Cryptococcal Meningitis Diagnostics and Screening in the Era of Point-of-Care Laboratory Testing

Rajasingham, Radha; Wake, Rachel; Beyene, Tafese; Katende, Andrew; Letang, Emílio; Boulware, David R.

doi:10.1128/jcm.01238-18

Cited by 144 publications

(154 citation statements)

References 30 publications

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“…One approach would be to use adjunctive antifungal treatment for all CrAg-positive patients or for those with higher blood CrAg titers, identified by quantitative CrAg assays [18,19]. We found blood CrAg titers of >160 to be predictive of death, consistent with previous studies [5,20,21]. Adjunctive treatment options include flucytosine (shown to be effective for treating cryptococcal meningitis in the Advancing Cryptococcal meningitis Treatment for Africa (ACTA) trial [22]) or a single dose of 10 mg/kg liposomal amphotericin (effective fungicidal activity in CSF [23] and currently in a phase 3 trial for treating cryptococcal meningitis [24]).…”

Section: Discussionsupporting

confidence: 89%

Cryptococcal-related Mortality Despite Fluconazole Preemptive Treatment in a Cryptococcal Antigen Screen-and-Treat Program

Wake

Govender

Touzani

et al. 2019

Clinical Infectious Diseases

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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.

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Section: Discussionsupporting

confidence: 89%

Cryptococcal-related Mortality Despite Fluconazole Preemptive Treatment in a Cryptococcal Antigen Screen-and-Treat Program

Wake

Govender

Touzani

et al. 2019

Clinical Infectious Diseases

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“…Cryptococcal meningitis is diagnosed by detection of capsular polysaccharide glucuronoxylomannan in body fluids, including serum and cerebrospinal fluid. A well-known example of this diagnostic approach is the latex agglutination test widely used during the last four decades [54,55]. Recently, latex agglutination and enzyme-based immunoassay tests have been replaced by the LFD assay, which has similar or higher sensitivity, similar specificity, and lower cost [56][57][58][59].…”

Section: Cryptococcosismentioning

confidence: 99%

Identification of Mycoses in Developing Countries

Arastehfar

Wickes

İlkit

et al. 2019

JoF

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Extensive advances in technology offer a vast variety of diagnostic methods that save time and costs, but identification of fungal species causing human infections remains challenging in developing countries. Since the echinocandins, antifungals widely used to treat invasive mycoses, are still unavailable in developing countries where a considerable number of problematic fungal species are present, rapid and reliable identification is of paramount importance. Unaffordability, large footprints, lack of skilled personnel, and high costs associated with maintenance and infrastructure are the main factors precluding the establishment of high-precision technologies that can replace inexpensive yet time-consuming and inaccurate phenotypic methods. In addition, point-of-care lateral flow assay tests are available for the diagnosis of Aspergillus and Cryptococcus and are highly relevant for developing countries. An Aspergillus galactomannan lateral flow assay is also now available. Real-time PCR remains difficult to standardize and is not widespread in countries with limited resources. Isothermal and conventional PCR-based amplification assays may be alternative solutions. The combination of real-time PCR and serological assays can significantly increase diagnostic efficiency. However, this approach is too expensive for medical institutions in developing countries. Further advances in next-generation sequencing and other innovative technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)-based diagnostic tools may lead to efficient, alternate methods that can be used in point-of-care assays, which may supplement or replace some of the current technologies and improve the diagnostics of fungal infections in developing countries.

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“…A limitation can be the persistence of the cryptococcal antigen in patients with a prior episode of cryptococcosis. Further the cryptococcal antigen titre should not be used to monitor the therapy [9,10].…”

Section: Discussionmentioning

confidence: 99%