The diagnosis of central nervous system infections in resource-limited settings and the use of novel and molecular diagnostic platforms to improve diagnosis

ABSTRACT

Introduction

Central nervous system infections (CNSI) disproportionately affect individuals in low-resource settings where diagnosis is challenging; large proportions of patients never receive a confirmed microbiological diagnosis resulting in inadequate management and high mortality. The epidemiology of CNSI varies globally and conventional diagnostics deployed in resource-limited settings have significant limitations, with an urgent need for improved diagnostic strategies.

Areas covered

This review describes molecular platforms and other novel diagnostics used in the diagnosis of CNSI that are applicable to resource-limited settings. An extensive literature search of Medline and PubMed was performed. The emphasis is on investigations targeting infections of relevance to resource-limited settings either due to variation in regional CNSI epidemiology or due to increased prevalence in patients with immunosuppression. This includes commercially available multiplex PCR platforms, mycobacterial PCR platforms, and rapid diagnostics tests. To offer a framework for the optimal implementation in clinical settings, existing evidence highlighting the advantages and limitations of available platforms is reviewed.

Expert opinion

The implementation of molecular platforms and other novel diagnostics has the potential to transform CNSI diagnosis in resource-limited settings, with several examples of successful rollout of novel diagnostics such as Xpert MTB/RIF Ultra and cryptococcal antigen testing.

KEYWORDS:

• Meningitis
• central nervous system infection
• diagnostics
• molecular diagnostics
• polymerase chain reaction
• resource-limited
• low- and middle-income country

Article highlights

• Central nervous system infections continue to cause significant morbidity and mortality in low-resource settings with a substantial proportion of patients never receiving a confirmed diagnosis largely due to limitations in access to novel and molecular diagnostics. There is an urgent need to implement improved diagnostic platforms tailored to local epidemiology in resource-limited settings.

• Multiplex PCR platforms have the potential to improve diagnostic capability in resource-limited settings and have been successfully implemented in laboratories with little to no experience of using molecular diagnostics but financial constraints often limit their use.

• Tuberculous meningitis (TBM) is a leading cause of central nervous system infections in resource-limited settings however limitations in the diagnosis in TBM persist. Although Xpert MTB/RIF Ultra is a notable advancement in the diagnosis of TBM it remains insufficiently sensitive to exclude TBM.

• Although metagenomic sequencing costs remain high they have decreased in recent years and the COVID-19 pandemic has resulted in significantly expanded sequencing capacity. Strategic, targeted use of metagenomic sequencing on CSF samples has the potential to identify rare or novel pathogens and guide analyte selection in multiplex PCR panels deployed in resource-limited settings.

Declaration of interest

J Milburn and JN Jarvis have received investigator-initiated funding from BioMérieux. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

JM and JNJ received investigator-initiated funding from BioMerieux. JNJ is funded by the National Institute for Health Research (NIHR) through a Global Health Research Professorship to JNJ (RP-2017-08-ST2- 012) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care.