Early risk assessment in paediatric and adult household contacts of confirmed tuberculosis cases by novel diagnostic tests (ERASE-TB): protocol for a prospective, non-interventional, longitudinal, multicountry cohort study

Abstract

Introduction: The WHO End-TB Strategy calls for the development of novel diagnostics to detect tuberculosis (TB) earlier and more accurately. Better diagnostics, together with tools to predict disease progression, are critical for achieving WHO End-TB targets. The Early Risk Assessment in TB Contacts by new diagnoStic tEsts (ERASE-TB) study aims to evaluate novel diagnostics and testing algorithms for early TB diagnosis and accurate prediction of disease progression among household contacts (HHCs) exposed to confirmed index cases in Mozambique, Tanzania and Zimbabwe.

Methods and analysis: A total of 2100 HHCs (aged ≥10 years) of adults with microbiologically-confirmed pulmonary TB will be recruited and followed up at 6-month intervals for 18-24 months. At each time point, a WHO symptom screen and digital chest radiograph (dCXR) will be performed, and blood and urine samples will be collected. Individuals screening positive (WHO symptom screen or dCXR) will be requested to provide sputum for Xpert MTB/Rif Ultra. At baseline, HHCs will also be screened for HIV, diabetes (HbA1c), chronic lung disease (spirometry), hypertension and anaemia. Study outcomes will be coprevalent TB (diagnosed at enrolment), incident TB (diagnosed during follow-up) or no TB at completion of follow-up. Novel diagnostics will be validated using fresh and biobanked samples with a nested case-control design. Cases are defined as HHCs diagnosed with TB (for early diagnosis) or with incident TB (for prediction of progression) and will be matched by age, sex and country to HHCs who remain healthy (controls). Statistical analyses will include assessment of diagnostic accuracy by constructing receiver operating curves and calculation of sensitivity and specificity.

Ethics and dissemination: ERASE-TB has been approved by regulatory and ethical committees in each African country and by each partner organisation. Consent, with additional assent for participants <18 years, is voluntary. Attestation by impartial witnesses is sought in case of illiteracy. Confidentiality of participants is being maintained throughout. Study findings will be presented at scientific conferences and published in peer-reviewed international journals.

Trial registration number: NCT04781257.Cite Now.

Keywords: Diagnostic microbiology; RESPIRATORY MEDICINE (see Thoracic Medicine); Tuberculosis.

Figure 1

The ERASE-TB consortium. ERASE-TB, Early Risk Assessment in TB contactS by new diagnostic tEsts.

Figure 2

Location and characteristics of ERASE-TB study sites. The location of each study site is indicated by a red asterisk. Source data used within this figure are taken from the references. ERASE, Early Risk Assessment in TB contactS by new diagnostic tEsts; TB, tuberculosis.

Figure 3

Eligibility criteria and schedules of events for index cases and household contacts. A=depending on the time point of study enrolment and consequently on the duration available for follow-up, that is, 18 or 24 months, the follow-up visit at 24 months±30 days may be conditional; B=the follow-up visit by phone may be conducted after the last scheduled follow-up visit at 18 months±30 days or 24 months ±30 days to assess whether symptoms suggestive of TB have occurred, TB diagnosis has been made or anti-TB treatment has been initiated; C=unwell visits by phone or on-site may be conducted between scheduled follow-up visits if a participant presents at a recruitment healthcare facility with signs and symptoms suggestive of TB; D=coached spontaneous or induced sputum collection for storage at scheduled follow-up visit at 18 months±30 days or 24 months ±30 days, and for repetition of HIV testing if tested negative at baseline; E=coached spontaneous or induced sputum collection on the decision of the investigating team for testing by Xpert MTB/RIF Ultra if participant presents with signs and symptoms suggestive of TB; F=coached spontaneous or induced sputum collection in case of Xpert MTB/RIF Ultra positivity or strong clinical suspicion of TB for repetition of the Xpert MTB/RIF Ultra; G=in case of HIV positivity to be followed by the assessment of CD4 counts; H=CXR to be conducted at an unscheduled on-site unwell visit on the decision of the investigating team depending on the nature of symptoms reported, and the time elapsed since the last CXR including its findings; I=not to be conducted among pregnant women; J=stored venous blood includes 6 mL EDTA blood for whole blood and plasma, 4 mL serum and 2.5 mL PAXgene blood, all samples will be deep frozen for retrospective testing using new diagnostics as described in text; K=in case the evaluation of symptoms of a participant unable to present at a recruitment healthcare facility is required an unscheduled on-site or home visit will be arranged by phone, the resolution of symptoms can alternatively be addressed by phone; L=collection of PBMC at baseline and follow-up visit at 6 months±30 days is optional, thus will not be performed at each participating site and for each participant; M=in case the evaluation of symptoms of a participant unable to present at a recruitment healthcare facility is required or doubtful if required an unscheduled unwell visit by phone will be arranged, the resolution of symptoms can alternatively be addressed by phone; N=spirometry and/or diabetes (HbA1c) will be performed at scheduled follow-up visits at 6 months±30 days, 12 months ±30 days and 18 or 24 months±30 days if required or not performed at baseline, anaemia (Hb) will be performed at baseline and scheduled follow-up visits at 6 months±30 days, 12 months ±30 days and 18 or 24 months±30 days if possible; O=blood pressure measurement will be performed at baseline and scheduled follow-up visits at 6 months±30 days, 12 months ±30 days and 18 or 24 months±30 days; P=WGS to be performed once Mtb infection is confirmed and an isolate could be recovered. CD4, cluster of differentiation 4; CXR, chest radiograph; Hb, haemoglobin; HbA1c, glycated haemoglobin; IGRA, interferon gamma release assay; LAM, lioparabinomannan; MTB, Mycobacterium tuberculosis; MBLA, molecular bacterial load assay; PBMC, peripheral blood mononuclear cell; RIF, rifampicin; TAM-TB, T- cell activation marker tuberculosis; TB, tuberculosis; WGS, whole genome sequencing.

Figure 4

Study design. CXR, chest radiograph; FU, follow-up; HHC, household contact; IC, index case; MTB, Mycobacterium tuberculosis; pos=positive; RIF, rifampicin; SS, symptom score; TB, tuberculosis.