Impact of Systematic Early Tuberculosis Detection Using Xpert MTB/RIF Ultra in Children With Severe Pneumonia in High Tuberculosis Burden Countries (TB-Speed Pneumonia)
Condition: Tuberculosis; Severe Pneumonia; Covid19
MeSH terms: Pneumonia; Tuberculosis
Study type: Interventional

Summary: 
      Despite progress in reducing tuberculosis (TB) incidence and mortality in the past 20 years,
      TB is a top ten cause of death in children under 5 years worldwide. However, childhood TB
      remains massively underreported and undiagnosed, mostly because of the challenges in
      confirming its diagnosis due to the paucibacillary nature of the disease and the difficulty
      in obtaining expectorated sputum in children.

      Pneumonia is the leading cause of death in children under the age of 5 years worldwide. There
      is growing evidence that, in high TB burden settings, TB is common in children with
      pneumonia, with up to 23% of those admitted to hospital with an initial diagnosis of
      pneumonia later being diagnosed as TB. However, the current World Health Organization (WHO)
      standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if
      the child has a history of prolonged symptoms or fails to respond to antibiotic treatments.
      Hence, TB is often under-diagnosed or diagnosed late in children presenting with pneumonia.

      In this context, the investigators are proposing to assess the impact on mortality of adding
      the systematic early detection of TB using Xpert MTB/RIF Ultra, performed on NPAs and stool
      samples, to the WHO SOC for children with severe pneumonia, followed by immediate initiation
      of anti-TB treatment in children testing positive on any of the samples.

      TB-Speed Pneumonia is a multicentric, stepped wedge diagnostic trial conducted in six
      countries with high TB incidence: Cote d'Ivoire, Cameroon, Uganda, Mozambique, Zambia and
      Cambodia.

      The sub-study on Covid-19 will assess the prevalence and impact of the Covid-19 in young
      children hospitalized with severe pneumonia. The sub-study findings are expected to guide
      policy makers and clinicians on potential specific screening and management measures for
      these vulnerable groups of children. They are also key to analysing TB-Speed Pneumonia
      results on mortality in a context of the Covid-19 outbreak and to take into consideration
      SARS-CoV-2 infection status in the main study analysis.
    

Detailed description: 
      Pneumonia is the leading cause of death in children under the age of 5 years worldwide.

      There is growing evidence that, in high TB burden settings, TB is common in children with
      pneumonia, with up to 23% of those admitted to hospital with an initial diagnosis of
      pneumonia later being diagnosed as TB]. This is particularly true in the African and Asian
      WHO regions, which accounted for 30% and 35% of all paediatric TB cases in 2016 respectively.

      In these regions, the case fatality rate for childhood pneumonia associated with TB is high,
      ranging from 4% to 21% [8], with younger age, malnutrition and HIV infection increasing the
      risk of death.

      The current standard of care (SOC) for young children with pneumonia considers a diagnosis of
      TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic
      treatments. Hence, TB is often under-diagnosed or diagnosed late in children presenting with
      pneumonia. Although TB is a chronic disease in adults, recent data show that the duration of
      respiratory symptoms before admission can be acute in children with severe pneumonia
      associated with TB [8]. Hence, Identifying TB cases early and shortening the diagnostic delay
      to initiate appropriate TB treatment in children with clinical presentation of severe acute
      pneumonia is likely to reduce mortality.

      An improved molecular diagnostic tool for paediatric TB:

      Xpert MTB/RIF (Cepheid, USA) is an automated nucleic acid amplification test (NAAT) that
      simultaneously detects Mycobacterium tuberculosis (MTB) and genes associated with resistance
      to rifampicin. The assay was a major breakthrough in bringing molecular tests for the
      diagnosis of TB closer to the community, with performances close to mycobacterial culture.
      WHO therefore recommended Xpert MTB/RIF as the first test to be used for the diagnosis of TB
      among populations who may have drug-resistant and/or HIV-associated TB.

      In 2013, WHO updated its policy to include Xpert MTB/RIF as the initial test for the
      diagnosis of TB in children, based on a systematic review and meta-analysis showing a pooled
      sensitivity of 66% (CI 95% 51-81) and a specificity of 98% (CI 95% 96-99) of Xpert MTB/RIF
      performed on gastric lavages when compared with culture. WHO recommendations, detailed in the
      2014 guidance on paediatric TB, stated that Xpert MTB/RIF may be used instead of smear
      microscopy in all children and should be used in children with HIV infection or presumptive
      multidrug-resistant TB.

      Although data on the performance of Xpert MTB/RIF in children with pneumonia is limited, in
      Bangladesh, sensitivity on gastric aspirates or sputum samples compared to culture in this
      group was equivalent to that reported in other studies.

      The next-generation of Xpert MTB/RIF assay, Xpert MTB/RIF Ultra (Ultra), has a limit of
      detection of 16 colony forming units (CFU)/mL (compared to the current version which detects
      130 CFU/mL), representing an approximately 8-fold improvement. This lower threshold is
      similar to the detection level of culture and would facilitate the rapid diagnosis of
      paucibacillary TB disease as seen in children. Retrospective analyses on frozen respiratory
      samples in children have shown a sensitivity of 71% for Ultra versus 47% for Xpert MTB/RIF. A
      recently published study reveals, however, a lower specificity of U ltra in adults,
      particularly in those with a previous history of TB, potentially resulting in false diagnoses
      and overtreatment of TB. Though further prospective studies are needed, the risk of
      false-positive results could be less significant in children as only a small proportion of
      children have previously had TB. The estimated clinical impact of Ultra is therefore likely
      to vary depending on the settings, with a recent modelling exercise finding a larger
      mortality benefit in patient populations with high TB prevalence, high HIV prevalence, and
      high case fatality ratios for untreated TB.

      The current WHO recommendations for the use of Xpert MTB/RIF also apply to the use of Ultra
      as the initial diagnostic test for all adults and children with signs and symptoms of TB. An
      update of the current guidelines for the use of Ultra is planned for 2018.

      Alternative specimen collection methods adapted to children:

      Young children are frequently unable to expectorate sputum and there is no clear evidence and
      guidance on which specimen or combination of specimens should be used in order to maximize
      the probability of bacteriological confirmation of TB in children. At the programmatic level,
      implementation of gastric aspirates and induced sputum can be challenging].

      Our research group and other groups in Africa and Asia have shown that alternative specimen
      collection methods such as nasopharyngeal aspirates (NPA) and stool samples are easier to be
      implemented in resource-limited settings and are better tolerated in young and sick children.
      These methods do not require a child to fast (as for gastric aspirates) and are more suitable
      than induced sputum in children with severe respiratory deficit. In children with presumptive
      TB, Xpert MTB/RIF has a sensitivity on NPAs close to the one achieved with induced sputum
      [28], [35]. Recent studies have shown similar sensitivity of Xpert MTB/RIF on the combination
      of one stool and one NPA as compared to two induced sputum or two gastric aspirates. Stool
      testing by Xpert MTB/RIF shows results close to respiratory samples in terms of sensitivity
      but requires a simplified specimen processing methodology for further field use. The
      flotation method, based on Sheather's sucrose solution used in the PAANTHER study, showed
      promising results but relies on centrifugation and other labour-intensive processes. Stool
      processing will be further optimized in Output 4 of the TB-Speed project to enable
      implementation at a lower healthcare level.

      Most studies on childhood TB diagnostics are early proof-of-concepts or studies that evaluate
      diagnostic accuracy, collecting and testing multiples samples using existing microbiological
      tests. Implementation studies, with patient health outcomes as the primary endpoint of
      interest, are seldom implemented despite the need for such studies to inform policies. The
      WHO recommendation to use Xpert MTB/RIF in children was based on diagnostic accuracy, but
      evidence of its impact on TB outcome has not been evaluated. As in adults, its use in
      children may have a limited impact on outcome in children with a strong suspicion of TB, due
      to the common use of empirical treatment in these populations [48]-[51]. However, this is
      likely to be different in children with severe pneumonia presenting with acute symptoms, for
      which TB is usually suspected only after empiric antibiotic treatment has been shown to be
      ineffective.

      The TB-Speed approach to early detection of TB in children with severe pneumonia:

      In line with the strategies advocated by the National Tuberculosis Programmes (NTPs) in
      participating countries, the TB-Speed project aims not only to contribute to the reduction of
      TB-associated mortality, but also to initiate an innovative approach for the early detection
      and treatment of TB in young children with severe pneumonia to enable access to high-quality
      healthcare in this highly vulnerable group.

      Our hypothesis is that in high TB burden countries, testing young children with severe
      pneumonia for TB and starting those who test positive on anti-TB treatment on the day of
      presentation, could reduce all-cause mortality through reduction of mortality attributed to
      TB. In this context, the investigators are proposing a research study to assess the impact on
      mortality of adding the systematic early detection of TB using Ultra performed on NPAs and
      stool samples to the WHO SOC for children with severe pneumonia, followed by immediate
      initiation of anti-TB treatment in children testing positive on any of the samples. If
      successful, this intervention could be systematically implemented at district hospital level
      where children with severe pneumonia are referred. Furthermore, the investigators hypothesize
      that the intervention will raise TB awareness among clinicians and may lead to more empirical
      TB treatment initiated as compared to the control. This further justifies the stepped-wedge
      design chosen for this study.

      From a health economics perspective, the investigators hypothesize that benefits in terms of
      survival and Disability Adjusted Life Years (DALYs) will outweigh extra costs incurred by
      systematic Ultra testing in children with severe pneumonia.

      Mortality in children aged 2 to 59 months hospitalized with severe pneumonia and mortality
      attributable to TB:

      There were an estimated 120 million pneumonia episodes in children younger than 5 years in
      2011, including 14 million severe episodes. 1.3 million pneumonia episodes led to death. In
      2014, WHO revised definitions for pneumonia and severe pneumonia, considering
      'chest-indrawing pneumonia' as non-severe and downgrading 'pneumonia with severity signs'
      from very severe to severe. Ambulatory care and oral antibiotics are now recommended for
      'chest-indrawing pneumonia' and now only severe pneumonia justifies referral from primary
      health centres to district hospitals for intra-venous (IV) antibiotics and oxygen therapy if
      needed.

      Participating countries and added value of the multi-country aspect:

      The impact of this innovative approach may vary with TB incidence as well as some
      geographical and seasonal variability that can affect the prevalence and aetiology of
      pneumonia in young children. To provide a better basis for the generalizability of results,
      the project will take place in six countries with different epidemiological and environmental
      backgrounds, in Sub-Saharan Africa (Cameroon, Cote d'Ivoire, Mozambique, Uganda, and Zambia)
      and South East Asia (Cambodia). Cambodia, Zambia and Mozambique are among the 30 high TB
      burden countries according to WHO classification.

      The sub-study on Covid-19 will assess the prevalence and impact of the Covid-19 in young
      children hospitalized with severe pneumonia. The sub-study findings are expected to guide
      policy makers and clinicians on potential specific screening and management measures for
      these vulnerable groups of children. They are also key to analysing TB-Speed Pneumonia
      results on mortality in a context of the Covid-19 outbreak and to take into consideration
      SARS-CoV-2 infection status in the main study analysis. The sub-study will be implemented in
      all participating countries except Cambodia.

      At the time of enrolment in the TB-Speed Pneumonia main study, patients will be also offered
      to participate to the Covid ancillary study. Children will be tested for SARS-Cov-2 on the
      day of enrolment. The duration of enrolment in the sub-study will be of 6 months in total.
      Duration of follow-up for a particular participant will be 12 weeks, as in the main Pneumonia
      study.
    

Intervention name(s): Xpert MTB/RIF Ultra (Ultra)
Intervention type(s): Diagnostic Test
Intervention description(s): The intervention will consist of the WHO standard of care for children with severe pneumonia plus the study intervention consisting in rapid detection of TB on the day of hospital admission using the Ultra assay performed on 1 NPA and 1 stool sample.
The sample flow will be organised to reduce time-to-results to 3 hours. Ultra will be performed at the hospital laboratory using a standard GeneXpert device, or implemented directly inward using a one-module, battery-operated GeneXpert device (G1 Edge).
Drugs will be available at the inpatient level to enable immediate initiation of TB treatment, as soon as a positive Ultra result is available.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The TB-Speed Pneumonia study is a stepped wedge cluster-randomised trial. Clusters, i.e.hospitals, will successively switch from control to intervention in an order randomly assigned, until all clusters are eventually exposed to the intervention.
The TB-Speed Pneumonia study will be implemented in 15 hospitals. At the start of the study, all hospital will be implementing the WHO SOC for severe pneumonia (control arm). One hospital will then switch to the TB-Speed strategy (intervention arm) every 5 weeks.
Randomisation will be stratified on the country estimated TB incidence rate (see Table 3): <300/100,000 patients-years (Cameroon, Cote d'Ivoire and Uganda) vs. ≥300/100,000 patients-years (Cambodia, Mozambique and Zambia).
Masking: None (Open Label)
Primary purpose: Diagnostic