Over the past ten years, standard diagnostics for cryptococcal meningitis in HIV-infected persons have evolved from culture to India ink to detection of cryptococcal antigen (CrAg), with the recent ...development and distribution of a point-of-care lateral flow assay. This assay is highly sensitive and specific in cerebrospinal fluid (CSF), but is also sensitive in the blood to detect CrAg prior to meningitis symptoms. CrAg screening of HIV-infected persons in the blood prior to development of fulminant meningitis and preemptive treatment for CrAg-positive persons are recommended by the World Health Organization and many national HIV guidelines. Thus, CrAg testing is occurring more widely, especially in resource-limited laboratory settings. CrAg titer predicts meningitis and death and could be used in the future to customize therapy according to burden of infection.
Nosocomial transmission of COVID-19 puts patients with other medical problems at risk of severe illness and death. Of 662 inpatients with COVID-19 at an NHS Trust in South London, 45 (6.8%) were ...likely to have acquired COVID-19 in hospital. These patients had no evidence of respiratory or influenza-like illness on admission and developed symptoms, with positive SARS-CoV-2 PCR test results, more than 7 days after admission (>14 days for 38 5.7% patients). Forty (88.9%) of these patients had shared a ward with a confirmed COVID-19 case prior to testing positive. Implementation of a triage system combining clinical assessment with rapid SARS-CoV-2 testing facilitated cohorting so that fewer susceptible patients were exposed to COVID-19 on shared wards. With hospital service resumption alongside the possibility of future waves of COVID-19 related admissions, strategies to prevent nosocomial transmission are essential. Point-of-care diagnostics can complement clinical assessment to rapidly identify patients with COVID-19 and reduce risk of transmission within hospitals.
High mortality rates among asymptomatic cryptococcal antigen (CrAg)-positive patients identified through CrAg screening, despite preemptive fluconazole treatment, may be due to undiagnosed ...cryptococcal meningitis.
Symptoms were reviewed in CrAg-positive patients identified by screening 19233 individuals with human immunodeficiency virus infection and CD4 cell counts <100/µL at 17 clinics and 3 hospitals in Johannesburg from September 2012 until September 2015, and at 2 hospitals until June 2016. Cerebrospinal fluid samples from 90 of 254 asymptomatic patients (35%) and 78 of 173 (45%) with headache only were analyzed for cryptococcal meningitis, considered present if Cryptococcus was identified by means of India ink microscopy, culture, or CrAg test. CrAg titers were determined with stored blood samples from 62 of these patients. The associations between blood CrAg titer, concurrent cryptococcal meningitis, and mortality rate were assessed.
Cryptococcal meningitis was confirmed in 34% (95% confidence interval, 25%-43%; 31 of 90) of asymptomatic CrAg-positive patients and 90% (81%-96%; 70 of 78) with headache only. Blood CrAg titer was significantly associated with concurrent cryptococcal meningitis in asymptomatic patients (P < .001) and patients with headache only (P = .003). The optimal titer for predicting cryptococcal meningitis was >160 (sensitivity, 88.2%; specificity, 82.1%); the odds ratio for concurrent cryptococcal meningitis was 34.5 (95% confidence interval, 8.3-143.1; P < .001).
About a third of asymptomatic CrAg-positive patients have concurrent cryptococcal meningitis. More effective clinical assessment strategies and antifungal regimens are required for CrAg-positive patients, including investigation for cryptococcal meningitis irrespective of symptoms. Where it is not possible to perform lumbar punctures in all CrAg-positive patients, blood CrAg titers should be used to target those most at risk of cryptococcal meningitis.
Immunosuppressive therapies have become a cornerstone of the management of severe COVID-19. The impact of these therapies on secondary infections and antimicrobial prescribing remains unclear. We ...sought to assess antimicrobial use and the incidence of bacterial and fungal infections in patients with severe COVID-19, and to explore their associations with receipt of immunosuppressive therapies.
Our retrospective cohort study included 715 hospitalised, adult patients with severe COVID-19 admitted to St George's Hospital, London, UK, during the first UK pandemic wave (1
March-10
June 2020). Co-infections (occurring within 48 h of admission) and secondary infections (≥ 48 h) were defined as a positive microbiological culture with supporting clinical, radiological or laboratory data to suggest true infection. Cox regression models with time-dependent covariates were used to explore the association between immunosuppressant use and secondary infection.
Microbiologically confirmed co-infection occurred in 4.2% (n = 30) and secondary infection in 9.3% (n = 66) of the cohort (n = 715) and were associated with in-hospital mortality (48% vs 35%, OR 1.8, 95%CI 1.1-2.7, p = 0.01). Respiratory (n = 41, 39%) and bloodstream infections (n = 38, 36%) predominated, with primarily Gram-negative pathogens. 606 (84.7%) patients received an antimicrobial, amounting to 742 days of therapy per 1000 patient-days (DOTs). In multivariable models, receipt of high-dose steroids (≥ 30 mg prednisolone or equivalent) or tocilizumab was significantly associated with increased antimicrobial consumption (+ 5.5 DOTs, 95%CI 3.4-7.7 days) but not secondary infection (HR 0.56, 95%CI 0.26-1.18).
Bacterial and fungal infections in severe COVID-19 were uncommon. Receipt of steroids or tocilizumab was independently associated with antimicrobial consumption despite its lack of association with secondary infection. These findings should galvanise efforts to promote antimicrobial stewardship in patients with COVID-19.
Cryptococcal antigen (CrAg) is detectable in blood prior to the onset of symptomatic cryptococcal meningitis (CM), a leading cause of death among people with advanced human immunodeficiency virus ...(HIV) disease globally. Highly sensitive assays can detect CrAg in blood, and screening people with HIV with low CD4 counts, followed by preemptive antifungal treatment, is recommended and widely implemented as part of a global strategy to prevent CM and end cryptococcal-related deaths. Cryptococcal antigenemia encompasses a spectrum of conditions from preclinical asymptomatic infection (cerebrospinal fluid CSF CrAg-negative) through subclinical (CSF CrAg-positive without overt meningism) to clinical symptomatic cryptococcal disease, usually manifesting as CM. In this review, we summarize current understanding of the pathophysiology, risk factors for, and clinical implications of cryptococcal antigenemia within this spectrum. We also provide an update on global prevalence, recommended screening and treatment strategies, and future considerations for improving outcomes among patients with cryptococcal antigenemia.
Cryptococcal antigen (CrAg) screening at the point of care could improve cryptococcal meningitis prevention where laboratory resources are limited. We evaluated the accuracy of Immunomycologics ...(IMMY, Norman, OK) CrAg lateral flow assay (LFA) using different techniques at point of care.
Two tertiary-level hospitals in Johannesburg and a community health clinic in Soweto, South Africa.
A case-control diagnostic validation study and a prospective clinic-based implementation study using the IMMY CrAg LFA on finger-prick blood. Accuracy, using direct application of LFA to sample, or pipette to transfer sample to diluent, and reading after 10 and 20 minutes, was compared with laboratory-based plasma testing.
The validation study tested 64 CrAg-positive and 152 CrAg-negative patients with no symptoms or signs of meningitis, identified by routine laboratory screening, recruited by convenience sampling. Consecutively diagnosed HIV-infected adults (n = 654) were included in the implementation study. Sensitivity was 82% and 20% when the LFA was read 10 minutes after direct application to finger-prick blood in the validation and implementation studies, respectively. Using a pipette to transfer blood and reading after 20 minutes improved sensitivity to 100%, while retaining 100% specificity, in both studies.
Although the IMMY CrAg LFA performs well when applied directly to finger-prick blood for diagnosing cryptococcal meningitis, this technique may not provide adequate volume to detect low concentrations of CrAg when screening asymptomatic patients. Using a pipette to transfer larger volumes of blood to diluent before CrAg LFA testing and reading results after 20 minutes is a more reliable point-of-care method.
Abstract
Background
Cryptococcal antigen (CrAg) screening and treatment with preemptive fluconazole reduces the incidence of clinically evident cryptococcal meningitis in individuals living with ...advanced human immunodeficiency virus (HIV) disease. However, mortality remains higher in CrAg-positive than in CrAg-negative patients with similar CD4+ T-lymphocyte counts.
Methods
We conducted a cohort study to investigate causes of morbidity and mortality during 6 months of follow-up among asymptomatic CrAg-positive and CrAg-negative (ratio of 1:2) patients living with HIV with CD4 counts <100 cells/µL attending 2 hospitals in Johannesburg, South Africa. When possible, minimally invasive autopsy (MIA) was performed on participants who died.
Results
Sixty-seven CrAg-positive and 134 CrAg-negative patients were enrolled. Death occurred in 17/67 (25%) CrAg-positive and 12/134 (9%) CrAg-negative participants (hazard ratio for death, adjusted for CD4 count, 3.0; 95% confidence interval, 1.4–6.7; P = .006). Cryptococcal disease was an immediate or contributing cause of death in 12/17 (71%) CrAg-positive participants. Postmortem cryptococcal meningitis and pulmonary cryptococcosis were identified at MIA in all 4 CrAg-positive participants, 3 of whom had negative cerebrospinal fluid CrAg tests from lumbar punctures (LPs) at the time of CrAg screening.
Conclusions
Cryptococcal disease was an important cause of mortality among asymptomatic CrAg-positive participants despite LPs to identify and treat those with subclinical cryptococcal meningitis and preemptive fluconazole for those without meningitis. Thorough investigation for cryptococcal disease with LPs and blood cultures, prompt ART initiation, and more intensive antifungals may reduce mortality among asymptomatic CrAg-positive patients identified through screening.
Asymptomatic cryptococcal antigenemia was a risk factor for mortality despite a screen-and-treat program with preemptive fluconazole treatment. Cryptococcal disease was a significant cause of death on the basis of clinical and autopsy evidence. Fluconazole monotherapy may be inadequate preemptive treatment.
Investigation of the diagnostic yield of urine-based tuberculosis (TB) screening in patients with advanced HIV disease.
A cross-sectional screening study.
HIV outpatient clinics and wards at two ...hospitals in Johannesburg, South Africa, between June 2015 and October 2017.
Two hundred and one patients living with advanced HIV disease (CD4+ T-lymphocytes <100 cells/μl) attending healthcare facilities following cryptococcal antigen (CrAg) screening.
Screening for TB using sputum for microscopy, culture, and Xpert MTB/Rif and urine for lipoarabinomannan (LAM) and Xpert Ultra.
Proportion of positive results using each testing modality, sensitivity, and specificity of urine-based testing compared with culture, and survival outcomes during 6 months follow up.
Urine was obtained from 177 of 181 (98%) participants and sputum from 91 (50%). Urine-based screening increased same-day diagnostic yield from 7 (4%) to 31 (17%). A positive urine test with either LAM or Xpert Ultra had 100% sensitivity (95% confidence interval, 59-100%) for detecting culture-positive TB at any site. Patients with newly diagnosed TB on urine-based screening were initiated on treatment and did not have excess mortality compared with the remainder of the cohort.
Urine is an easily obtainable sample with utility for detecting TB in patients with advanced HIV disease. Combining urine and sputum-based screening in this population facilitates additional same-day TB diagnoses and early treatment initiation, potentially reducing the risk of TB-related mortality. Urine-based as well as sputum-based screening for TB should be integrated with CrAg screening in patients living with advanced HIV disease.
Asymptomatic cryptococcal antigenemia (positive blood cryptococcal antigen CrAg) is associated with increased mortality in individuals with human immunodeficiency virus (HIV) even after adjusting for ...CD4 count and despite receiving antifungal treatment. The association of antibody immunity with mortality in adults with HIV with cryptococcal antigenemia is unknown.
Cryptococcal capsular glucuronoxylomannan (GXM)- and naturally occurring β-glucans (laminarin, curdlan)-binding antibodies were measured in blood samples of 197 South Africans with HIV who underwent CrAg screening and were followed up to 6 months. Associations between antibody titers, CrAg status, and all-cause mortality were sought using logistic and Cox regression, respectively.
Compared with CrAg-negative individuals (n = 130), CrAg-positive individuals (n = 67) had significantly higher IgG1 (median, 6672; interquartile range IQR, 4696-10 414 vs 5343, 3808-7722 μg/mL; P = .007), IgG2 (1467, 813-2607 vs 1036, 519-2012 μg/mL; P = .01), and GXM-IgG (1:170, 61-412 vs 1:117, 47-176; P = .0009) and lower curdlan-IgG (1:47, 11-133 vs 1:93, 40-206; P = .01) titers. GXM-IgG was associated directly with cryptococcal antigenemia adjusted for CD4 count and antiretroviral therapy use (odds ratio, 1.64; 95% confidence interval CI, 1.21 to 2.22). Among CrAg-positive individuals, GXM-IgG was inversely associated with mortality at 6 months adjusted for CD4 count and tuberculosis (hazard ratio, 0.50; 95% CI, .33 to .77).
The inverse association of GXM-IgG with mortality in CrAg-positive individuals suggests that GXM-IgG titer may have prognostic value in those individuals. Prospective longitudinal studies to investigate this hypothesis and identify mechanisms by which antibody may protect against mortality are warranted.
Abstract
Blood cryptococcal antigen (CrAg) titers >160 are associated with concurrent subclinical cryptococcal meningitis (CM). When lumbar puncture (LP) is not immediately available in a CrAg ...screening program, semi-quantitative CrAg assays may provide risk stratification for CM. Two semi-quantitative assays (SQ Immuno-Mycologics, Norman, OK, USA and CryptoPS Biosynex, Strasbourg, France) were evaluated against a qualitative lateral flow assay (LFA) using 194 plasma samples from a cohort of HIV-seropositive individuals with CD4 counts <100 cells/μl. We compared SQ and CryptoPS results to titers for LFA-positive samples. Among patients with LP, we examined the association between semi-quantitative CrAg results and CM. We used a Cox proportional hazards model to determine the association between SQ score and mortality. Of 194 participants, 60 (31%) had positive LFA results, of whom 41 (68%) had a titer of ≤160 and 19 (32%) a titer >160. Fifty individuals with antigenemia had an LP; a clinically useful SQ score that identified all ten cases of subclinical CM was ≥3 (100% sensitivity, 55% specificity). Patients with an SQ score of 3 or 4 also had a 2.2-fold increased adjusted hazards of 6-month mortality (95% CI: 0.79–6.34; p = 0.13) versus those with score of <3. Nine of ten patients with subclinical CM had a strong-positive CryptoPS result versus 10/40 without subclinical CM (p < 0.001). Semi-quantitative assays offered a sensitive though not specific means of gauging the risk of concurrent CM in this patient population.
Lay summary
We evaluated two single-step laboratory tests that can quantify the amount of cryptococcal antigen in plasma of patients with advanced HIV disease and could thus gauge the risk of concurrent cryptococcal meningitis and subsequent mortality. These tests are not a substitute for a lumbar puncture.
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