Reduced lung function and health-related quality of life after treatment for pulmonary tuberculosis in Gambian children: a cross-sectional comparative study.

BACKGROUND: Post-tuberculosis (post-TB) lung disease is an under-recognised consequence of pulmonary tuberculosis (pTB). We aimed to estimate the prevalence of residual lung function impairment and reduced health-related quality of life (HRQoL) in children after pTB treatment completion. METHODS: We conducted a cross-sectional comparative study of children aged less than 15 years at TB diagnosis who had completed treatment for pTB at least 6 months previously with a comparator group of age-matched children without a history of pTB. Symptoms, spirometry and HRQoL measured with PedsQL scale were collected. Variables associated with lung function impairment were identified through logistic regression models. RESULTS: We enrolled 68 post-TB cases (median age 8.9 (IQR 7.2-11.2) years) and 91 children in the comparison group (11.5 (8.0-13.7) years). Spirometry from 52 (76.5%) post-TB cases and 89 (94.5%) of the comparison group met the quality criteria for acceptability and repeatability. Lung function impairment was present in 20/52 (38.5%) post-TB cases and 15/86 (17.4%) in the comparison group, p=0.009. Previous pTB and a history of chronic cough were significantly associated with the presence of lung function impairment (p=0.047 and 0.006 respectively). Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC z-scores were significantly lower in the post-TB cases compared with the comparison group (p= <0.001, 0.014 and <0.001, respectively). The distribution of the self-reported physical health score, and parent-reported physical, emotional, psychological, social and total HRQoL scores were significantly lower in the post-TB cases compared with the comparison group. CONCLUSIONS: Previous TB in children is associated with significantly impaired lung function and HRQoL.

The impact of prior SARS-CoV-2 infection on host inflammatory cytokine profiles in patients with TB or other respiratory diseases.

Background: Tuberculosis (TB) and COVID-19 are the two leading causes of infectious disease mortality worldwide, and their overlap is likely frequent and inevitable. Previous research has shown increased mortality in TB/COVID-coinfected individuals, and emerging evidence suggests that COVID-19 may increase susceptibility to TB. However, the immunological mechanisms underlying these interactions remain unclear. In this study, we aimed to elucidate the impact of prior or concurrent COVID-19 infection on immune profiles of TB patients and those with other respiratory diseases (ORD). Methods: Serum and nasopharyngeal samples were collected from 161 Gambian adolescents and adults with either TB or an ORD. Concurrent COVID-19 infection was determined by PCR, while prior COVID-19 was defined by antibody seropositivity. Multiplex cytokine immunoassays were used to quantify 27 cytokines and chemokines in patient serum samples at baseline, and throughout treatment in TB patients. Results: Strikingly, TB and ORD patients with prior COVID-19 infection were found to have significantly reduced expression of several cytokines, including IL-1ß, TNF-α and IL-7, compared to those without (p<0.035). Moreover, at month-six of anti-TB treatment, seropositive patients had lower serum Basic FGF (p=0.0115), IL-1ß (p=0.0326) and IL-8 (p=0.0021) than seronegative. TB patients with acute COVID-19 coinfection had lower levels of IL-8, IL-13, TNF-α and IP-10 than TB-only patients, though these trends did not reach significance (p>0.035). Conclusions: Our findings demonstrate that COVID-19 infection alters the subsequent response to TB and ORDs, potentially contributing to pathogenesis. Further work is necessary to determine whether COVID-19 infection accelerates TB disease progression, though our results experimentally support this hypothesis.

Vitamin D in Gambian children with discordant tuberculosis (TB) infection status despite matched TB exposure: a case control study.

Using a matched case control design conducted at MRC Gambia in 2015, we measured vitamin D levels in pairs of asymptomatic children with discordant tuberculin skin test status despite the same sleeping proximity to the same adult TB index case. Median ages of groups (infected; 10.0 years, uninfected 8.8 years) were not significantly different (p = 0.13). Mean vitamin D levels were 2.05 ng/mL (95% CI - 0.288 to 4.38) higher in 24 highly TB-exposed uninfected children compared with 24 matched highly TB-exposed infected children (p = 0.08). The findings warrant further investigation in larger studies to understand the implications and significance. Conclusion: Vitamin D levels were higher in TB-uninfected children compared with TB-infected despite equal high exposure to a TB case.

Exploring the perspectives of members of international tuberculosis control and research networks on the impact of COVID-19 on tuberculosis services: a cross sectional survey.

BACKGROUND: The COVID-19 pandemic has caused major disruption to healthcare services globally and has impacted on tuberculosis (TB) patients and TB diagnosis and treatment services both in low- and high-income countries. We therefore explored the perspectives of members of regional and international TB control and research networks to further understand TB service disruptions and compared the experiences of members from West African and European countries. METHODS: This cross-sectional, explorative descriptive study was conducted from May to July 2020 using an open online survey with target respondents from both West African and European countries. The survey comprised discrete questions exploring challenges faced with TB screening, diagnosis, treatment, prevention, and changes implemented. Additionally, respondents were asked to provide recommendations for remedial actions. RESULTS: We analysed responses from 124 respondents based in 29 countries located in Europe and West Africa. About half of the respondents reported challenges in delivering routine TB services during the COVID-19 pandemic, with over one third reporting having some form of guidance issued regarding maintaining delivery of routine TB services. Respondents emphasised the need for strengthening TB services especially in light of COVID-19 pandemic. Considerable similarities were found between the challenges experienced by TB professionals in both West African and European settings. Responses also highlighted the hidden challenges faced in some countries prior to the COVID-19 pandemic, especially in some West African settings where staff shortages and laboratory issues predated COVID-19. CONCLUSIONS: TB control and research professionals in West African and European settings experienced similar challenges to the delivery of TB diagnosis and treatment services due to the COVID-19 pandemic, and highlighted the need for clear communication of guidelines, prioritisation of routine TB service delivery, ongoing health education, and possible integration of TB and COVID-19 services to ensure that TB services are more resilient against the impact of the pandemic.

Adaptation of WHO's generic tuberculosis patient cost instrument for a longitudinal study in Africa.

The WHO developed a generic 'TB patient cost survey' tool and a standardized approach to assess the direct and indirect costs of TB incurred by patients and their households, estimate the proportion of patients experiencing catastrophic costs, and measure the impact of interventions to reduce patient costs. While the generic tool is a facility-based cross-sectional survey, this standardized approach needs to be adapted for longitudinal studies. A longitudinal approach may overcome some of the limitations of a cross-sectional design and estimate the economic burden of TB more precisely. We describe the process of creating a longitudinal instrument and its application to the TB Sequel study, an ongoing multi-country, multi-center observational cohort study. We adapted the cross-sectional WHO generic TB patient cost survey instrument for the longitudinal study design of TB Sequel and the local context in each study country (South Africa, Mozambique, Tanzania, and The Gambia). The generic instrument was adapted for use at enrollment (start of TB treatment; Day 0) and at 2, 6, 12 and 24 months after enrollment, time points intended to capture costs incurred for diagnosis, during treatment, at the end of treatment, and during long-term follow-up once treatment has been completed. These time points make the adapted version suitable for use in patients with either drug-sensitive or drug-resistant TB. Using the adapted tool provides the opportunity to repeat measures and make comparisons over time, describe changes that extend beyond treatment completion, and link cost survey data to treatment outcomes and post-TB sequelae. Trial registration: ClinicalTrials.gov: NCT032516 August 1196, 2017. Abbreviations: DOTS: Directly observed treatment, short-course; DR-TB: Drug-resistant tuberculosis; MDR-TB: Multi-drug resistant tuberculosis; NTP: National Tuberculosis Programme; TB: Tuberculosis; USD: United States Dollar; WHO: World Health Organization.

A three-marker protein biosignature distinguishes tuberculosis from other respiratory diseases in Gambian children.

BACKGROUND: Our study aimed to identify a host cytokine biosignature that could distinguish childhood tuberculosis (TB) from other respiratory diseases (OD). METHODS: Cytokine responses in prospectively recruited children with symptoms suggestive of TB were measured in whole blood assay supernatants, harvested after overnight incubation, using a Luminex platform. We used logistic regression models with Least Absolute Shrinkage and Selection Operator (LASSO) penalty to identify the optimal biosignature associated with confirmed TB disease in the training set. We subsequently assessed its performance in the test set. FINDINGS: Of the 431 children included in the study, 44 had bacteriologically confirmed TB, 60 had clinically diagnosed TB while 327 had OD. All children were HIV-negative. Application of LASSO regression models to the training set (n = 260) resulted in the combination of IL-1ra, IL-7 and IP-10 from unstimulated samples as the optimally discriminant cytokine biosignature associated with bacteriologically confirmed TB. In the test set (n = 171), this biosignature distinguished children diagnosed with TB disease, irrespective of microbiological confirmation, from OD with area under the receiver operator characteristic curve (AUC) of 0•74 (95% CI: 0•67, 0•81), and demonstrated sensitivity and specificity of 72•2% (95% CI: 60•4, 82•1%) and 75•0% (95% CI: 64•9, 83•4%) respectively, with its performance independent of their age group and their age- and sex-adjusted nutritional status. INTERPRETATION: This novel biosignature of childhood TB derived from unstimulated supernatants is promising. Independent validation with further optimisation will improve its performance and translational potential. FUNDING: Steinberg Fellowship (McGill University); Grand Challenges Canada; MRC Program Grant.

Protection against mycobacterial infection: A case-control study of mycobacterial immune responses in pairs of Gambian children with discordant infection status despite matched TB exposure.

BACKGROUND: Children are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design. METHODS: We recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly TB-Exposed Uninfected or Highly TB-Exposed Infected children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette-Guérin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses. FINDINGS: 29 pairs of matched Highly TB-Exposed Uninfected and Highly TB-Exposed Infected children aged 5 to 15 years old were enroled. Samples from Highly TB-Exposed Uninfected children had higher levels of mycobacterial luminescence at 96 hours than Highly TB-Exposed Infected children. Highly TB-Exposed Uninfected children also produced less BCG-specific interferon-γ than Highly TB-Exposed Infected children at 24 hours and at 96 hours. INTERPRETATION: Highly TB-Exposed Uninfected children showed less control of mycobacterial growth compared to Highly TB-Exposed Infected children in a functional assay, whilst cytokine responses mirrored infection status. FUNDING: Clinical Research Training Fellowship funded under UK Medical Research Council/Department for International Development Concordat agreement and part of EDCTP2 programme supported by European Union (MR/K023446/1). Also MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122).

Elevated serum 25-hydroxy (OH) vitamin D levels are associated with risk of TB progression in Gambian adults.

BACKGROUND: Vitamin D is essential in the host defence against tuberculosis (TB) as an immune modulator. The aim of this study was to determine the level of 25-hydroxyvitamin D (25 (OH) D) from adult TB index cases before and after treatment and their exposed household contacts (HHC) in The Gambia. METHODS: Serum from adult index TB cases and their TB-exposed household contacts (HHC) was analysed for 25(OH) D and Vitamin D binding protein (VDBP) concentrations. Tuberculin skin test (TST) status was used as a measure of Mycobacterium tuberculosis (Mtb) infectivity in the HHC. In addition, HHC who later progressed to active TB (incident cases) were assessed alongside non-progressors to determine the influence of 25 (OH) D levels on TB risk. RESULTS: Eighty-three TB cases, 46 TST+ and 52 TST- HHC were analysed. Generally levels of 25(OH) D were considered insufficient in all subjects. However, median levels of 25(OH) D and VDBP were significantly higher in TB cases compared to both TST+ and TST- HHC at recruitment and were significantly reduced after TB therapy (p < 0.0001 for all). In addition, levels of serum 25(OH) D at recruitment were significantly higher in TB progressors compared to non-progressors (median (IQR): 25.0(20.8-29.2) in progressors and 20.3 (16.3-24.6) ng/ml in non-progressors; p = 0.007). CONCLUSION: In The Gambia, an equatorial country, 25(OH) D levels are higher in serum of TB progressors and those with active disease compared to latently infected and uninfected subjects. These results contrast to findings in non-equatorial countries.

No added value of interferon-γ release to a prediction model for childhood tuberculosis.

The predictive value of a combination of clinical and radiological features with interferon-γ release assay (IGRA) for diagnosis of active tuberculosis (TB) disease among TB-exposed children is unknown.150 symptomatic HIV-negative children (aged 3 months to 14 years), prospectively recruited through active contact tracing, were included. Backward stepwise logistic regression and bootstrapping techniques were used for the development and internal validation of a clinical prediction model for active TB disease. Model discrimination and incremental value of a positive IGRA test were assessed by area under the receiver operating characteristic curve (AUC).35 (23%) children were diagnosed with active TB disease and started on treatment and 115 (77%) had other respiratory tract infections. A final parsimonious clinical model, comprising age <5 years (adjusted (a)OR 4.8, 95% CI 2.0-11.5) and lymphadenopathy on clinical examination (aOR 4.9, 95% CI 1.8-13.0) discriminated active TB disease from other disease with an AUC of 0.70 (95% CI 0.61-0.80). A positive IGRA result did not improve the discriminatory ability of the clinical model (c-statistic 0.72 versus 0.70; p=0.644).A clinical algorithm, including age <5 years and lymphadenopathy classified 70% of active TB disease among symptomatic TB-exposed children. IGRA does not add any discriminatory value to this prediction model.