serum CRAG and diagnosing CM.Materials and methods:Two hundred and ten patients of HIV/AIDS were submitted to SCRAG LFA by dipstick. A sample was also sent to laboratory for SCRAG by LAT. CSF examination was done for those who were positive for SCRAG LFA and those who had symptoms suggestive of meningitis. SCRAG by LFA was compared with SCRAG by LAT, CSF CRAG by LAT and LFA, CSF cryptococcal culture and CSF India ink examination for Cryptococcus.Results:Fifteen patients were found positive for SCRAG by LFA dipstick. All of them were also positive for SCRAG by LAT. Twelve of them had C. D4 count below below 100 cells/mm3. CSF CRAG was positive in all 12 SCRAG positive who were submitted to CSF examination.Conclusion:We found that serum detection of CRAG by LFA dipstick is as sensitive as CRAG detection in serum by LAT and CSF CRAG detection by LFA and LAT. It is thus a rapid test for diagnosing CM in HIV patients with low CD4 counts.

Cryptococcal meningitis in a case of mixed connective tissue disorder: A rare case report

We report a case of cryptococcal meningitis in a 48-year-old woman with underlying mixed connective tissue disease. She presented with multiple joint pains and low-grade fever for 3 months, headache for 1 month and weakness of all four limbs for 15 days. The neck was stiff, and Kernig's sign was positive. The cerebrospinal fluid cryptococcal antigen test was positive. Autoimmune profile revealed positive antinuclear and U1 ribonucleoprotein antibodies. Magnetic resonance imaging of the brain showed T2/fluid-attenuated inversion recovery hyperintensity in the midbrain and upper pons. The patient gradually improved on antifungal therapy.

Fatal adenovirus meningoencephalitis in end stage renal disease patient

Background: Severe disseminated adenovirus infections that presented with severe pneumonia in respiratory failure, encephalitis or septicemic shock causes high mortality in immunocompromised patients. We reported a case ofadenovirus encephalitis in an end stage renal disease (ESRD) who presented with seizure, subsequently adenovirus DNA was detected from his cerebrospinal fluid with typical findings on electroencephalography (EEG). It highlights the need for consideration of adenovirus as cause of encephalitis. Case Description: A 66 y old gentleman with (ESRD) on regular hemodialysis was initially admitted to another hospital for 1w. He was found unconscious in the bathroom at home and subsequently developed tonic-clonic seizure prior to arrival to hospital. Patient had fever and productive cough for three days prior. On arrival to emergency department, he was intubated in view of low Glasgow coma scale (GCS) (E1V2M3). Neurological examination revealed normal tone. Contrast enhanced Computer Tomography (CT) of brain revealed multifocal old infarct with small right parieto-temporal scalp hematoma. Cerebrospinal fluid (CSF) showed high protein 871 ng/L and normal glucose ratio with elevated white cell count 10 cells/mm3 predominantly lymphocytes. CSF cryptococcal antigen and Indian Ink were negative and other cultures had no growth. He was treated as meningoencephalitis and started on intravenous ceftriaxone 2 g BD and IV acyclovir 250 mg OD Second lumbar puncture repeated on day 9 on transfer to our hospital of illness in view of no clinical improvement showed elevated opening pressure 22 cm H2O. CSF analysis revealed elevated protein 510 ng/L with adenovirus PCR was positive (4.5 log 10 DNA copies/ml). (EEG) revealed periodic lateralized epileptiform discharges. No other bacterial or fungal pathogen was identified s and tuberculous PCR was negative Intravenous cidofovir was initiated. However, his condition continued to deteriorate and succumbed 5 d following first dose of cidofovir (day 17 of hospitalisation). Discussion: This case highlights the need of consideration of adenovirus meningoencephalitis and illustrates the potential fatal disease in dialysis dependent renal disease patient. The initial diagnosis in this case is challenging as the initial clinical presentation is mimicking severe bacterial infection or septicaemia. Conclusion: Adenovirus meningoencephalitis is a rare but fatal manifestation of severe adenovirus infection with mortality rate up to 39%.

Evolving cerebral infarction in a patient with tuberculous meningitis

Background: Tuberculosis (TB) is a major contributor of global morbidity and mortality worldwide. In 2018, 10 million people were infected with tuberculosis and 1.5 million died from the disease. On the other hand, tuberculous meningitis (TBM) is the most severe form of extra pulmonary tuberculosis with high mortality without treatment. Cerebral infarctions are common complications in patient with TBM with 15–57% patients affected. Here, we reported a case of TBM with evolving cerebral infarctions. Case Description: A 37 y old previously healthy man presented with fever for 1 w with chills and rigors. He also complained of persistent severe headache with occasional vomiting. Otherwise, he denied cough, difficulty in breathing, abdominal pain or diarrhoea. There was reduced appetite and weight loss for past 1week. On examination, his blood pressure was 110/60 mmHg, pulse rate was 105bpm, temperature 38.1. He was alert and conscious. Neurological examination showed reactive pupils and power of 5/5 in both limbs. He was admitted for suspected meningitis. A computed tomography of brain was done which showed ill-defined hypodensity at left head of caudate nucleus and internal capsule. There was leptomeningeal enhancement upon contrast. His CSF examination showed 100TWBC (90% lymphocytes), protein 5 g/l, glucose ratio of 0.33. CSF Genexpert and cryptococcal antigen were negative. He was then started on anti-tuberculous therapy with dexamethasone. 2d into anti-TB treatment, patient was noted to have slow in response. Repeated CT brain showed more prominent hypodensities. 2 d later, patient developed right sided body weakness with power of 3/5. A repeated CT brain showed worsening cerebral grey white matter edema. His condition subsequently stabilized with treatment. Discussion: Cerebral infarction is common in TBM. Commonly involved area is “TB zone” supplied by lenticulostriate, anterior choroidal and thalamogeniculate arteries. Several mechanisms have been proposed for development of infarctions in TBM. Basal exudates are responsible for ischemia. These inflammatory exudates will then lead to vasculitis, thrombosis and vasospasm of vessels. Area prone for infarctions include basal ganglia, internal capsule and thalamus. Conclusion: TBM is important cause of mortality worldwide. Recognising the area of infarction can facilitate early diagnosis and management of complications.

Utilization, Yield, and Accuracy of the FilmArray Meningitis/Encephalitis Panel with Diagnostic Stewardship and Testing Algorithm.

The impact of diagnostic stewardship and testing algorithms on the utilization and performance of the FilmArray meningitis/encephalitis (ME) panel has received limited investigation. We performed a retrospective single-center cohort study assessing all individuals with suspected ME between February 2017 and April 2019 for whom the ME panel was ordered. Testing was restricted to patients with cerebrospinal fluid (CSF) pleocytosis. Positive ME panel results were confirmed before reporting through correlation with direct staining (Gram and calcofluor white) and CSF cryptococcal antigen or by repeat ME panel testing. Outcomes included the ME panel test utilization rate, negative predictive value of nonpleocytic CSF samples, test yield and false-positivity rate, and time to appropriate deescalation of acyclovir. Restricting testing to pleocytic CSF samples reduced ME panel utilization by 42.7% (263 versus 459 tests performed) and increased the test yield by 61.8% (18.6% versus 11.5% positivity rate; P < 0.01) with the application of criteria. The negative predictive values of a normal CSF white blood cell (WBC) count for ME panel targets were 100% (195/195) for nonviral targets and 98.0% (192/196) overall. All pathogens detected in nonpleocytic CSF samples were herpesviruses. The application of a selective testing algorithm based on repeat testing of nonviral targets avoided 75% (3/4) of false-positive results without generating false-negative results. The introduction of the ME panel reduced the duration of acyclovir treatment from an average of 66 h (standard deviation [SD], 43 h) to 46 h (SD, 36 h) (P = 0.03). The implementation of the ME panel with restriction criteria and a selective testing algorithm for nonviral targets optimizes its utilization, yield, and accuracy.