Cerebrospinal Fluid Cryptococcal Antigen Research Articles

“False negative” CSF cryptococcal antigen with clinical meningitis: Case reports and review of literature

There is an increasing recognition of patients presenting with cryptococcal meningitis despite having a negative CSF cryptococcal antigen (CrAg). In this report, we describe three cases of patients with advanced immunosuppression who presented to hospital with “false negative” CSF cryptococcal antigen, two of whom had a positive fungal culture. We describe the challenge of CSF-CrAg negative cryptococcal meningitis and explore ways to overcome this challenge using newer diagnostic techniques.

Clinical characteristics of 81 cases with acquired immunodeficiency syndrome complicated with cryptococcal meningitis

Objective To investigate the clinical features and prognosis factors of acquired immunodeficiency syndrome (AIDS) patients complicated with cryptococcal meningitis (CM). Methods Retrospective analyses were performed on clinical features, laboratory data, treatment status and related prognosis factors in 81 AIDS patients with CM admitted to the Department of Infectious Diseases, Beijing You′an Hospital, Capital Medical University from January 2010 to December 2017. The t test, rank sum test and χ2 test were employed to analyze the data. Results Of the 81 AIDS patients with CM, 71 cases were infected with human immunodeficiency virus (HIV) by sexual transmission (87.7%). The most common clinical symptoms were fever in 60 (74.1%), headache in 72 (88.9%), and nausea and vomiting in 56 (69.1%). Cerebrospinal fluid (CSF) examination results show that 60 cases (74.1%) had elevated opening pressure, the white blood cell count was 17.0 (6.0, 44.5)×106/L, monocyte count was 9.0 (3.0, 29.5)×106/L, the level of chloride was (117.26±5.61) mmol/L, of glucose was 2.89 (2.05, 3.41) mmol/L, of protein was 0.32 (0.21, 0.65) g/L, ink staining positive rate was 84.0% (68/81), fungal culture positive rate was 59.3% (48/81). The positive rate of serum cryptococcal antigen was 96.3% (78/81), and CSF cryptococcal antigen positive rate was 93.8% (76/81). The clinical efficacies were not significant different among different treatment regimens (χ2=1.479, P=0.533). After treatment, 60 patients survived and 21 died, with an overall mortality rate of 25.9%. Univariate analysis showed that consciousness disorder and CSF opening pressure were significantly higher in the death group than those in the survival group (χ2=22.365, t=0.317, respectively, both P<0.05), while serum albumin (Alb) and CD4+ T lymphocyte counts were significantly lower in the death group than those in the survival group (t=7.975, Z=-3.073, respectively, both P<0.05). Multivariate logistic regression analysis showed that consciousness disorder and Alb were independent factors influencing the clinical outcome of AIDS patients with CM. Consciousness disorder was related with poor outcome (odd ratio (OR)=26.704, P=0.011, 95% confidence interval (CI) 2.115-337.247), and higher Alb was related with good outcome (OR=0.671, P=0.005, 95%CI 0.507-0.888). The area under the receiver operating characteristic curve of serum Alb for predicting poor outcomes of AIDS patients with CM was 0.932 (95% CI 0.859-0.998, P<0.01). By using 31.7 g/L as cut-off value, the sensitivity was 95% and the specificity was 81% for predicting poor outcome. Conclusions AIDS complicated with CM has a high mortality rate, and its clinical features are lack of specificity. Consciousness disorder and Alb are independent prognosis factors. Key words: Acquired immunodeficiency syndrome; Cryptococcus neoformans; Meningitis, cryptococcal; Clinical characteristics

1410. Serious Cryptococcal Infections with Ruxolitinib Use: A Case of Meningitis and a Review of the Literature

BackgroundRuxolitinib is an inhibitor of Janus kinase (JAK) 1 and 2 and is approved for the treatment of myelofibrosis and polycythemia vera. Infectious complications associated with its use include reactivation of herpes simplex, zoster, hepatitis B, and tuberculosis, mucormycosis, and progressive multifocal leukoencephalopathy.MethodsSeven cases of ruxolitinib-associated cryptococcal infections have been reported: three cases of meningitis, two cases of pulmonary disease, and two cases of disseminated disease (Table 1).ResultsWe present a 72-year-old male with a history of JAK-2-positive polycythemia vera with secondary myelofibrosis, and concurrent multiple myeloma who presented with 3 weeks of chronic cough and 3 days of fever with severe bifrontal headache after remodeling a large birdcage in his backyard. The patient was on ruxolitinib, ixazomib, and weekly dexamethasone. Cerebrospinal fluid (CSF) analysis showed an elevated opening pressure of 29 cm of CSF, 173 leucocytes with a predominance of lymphocytes, protein of 87 mg/dL and a normal glucose level. BioFire FilmArray® Meningitis/Encephalitis panel detected targets for Cryptococcus in the CSF, and CSF cryptococcal antigen was positive at 1:4. CSF fungal cultures were subsequently positive for Cryptococcus neoformans, susceptible to liposomal amphotericin B (LAMB) and fluconazole. Ruxolitinib was discontinued, treatment with LAMB and flucytosine (5-FC) was associated with significant improvement of headache over the next week. Repeat CSF analysis in 2 weeks was culture negative with a negative cryptococcal antigen test. The patient completed 3 weeks of LAMB and 5-FC and then transitioned to oral fluconazole for a year.ConclusionRuloxitinib and other JAK inhibitors suppress host immunity through impaired T-cell activation and downregulation of cytokines. The JAK-Signal Transducer and Activator of Transcription pathway is one of the most active pathways in host defense against cryptococcus, and use of JAK inhibitors like ruxolitinib may predispose to severe cryptococcal infections. Bird exposure is a risk factor, making environmental contact counseling for patients on ruxolitinib important. Fluconazole prophylaxis needs to be considered in select cases. Disclosures All authors: No reported disclosures.

1821. Evaluation of Cerebrospinal Fluid White Blood Cell Count Criteria for Use of the BioFire® FilmArray® Meningitis/Encephalitis Panel in Immunocompetent Patients

BackgroundIn 2016, our academic medical center implemented the BioFire® FilmArray® Meningitis/Encephalitis Panel (MEP), which detects 14 viral, bacterial, and fungal pathogens. Institutional guidelines recommended the test be used in nonimmunocompromised patients age ≥2 years only if the cerebrospinal fluid (CSF) white blood cell (WBC) count was >10 cells/mm3.MethodsWe reviewed all MEP performed at our institution over 2 years (January 1, 2017 to December 31, 2018). We collected CSF WBC count, protein, and glucose; MEP results; CSF culture results; and demographics. We excluded children age <2 years, immunocompromised patients, those without a CSF WBC count, and duplicate tests during the same illness.ResultsOf 453 patients, 311 met inclusion criteria. The median age was 51, 51% male. Median CSF indices: WBC/mm3 = 4, protein = 57 mg/dL, glucose = 66 mg/dL. MEP positivity rate = 12% (37/311): viruses (29/37), bacteria (7/37), and fungi (1/37). Positive bacterial/fungal MEP results compared with CSF culture are summarized in Table 1. No clinically significant discordant negative MEP results occurred compared with CSF culture, cryptococcal antigen, or other viral PCR testing. Of the 311 patients, 184 (59%) had ≤10 CSF WBC/mm3. Of these, 4 had positive MEP results: 1 enterovirus, 1 human herpes virus 6 (HHV-6) and 2 varicella zoster virus (VZV). The HHV-6 was judged clinically insignificant. The 2 VZV cases had concomitant shingles and were already on acyclovir. No clinically significant MEP results occurred in 110/311 (35%) patients with ≤ 2 CSF WBC/mm3.ConclusionIn nonimmunocompromised patients, age ≥ 2, with ≤ 10 CSF WBC/mm3 on lumbar puncture, positive MEP results were rare and the clinical significance of the 4 positives was debatable. A hard-stop restriction in this setting could have reduced overall use by up to 59% and resulted in significant cost savings. Lower CSF WBC/mm3 cut-offs could be considered and still improve MEP utilization. Disclosures All Authors: No reported Disclosures.

Cryptococcosis in HIV – Infected Hospitalized Patients in Latvia

Aims: To determine the prevalence of cryptococcal infection among HIV hospitalized patients, to evaluate clinical characteristics and outcomes in Latvia.&#x0D; Study Design: Cross-sectional study.&#x0D; Place and Duration of Study: Riga Eastern Clinical University Hospital, Latvian Center of Infectology, between January 2014 and February 2017.&#x0D; Methodology: We conducted the study reporting demographics, epidemiological (age, sex, clinical aspects, paraclinical results (cryptococcal antigen in cerebrospinal fluid, serum, urine, cryptococcal DNA, HIV RNA and lymphocyte T CD4+ count), treatment and outcome aspects. We analyze 69 patients (71% men, 29% women) with HIV infection and cryptococcosis.&#x0D; Results: 69 cases of cryptococcosis were confirmed for 699 HIV infected hospitalized patients tested, giving a prevalence of 9.9%. 38% (n=26/69) of patients were with clinical signs of infection with the central nervous system involvement, 19% (13/69) patients had pulmonary involvement.&#x0D; Other 43% (n=30/69) of patients had disseminated non-CNS disease (elevated serum cryptococcal Ag or DNA). Most patients had advanced HIV disease (Median lymphocyte T CD4+ count=48, 5 cells/uL, (1-1041), the average was 112, 9 cells/ uL (SD 184.98). 87% (n=59/68) of patients had lymphocyte T CD4+cell count &lt; 200 cells/μL Only 25% (n=14) of the patients known to have HIV infection (n=56/69) were receiving antiretroviral therapy at the time of presentation. Overall mortality rate was 59% (n=41/69).&#x0D; Conclusion: Prevalence of cryptococcal antigenemia was 9.9%, indicating that the prevalence of cryptococcal infection among HIV patients in Latvia may be high enough to consider targeted screening.HIV positive patients have high mortality (35%) following cryptococcal infection which persists beyond their initial hospitalization. Follow-up studies of late mortality would be beneficial.

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 is the initial AIDS defining illness in 2% of patients with CD4 levels less than 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. Presence of cerebrospinal fluid cryptococcal antigen (CSF CRAG) is diagnostic of CM. CRAG can be determined by latex agglutination (LAT), ELISA and now, by lateral flow (LFA) immunoassay. LFA is a point of care test that rapidly detects CRAG. This study compares LAT and LFA for detection of serum CRAG and diagnosing CM. Method: 210 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. Findings: Fifteen patients were found positive for SCRAG by LFA dipstick. All of them were also positive for SCRAG by LAT. Tweleve of them had CD4 count below 100 cells/mm3. CSF CRAG was positive in all 12 SCRAG positive who were submitted to CSF examination. Interpretation: We found that serum detection of cryptococcal antigen 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. Funding Statement: One of the authors (AC) was supported by the research grant from ICMR, Delhi vide grant no OMI/13/2014-ECD-I. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Ethical approval was taken from the institutional ethic committee for the study.

Audiologic and Otologic Complications of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Patients.

To identify audiologic and otologic outcomes in previously healthy non-HIV patients with cryptococcal meningoencephalitis (CM). Retrospective case review of a subset of patients recruited in a prospective observational study following previously healthy individuals who developed CM. Tertiary referral center, National Institutes of Health Clinical Center. Previously healthy adult patients with CM without immune suppressive therapy before disease onset. Diagnostic evaluations included audiometry, acoustic immittance, otoacoustic emissions, and auditory brainstem response studies, in addition to neurotologic assessment. Twenty-nine patients (58 years) underwent audiologic evaluation between 6 months and 3.5 years after CM diagnosis; 21 patients were seen for longitudinal assessment with an average duration of follow up of 20.3 months. Nearly three-quarters (73%) of the cohort presented with hearing loss, most commonly (90%) sensorineural in origin. The most frequent degree of loss was mild and then moderate, although some patients had severe or profound impairment. Hearing loss improved (43%) or remained stable (38%) in most cases. Ears with internal auditory canal enhancement on magnetic resonance imaging (MRI) had significantly more hearing loss than those without enhancement, although a similar finding was not observed with gyral enhancement or the presence of ependymitis or ventricular volume expansion. Hearing loss was not associated with reduced cerebrospinal fluid (CSF) glucose, CSF total protein, cryptococcal antigen, or total cell count. Hearing loss is a common manifestation of cryptococcal meningitis in previously healthy patients and may involve a cochlear or neural site of lesion, or both. Routine surveillance of hearing in patients is recommended, regardless of symptomatology, to ensure early and appropriate intervention and care.

64-Year-Old Man With Subacute Altered Mental Status and Headache

64-Year-Old Man With Subacute Altered Mental Status and Headache

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Cryptococcal Meningitis: A Retrospective Cohort of a Brazilian Reference Hospital in the Post-HAART Era of Universal Access.

Objective Cryptococcus neoformans is a common opportunistic infection in adults with acquired immunodeficiency syndrome worldwide. However, limited data exist for HIV-infected patients in the post-HAART (highly active antiretroviral therapy) era in Brazil. The aim of this study was to describe the clinical characteristics and outcomes of cryptococcosis in a cohort of patients attending a teaching tertiary care hospital in southern Brazil after the introduction of HAART in Brazil. Patients and Methods A retrospective study was conducted in tertiary care hospital in southern Brazil. Detailed data on risk factors, clinical manifestations, diagnosis methods, treatment, and prognosis of patients with meningeal cryptococcosis were evaluated from January 2009 to December 2016. Results Seventy-nine cases of cryptococcal meningitis were identified. Most of the patients presented positive CSF (cerebrospinal fluid) cultures for Cryptococcus neoformans (96%). The prevalence of males and females with meningeal cryptococcosis was similar. The age of the patients ranged from 5 to 67 years. The median time of hospitalization was 28 days. The most common underlying disease was HIV (82%), followed by solid transplant (10%). Fever, nausea, vomiting, headache, and altered mental status were the most common clinical manifestations. Initial opening intracranial pressures varied from 30 to 130 cm H2O. CNS imaging abnormalities include hydrocephalus and hypodensities. Widened Virchow–Robin spaces were described in only 2 patients (2.5%). Induction treatment of the majority of the patients consisted of amphotericin B and flucytosine (67%) followed by amphotericin B and fluconazole (19%). Multivariate analysis of Cox regression identified headache at presentation, mechanical ventilation, CSF glucose <20 mg/dL, and CSF cryptococcal antigen ≥1 : 1000 for independent risk factors for death. All-cause 30-day and 60-day mortalities were 19% and 24%, respectively. Conclusions Meningeal cryptococcosis mostly caused by C. neoformans continues to occur predominantly in HIV-infected adults despite HAART being widely distributed in Brazil. Cryptococcosis remains a significant opportunistic infection in solid organ transplant recipients. Despite adequate antifungal treatment and management of intracranial hypertension in a reference tertiary care hospital, mortality was high. Identification of risk factors and additional treatment modalities, especially for intracranial hypertension, are necessary to improve care for patients with cryptococcal meningitis.

Tuberculous meningitis diagnosis and outcomes during the Xpert MTB/Rif era: a 6.5-year cohort study in Uganda

Background: Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa and is notoriously difficult to diagnose. We describe the impact of improved TBM diagnostics over 6.5 years at two Ugandan referral hospitals. Methods: Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert MTB/Rif (Xpert) on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy,routine liquid-media culture and Xpert on large volume centrifuged CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen. We compared rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 HIV-infected adults presenting with suspected meningitis underwent lumbar puncture, of which 33% (558/1672) had negative CSF cryptococcal antigen and 12% (195/1672) were treated for TB meningitis. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27) amongst those with a known outcome. Adjusting for definite TBM diagnosis and antiretroviral therapy use, and using imputed data, assuming 50% of those with an unknown outcome died, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three. Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard. Conclusions: As TBM diagnostics have improved, microbiologically-confirmed TBM diagnoses have increased and in-hospital mortality has declined. Yet, mortality due to TB meningitis remains unacceptably high and further measures are needed to improve outcomes from TBM in Uganda.

Tuberculous meningitis diagnosis and outcomes during the Xpert MTB/Rif era: a 6.5-year cohort study in Uganda

Background: Tuberculous meningitis (TBM), a leading cause of meningitis in sub-Saharan Africa, is notoriously difficult to diagnose. In our Ugandan setting TB diagnostics have evolved rapidly in recent years, with introduction of Xpert MTB/Rif (Xpert) in 2011 and culture in 2013. We aim to describe the impact of improved TBM diagnostics at two Ugandan hospitals between 2010 and 2017. Methods: Adults presenting with meningitis (headache and objective meningism) were assessed for eligibility for enrolment in two consecutive trials investigating cryptococcal meningitis. Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen (crAg). In a post-hoc analysis of three prospective cohorts, we compare rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 predominantly HIV-infected adults underwent lumbar puncture, of which 33% (558/1672) had negative CSF crAg and 12% (195/1672) were treated for TBM. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27). Adjusting for definite TBM and antiretroviral therapy, and using imputed data, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three. Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard. Conclusions: Since 2010, as TBM diagnostics have evolved, microbiologically-confirmed TBM diagnoses have increased significantly. There has been a non-significant decline in TBM in-hospital mortality but due to multiple possible confounding factors it is not possible to conclude what has driven this decline in mortality.

Can improved diagnostics reduce mortality from Tuberculous meningitis? Findings from a 6.5-year cohort in Uganda

Background: Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa and is notoriously difficult to diagnose. We describe the impact of improved TBM diagnostics over 6.5 years at two Ugandan referral hospitals. Methods: Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert MTB/Rif (Xpert) on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume centrifuged CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen. We compared rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 HIV-infected adults presenting with suspected meningitis underwent lumbar puncture, of which 33% (558/1672) had negative CSF cryptococcal antigen and 12% (195/1672) were treated for TB meningitis. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P&lt;0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27) amongst those with a known outcome. Adjusting for definite TBM diagnosis and antiretroviral therapy use, and using imputed data, assuming 50% of those with an unknown outcome died, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three. Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard. Conclusions: As TBM diagnostics have improved, microbiologically-confirmed TBM diagnoses have increased and in-hospital mortality has declined. Yet, mortality due to TB meningitis remains unacceptably high and further measures are needed to improve outcomes from TBM in Uganda.

Evaluation of trypan blue stain in a haemocytometer for rapid detection of cerebrospinal fluid sterility in HIV patients with cryptococcal meningitis

BackgroundQuantitative culture is the most common method to determine the fungal burden and sterility of cerebrospinal fluid (CSF) among persons with cryptococcal meningitis. A major drawback of cultures is a long turnaround-time. Recent evidence demonstrates that live and dead Cryptococcus yeasts can be distinguished using trypan blue staining. We hypothesized that trypan blue staining combined with haemocytometer counting may provide a rapid estimation of quantitative culture count and detection of CSF sterility. To test this, we evaluated 194 CSF specimens from 96 HIV-infected participants with cryptococcal meningitis in Kampala, Uganda. Cryptococcal meningitis was diagnosed by CSF cryptococcal antigen (CRAG). We stained CSF with trypan blue and quantified yeasts using a haemocytometer. We compared the haemocytometer readings versus quantitative Cryptococcus CSF cultures.ResultsHaemocytometer counting with trypan blue staining had a sensitivity of 98% (64/65), while CSF cultures had a sensitivity of 95% (62/65) with reference to CSF CRAG for diagnostic CSF specimens. For samples that were positive in both tests, the haemocytometer had higher readings compared to culture. For diagnostic specimens, the median of log10 transformed counts were 5.59 (n = 64, IQR = 5.09 to 6.05) for haemocytometer and 4.98 (n = 62, IQR = 3.75 to 5.79) for culture; while the overall median counts were 5.35 (n = 189, IQR = 4.78–5.84) for haemocytometer and 3.99 (n = 151, IQR = 2.59–5.14) for cultures. The percentage agreement with culture sterility was 2.4% (1/42). Counts among non-sterile follow-up specimens had a median of 5.38 (n = 86, IQR = 4.74 to 6.03) for haemocytometer and 2.89 (n = 89, IQR = 2.11 to 4.38) for culture. At diagnosis, CSF quantitative cultures correlated with haemocytometer counts (R2 = 0.59, P < 0.001). At 7–14 days, quantitative cultures did not correlate with haemocytometer counts (R2 = 0.43, P = 0.4).ConclusionDespite a positive correlation, the haemocytometer counts with trypan blue staining did not predict the outcome of quantitative cultures in patients receiving antifungal therapy.

Inadequacy of High-Dose Fluconazole Monotherapy Among Cerebrospinal Fluid Cryptococcal Antigen (CrAg)-Positive Human Immunodeficiency Virus-Infected Persons in an Ethiopian CrAg Screening Program.

A total of 817 human immunodeficiency virus-infected Ethiopians with CD4 <150 cells/mL underwent plasma cryptococcal antigen (CRAG) screening. CRAG prevalence was 6.2%. Of participants with plasma CRAG titers >1:640, 96% (27 of 28) had cryptococcal meningitis (cerebrospinal fluid CRAG-positive) whereas 50% (7 of 14) with 1:160-1:320 titers had meningitis. With fluconazole 1200 mg/d therapy, 68% of meningitis patients (23 of 34) died within 3 months. Plasma CRAG titers >1:160 predict meningitis, requiring more intensive antifungal therapy.

Cryptococcosis in patients with hematological diseases: a 14-year retrospective clinical analysis in a Chinese tertiary hospital

BackgroundCryptococcal infection has become a public health challenge globally. However, information about cryptococcal infection in patients with hematological diseases remains relatively rare.MethodsHIV-uninfected cryptococcosis cases with hematological diseases admitted to Huashan Hospital from January 2001 to December 2014 were reviewed.ResultsIn total, 33 cryptococcosis patients were enrolled, including 12 malignant and 21 non-malignant hematological cases. Twenty-six patients had central nervous system (CNS) involvement, which was observed more often in patients with non-malignancies than with malignancies (20/21 vs. 6/12, P = 0.001) Most patients (25/26) with CNS infection were confirmed by cerebrospinal fluid (CSF) culture or smear, and 100% (20/20) of them tested positive for the CSF cryptococcal antigen test. Eighteen out of 26 cryptococcal meningitis patients were treated with amphotericin B (AmB)-based therapy, 16 of them with AmB deoxycholate (d-AmB) and 2 patients with liposomal AmB. The clinical success rate was 55.6%. D-AmB was well-tolerated at 0.35–0.59 mg/kg/d (median 0.43 mg/kg/d) and only 12 patients had mild adverse events.ConclusionsCNS cryptococcal infection was more frequent in patients with hematological non-malignancies, and cryptococcal antigen test as well as the CSF fungal culture or smear are suggested for early diagnosis. D-AmB could be used as an alternative therapy for CNS-infected patients with hematological diseases.

Differences in Immunologic Factors Among Patients Presenting with Altered Mental Status During Cryptococcal Meningitis.

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 opening pressures (320 vs. 269 mm H2O; P = .016), IL-10 (P = .044), and CCL3 (P = .008) compared with persons with GCS=15. Altered mental status may be associated with host immune response rather than Cryptococcus burden.

Characteristics and outcomes of cryptococcal meningitis in HIV seronegative children in Beijing, China, 2002-2013.

BackgroundData regarding HIV-seronegative pediatric patients with cryptococcal meningitis (CM) have been very limited.MethodsWe retrospectively reviewed non-HIV-infected in patients with CM from January 2002 through December 2013 in Beijing Children’s Hospital. Records of the all patients were obtained and compared.ResultsThe 34 children had a median age of 5.6 years. Most of the patients were male (67.6 %). Only 23.5 % of the cases had identifiable underlying diseases. The sensitivity of the CSF cryptococcal antigen, India ink smear and CSF culture in our study were 81.5, 85.3 and 82.4 %, respectively. And the sensitivity of combinations of these tests was 91.2 %. Out of the 34 patients, 16 (47.1 %) had other organs involvement in addition to the brain. The main abnormal features via magnetic resonance imaging (MRI) were Virchow-Robin space dilatation (44.4 %), hydrocephalus (38.9 %), gelatinous pseudocysts (33.3 %), brain atrophy (33.3 %), meningeal enhancement (27.8 %) and local lesions (27.8 %). In total, 64.7 % of the patients were successfully treated at discharge, whereas treatment failed in 35.3 % of the patients.ConclusionsCryptococcal meningitis is an infrequent disease with a high fatality rate in children in China. The majority of patients were apparently healthy. Clinicians should consider cryptococcal infection as a potential pathogen of pediatric meningitis. Cryptococcal antigen, India ink smear and culture tests are recommended for diagnosis.

Cryptococcal meningitis complicating sarcoidosis

Cryptococcal meningitis is an uncommon but severe complication of sarcoidosis. We present 2 patients with cryptococcal meningitis complicating sarcoidosis and compared findings with 38 cases reported in the literature. When 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. Cryptococcal 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.

Cryptococcosis in Anti-Interferon-Gamma Autoantibody-Positive Patients: a Different Clinical Manifestation from HIV-Infected Patients

Disseminated nontuberculous mycobacterial (NTM) infection is the most common feature of patients who test positive for anti-interferon-gamma autoantibodies (IFN-γ Ab). Cryptococcus co-infects these patients. A retrospective, matched case-control study was conducted at Srinagarind Hospital between 1992 and 2013. We reviewed the medical records of non-HIV-infected patients with cryptococcosis and disseminated NTM infection (case) and matched 2 HIV-infected patients (control) with cryptococcosis to each case. There were 16 patients in the case group and 32 in the control group. Ten of the 16 patients in the case group had sera available for testing, and all tested positive for IFN-γ Ab. Compared to those in the control group, patients in the case group were significantly older, had a longer of illness duration and were less likely to present with meningitis but more likely to present with bone and/or joint, lung/pleura, and skin infections. Based on culture and staining results, patients in the case group were significantly less likely to test positive for the cryptococcal antigen in cerebrospinal fluid and serum samples, but were more likely to test positive in pus and skin lesion(s), compared to control patients. This is the first study of cryptococcosis in patients with disseminated NTM infection who tested positive for IFN-γ Ab. The clinical manifestations of cryptococcosis are different in these patients compared to those in HIV-infected patients. Recognizing the clinical features of these patients may improve diagnosis and promote timely treatment.