Diagnostic accuracy of novel sputum and non-sputum-based tuberculosis diagnostics in HIV-positive patients initiating anti-retroviral therapy

Date
2023-12
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Stellenbosch : Stellenbosch University
Abstract
ENGLISH ABSTRACT: Tuberculosis (TB) is a major health problem killing millions of people worldwide and is the leading cause of death among people living with HIV (PLHIV). PLHIV are at high risk of TB due to their weakened immune systems and 18 times more likely develop TB than people without HIV. Therefore, early detection of TB among PLHIV is fundamental and dependent on good TB diagnostics. The study addressed barriers and limitations of TB screening (triage) and diagnosis, with some limitations being facility-based active case finding, which is challenging, and delayed patient results. To highlight limitations and utility of tests in the pipeline, current and novel TB diagnostics were extensively reviewed (Chapter 2). Additionally, we tested selected PLHIV initiating antiretroviral therapy (ART), in whom TB detection is difficult due to their paucibacillary nature, are negative by the World Health Organization (WHO) recommended four-symptom screen (W4SS), and unable to produce sputum (Chapters 3 to 5). ART initiators were included irrespective of W4SS status, to challenge the existing TB testing algorithm in PLHIV. Formerly, W4SS was exclusively recommended for triage for further TB testing even in PLHIV. Due to W4SS’ suboptimal specificity and poor implementation, alternative triage tools are required, which we investigated. This includes C-reactive protein (CRP) (Chapter 3). CRP (≥10mg/l) had higher specificity than W4SS in ART initiators and reduces unnecessary downstream testing. Since CRP levels varied within groups of the same culture status, Chapter 4 investigated clinical and demographic factors associated with CRP levels, thereby informing which types of patients might be missed or falsely included by CRP-based triage algorithms. Low CD4 cell count, culture-confirmed TB, and increased TBScore II were strongly associated with elevated CRP. Sputum Xpert MTB/RIF Ultra (Ultra) is the frontline rapid pulmonary TB test in South Africa, however, supporting data PLHIV, among whom Ultra may offer sensitivity improvement over Xpert MTB/RIF (Xpert) is limited. Sputum expectoration is challenging in PLHIV, and easily accessible urine can mitigate this. Chapters 3 and 5 investigated the diagnostic accuracy of Ultra using urine versus Determine TB LAM Ag test (LF-LAM). Their performance was similar. We further investigated urine Fujifilm SILVAMP TB-LAM (FujiLAM) diagnostic accuracy versus that of LF-LAM (Chapter 5). FujiLAM had increased sensitivity and comparable specificity versus LF-LAM. However, FujiLAM’s diagnostic accuracy varied between different manufacturer lots. In summary, CRP (>10mg/l) would reduce unnecessary expensive downstream TB testing. CRP increases case detection especially in key and vulnerable populations. CRP data from this study contributed to a meta-analysis that informed the latest screening guidelines for TB, changing decades old triaging approaches. Sputum-Ultra is more sensitive than Xpert and detects ~1/2 W4SS-negative cases. Our sputum-Ultra data contributed to a systematic review evaluating the diagnostic accuracy of Xpert and Ultra, irrespective of W4SS status, and was the only study with Ultra data among PLHIV. TB detection in outpatient PLHIV can be improved with FujiLAM implementation if improved versions of the tests would be available. Non-sputum-based confirmatory tests with improved sensitivity are urgently needed to improve case detection especially in sputum-scarce and W4SS-negative people.
AFRIKAANSE OPSOMMING: Tuberkulose (TB) is 'n groot gesondheidsprobleem wat die dood van miljoene mense wêreldwyd veroorsaak en is die grootste oorsaak van sterftes onder mense wat met MIV (PLHIV) leef. PLHIV loop 'n hoë risiko om TB te kry as gevolg van hul verswakte immuunstelsels en is 18 keer meer geneig om TB te ontwikkel as mense sonder MIV. Daarom is vroeë opsporing van TB onder PLHIV fundamenteel en is ook afhanklik van goeie TB-diagnostiese hulpmiddels. Die studie het die belangrikste hindernisse en/of beperkings binne TB-diagnose geïdentifiseer, waarvan sommige, beperking fasiliteit-gebaseerde aktiewe gevallebevinding is, wat steeds uitdagend is, sowel as vertraagde pasiënt resultate. Om hierdie beperkings en bruikbaarheid van die toetse in die pyplyn uit te lig, is huidige en nuwe TB-diagnostieke breedvoerig in Hoofstuk 2 hersien. Daarbenewens het die huidige studie PLHIV-wie antiretrovirale terapie (ART) inisieer, wat tipies gemis word weens hul paucibacillêre aard, negatief is by die Wêreldgesondheidsorganisasie (WHO) vier-simptome skerm (W4SS), en onvermoë om sputum te produseer, gekies. Alle ART-inisieerders, ongeag hul W4SS-status is by die studie ingesluit, om die algoritme wat in plek is vir die toets van TB in PLHIV uit te daag. Tot onlangs was die W4SS die enigste instrument wat gebruik was vir verdere TB-toetse, selfs in PLHIV. As gevolg van die suboptimale spesifisiteit en swak implementering daarvan, is alternatiewe triage-instrumente ondersoek. Daarbenewens het ons C-reaktiewe proteïen (CRP) as 'n triage-toets in Hoofstuk 3 ondersoek. Die bevindinge van hierdie werk het getoon dat CRP (>10mg/l) hoër spesifisiteit as W4SS in ART-inisieerders gehad het, en dus onnodige stroomaf-toetse verminder. By die waarneming dat CRP-vlakke gewissel het binne groepe van dieselfde kultuur (en soms tussen verskillende kulture) status, het Hoofstuk 4 die kliniese en demografiese faktore wat met CRP geassosieer word, ondersoek, wat sodoende inlig watter tipe pasiënte gemis kan word of valslik deur CRP-gebaseerde triage-algoritmes ingesluit kan word. CD4-seltelling, kultuur-bevestigde TB en verhoogde TBScore II was sterk geassosieer met CRP. Sputum Xpert MTB/RIF Ultra (Ultra) is aan die voorpunt en die vinnige pulmonêre TB-toets in Suid-Afrika, maar ondersteunende data in PLHIV, onder wie Ultra sensitiwiteitsverbetering bo Xpert MTB/RIF (Xpert) kan bied, is beperk. Sputum-ekspektorasie is uitdagend in PLHIV, en maklik toeganklike urine kan sulke uitdagings beperk. Hoofstuk 3 en 5 het die diagnostiese akkuraatheid van Ultra met urine ondersoek, en hoe dit vergelyk word met dié van Determine TB LAM (LF-LAM). Hierdie twee toetse was soortgelyk. Ons het verder ondersoek ingestel na die diagnostiese akkuraatheid van urine Fujifilm SILVAMP TB-LAM (FujiLAM) teenoor dié van LF-LAM (Hoofstuk 5). FujiLAM het verhoogde sensitiwiteit en vergelykbare spesifisiteit teenoor LF-LAM. FujiLAM se diagnostiese akkuraatheid het egter gewissel tussen verskillende vervaardiger lotte. Samevattend sal CRP (>10mg/l) onnodige duur stroomaf TB-toetsing verminder. CRP verhoog die opsporing van gevalle, veral in sleutel- en kwesbare bevolkings. CRP-data uit hierdie studie het bygedra tot 'n meta-analise wat die jongste siftingsriglyne vir TB ingelig het, wat dekades oue triage-benaderings verander het. Sputum-Ultra is meer sensitief as Xpert en bespeur ~ 1/2 W4SS-negatiewe gevalle. Ons sputum-Ultra-data het bygedra tot 'n sistematiese oorsig wat die diagnostiese akkuraatheid van Xpert en Ultra evalueer, ongeag die W4SS-status, en was die enigste studie met Ultra-data onder PLHIV. TB-opsporing in buitepasiënt PLHIV kan verbeter word met FujiLAM-implementering indien verbeterde weergawes van die toets beskikbaar sou wees. Nie-sputum-gebaseerde bevestigende toetse met verbeterde sensitiwiteit is dringend nodig om gevalleopsporing te verbeter, veral by sputumskaars en W4SS-negatiewe mense.
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Thesis (PhD)--Stellenbosch University, 2023.
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