Undernutrition as a risk factor for tuberculosis disease.

BACKGROUND: Tuberculosis (TB) is a leading cause of mortality due to an infectious disease, with an estimated 1.6 million deaths due to TB in 2022. Approximately 25% of the global population has TB infection, giving rise to 10.6 million episodes of TB disease in 2022. Undernutrition is a key risk factor for TB and was linked to an estimated 2.2 million TB episodes in 2022, as outlined in the World Health Organization (WHO) Global Tuberculosis Report. OBJECTIVES: To determine the prognostic value of undernutrition in the general population of adults, adolescents, and children for predicting tuberculosis disease over any time period. SEARCH METHODS: We searched the literature databases MEDLINE (via PubMed) and WHO Global Index Medicus, as well as the WHO International Clinical Trials Registry Platform (ICTRP) on 3 May 2023 (date of last search for all databases). We placed no restrictions on the language of publication. SELECTION CRITERIA: We included retrospective and prospective cohort studies, irrespective of publication status or language. The target population comprised adults, adolescents, and children from diverse settings, encompassing outpatient and inpatient cohorts, with varying comorbidities and risk of exposure to tuberculosis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and the Quality In Prognosis Studies (QUIPS) tool to assess the risk of bias of the studies. Prognostic factors included undernutrition, defined as wasting, stunting, and underweight, with specific measures such as body mass index (BMI) less than two standard deviations below the median for children and adolescents and low BMI scores (< 18.5) for adults and adolescents. Prognostication occurred at enrolment/baseline. The primary outcome was the incidence of TB disease. The secondary outcome was recurrent TB disease. We performed a random-effects meta-analysis for the adjusted hazard ratios (HR), risk ratios (RR), or odds ratios (OR), employing the restricted maximum likelihood estimation. We rated the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 51 cohort studies with over 27 million participants from the six WHO regions. Sixteen large population-based studies were conducted in China, Singapore, South Korea, and the USA, and 25 studies focused on people living with HIV, which were mainly conducted in the African region. Most studies were in adults, four in children, and three in children and adults. Undernutrition as an exposure was usually defined according to standard criteria; however, the diagnosis of TB did not include a confirmatory culture or molecular diagnosis using a WHO-approved rapid diagnostic test in eight studies. The median follow-up time was 3.5 years, and the studies primarily reported an adjusted hazard ratio from a multivariable Cox-proportional hazard model. Hazard ratios (HR) The HR estimates represent the highest certainty of the evidence, explored through sensitivity analyses and excluding studies at high risk of bias. We present 95% confidence intervals (CI) and prediction intervals, which present between-study heterogeneity represented in a measurement of the variability of effect sizes (i.e. the interval within which the effect size of a new study would fall considering the same population of studies included in the meta-analysis). Undernutrition may increase the risk of TB disease (HR 2.23, 95% CI 1.83 to 2.72; prediction interval 0.98 to 5.05; 23 studies; 2,883,266 participants). The certainty of the evidence is low due to a moderate risk of bias across studies and inconsistency. When stratified by follow-up time, the results are more consistent across < 10 years follow-up (HR 2.02, 95% CI 1.74 to 2.34; prediction interval 1.20 to 3.39; 22 studies; 2,869,077 participants). This results in a moderate certainty of evidence due to a moderate risk of bias across studies. However, at 10 or more years of follow-up, we found only one study with a wider CI and higher HR (HR 12.43, 95% CI 5.74 to 26.91; 14,189 participants). The certainty of the evidence is low due to the moderate risk of bias and indirectness. Odds ratio (OR) Undernutrition may increase the odds of TB disease, but the results are uncertain (OR 1.56, 95% CI 1.13 to 2.17; prediction interval 0.61 to 3.99; 8 studies; 173,497 participants). Stratification by follow-up was not possible as all studies had a follow-up of < 10 years. The certainty of the evidence is very low due to the high risk of bias and inconsistency. Contour-enhanced funnel plots were not reported due to the few studies included. Risk ratio (RR) Undernutrition may increase the risk of TB disease (RR 1.95, 95% CI 1.72 to 2.20; prediction interval 1.49 to 2.55; 4 studies; 1,475,867 participants). Stratification by follow-up was not possible as all studies had a follow-up of < 10 years. The certainty of the evidence is low due to the high risk of bias. Contour-enhanced funnel plots were not reported due to the few studies included. AUTHORS' CONCLUSIONS: Undernutrition probably increases the risk of TB two-fold in the short term (< 10 years) and may also increase the risk in the long term (> 10 years). Policies targeted towards the reduction of the burden of undernutrition are not only needed to alleviate human suffering due to undernutrition and its many adverse consequences, but are also an important part of the critical measures for ending the TB epidemic by 2030. Large population-based cohorts, including those derived from high-quality national registries of exposures (undernutrition) and outcomes (TB disease), are needed to provide high-certainty estimates of this risk across different settings and populations, including low and middle-income countries from different WHO regions. Moreover, studies including children and adolescents and state-of-the-art methods for diagnosing TB would provide more up-to-date information relevant to practice and policy. FUNDING: World Health Organization (203256442). REGISTRATION: PROSPERO registration: CRD42023408807 Protocol: https://doi.org/10.1002/14651858.CD015890.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

Evaluation of the uptake of tuberculosis preventative therapy for people living with HIV in Namibia: a multiple methods analysis.

BACKGROUND: In 2016, Namibia had ~ 230,000 people living with HIV (PLHIV) and 9154 new tuberculosis (TB) cases, including 3410 (38%) co-infected cases. TB preventative therapy (TPT), consisting of intensive case finding and isoniazid preventative therapy, is critical to reducing TB disease and mortality. METHODS: Between November 2014 and February 2015, data was abstracted from charts of PLHIV enrolled in HIV treatment. Fifty-five facilities were purposively selected based on patient volume, type and location. Charts were randomly sampled. The primary outcome was to estimate baseline TPT in PLHIV, using nationally weighted proportions. Qualitative surveys were conducted and summarized to evaluate TPT practices and quantify challenges encountered by health care workers (HCW). RESULTS: Among 861 PLHIV sampled, 96% were eligible for TPT services, of which 87.1% were screened for TB at least once. For PLHIV eligible for preventative therapy (646/810; 82.6%), 45.4% (294/646) initiated therapy and 45.7% (139/294) of those completed therapy. The proportion of eligible PLHIV completing TB screening, initiating preventative therapy and then completing preventative therapy was 20.7%. Qualitative surveys with 271 HCW identified barriers to TPT implementation including: lack of training (61.3% reported receiving training on TPT); misunderstandings about timing of TPT initiation (46.7% correctly reported TPT should be started with antiretroviral therapy); and variable screening practices and responsibilities (66.1% of HCWs screened for TB at every encounter). Though barriers were evident, 72.2% HCWs surveyed described their clinical performance as very good, often placing responsibility of difficulties on patients and downplaying challenges like staff shortages and medication stock outs. CONCLUSIONS: In this study, only 1 in 5 eligible PLHIV completed the TPT cascade in Namibia. Lack of training, irregularities with TB screening and timing of TPT, unclear prescribing and recording responsibilities, and a clinical misperception may have contributed to suboptimal programmatic implementation. Addressing these challenges will be critical with continued TPT scale-up.

Predictors of tuberculosis treatment success under the DOTS program in Namibia.

OBJECTIVES: Optimal treatment success rates are critical to end tuberculosis in Namibia. Despite the scale-up of high quality directly observed therapy short-course strategy (DOTS) in Namibia, treatment success falls short of the global target of 90%. The objective of this study was to ascertain the predictors of treatment success rates under DOTS in Namibia to provide future direction. METHODS: A nation-wide comparative analysis of predictors of treatment success was undertaken. Tuberculosis cases in the electronic tuberculosis register were retrospectively reviewed over a 10-year period, 2004-2016. The patient, programmatic, clinical, and treatment predictors of treatment success were determined by multivariate logistic regression modeling using R software. RESULTS: 104,603 TB cases were registered at 300 DOTS sites in 37 districts. The 10-year period treatment success rate was 80%, and varied by region (77.2%-89.2%). The patient's sex and age were not significant predictors. The independent predictors for treatment success as were: Region of DOTS implementation (p=0.001), type of directly observed treatment (DOT) supporter (p<0.001), sputum conversion at 2 months (p=0.013), DOT regimen (p<0.001), cotrimoxazole prophylaxis (p=0.002), and HIV co-infection (p=0.001). CONCLUSION: Targeted programmatic, clinical and treatment interventions are required to enhance DOTS treatment success in Namibia. These are now ongoing.

Adverse events and patients' perceived health-related quality of life at the end of multidrug-resistant tuberculosis treatment in Namibia.

PURPOSE: The health-related quality of life (HRQoL) of patients completing multidrug-resistant tuberculosis (MDR-TB) treatment in Namibia and whether the occurrence of adverse events influenced patients' rating of their HRQoL was evaluated. PATIENTS AND METHODS: A cross-sectional analytic survey of patients completing or who recently completed MDR-TB treatment was conducted. The patients rated their HRQoL using the simplified Short Form-™ (SF-8) questionnaire consisting of eight Likert-type questions. Three supplemental questions on the adverse events that the patients may have experienced during their MDR-TB treatment were also included. Scoring of HRQoL ratings was norm-based (mean =50, standard deviation =10) ranging from 20 (worst health) to 80 (best health), rather than the conventional 0-100 scores. We evaluated the internal consistency of the scale items using the Cronbach's alpha, performed descriptive analyses, and analyzed the association between the patients' HRQoL scores and adverse events. RESULTS: Overall, 36 patients (20 males, 56%) aged 17-54 years (median =40 years) responded to the questionnaire. The median (range) HRQoL score for the physical component summary was 58.6 (35.3-60.5), while the median score for the mental component summary was 59.3 (26.6-61.9), indicating not-so-high self-rating of health. There was good internal consistency of the scale scores, with a Cronbach's alpha value of >0.80. In all, 32 (89%) of the 36 patients experienced at least one adverse drug event of any severity during their treatment (median events =3, range 1-6), of which none was life-threatening. The occurrence of adverse events was not related to HRQoL scores. For patients reporting zero to two events, the median (range) HRQoL score was 56.8 (44.4-56.8), while for those reporting three or more events, the median score was 55.2 (38.6-56.8); P=0.34 for difference between these scores. CONCLUSION: Patients completing treatment for MDR-TB in Namibia tended to score moderately low on their HRQoL, using the generic SF-8 questionnaire. The occurrence of adverse events did not lead to lower HRQoL scores upon treatment completion.

Comparing amikacin and kanamycin-induced hearing loss in multidrug-resistant tuberculosis treatment under programmatic conditions in a Namibian retrospective cohort.

BACKGROUND: Amikacin and kanamycin are mainly used for treating multidrug-resistant tuberculosis (MDR-TB), especially in developing countries where the burden of MDR-TB is highest. Their protracted use in MDR-TB treatment is known to cause dose-dependent irreversible hearing loss, requiring hearing aids, cochlear implants or rehabilitation. Therapeutic drug monitoring and regular audiological assessments may help to prevent or detect the onset of hearing loss, but these services are not always available or affordable in many developing countries. We aimed to compare the cumulative incidence of hearing loss among patients treated for MDR-TB with amikacin or kanamycin-based regimens, and to identify the most-at-risk patients, based on the real-life clinical practice experiences in Namibia. METHODS: We conducted a retrospective cohort study of patients treated with amikacin or kanamycin-based regimens in four public sector MDR-TB treatment sites in Namibia between June 2004 and March 2014. Patients were audiologically assessed as part of clinical care. The study outcome was the occurrence of any hearing loss. Data were manually extracted from patients' treatment records. We compared proportions using the Chi-square test; applied stratified analysis and logistic regression to study the risk of hearing loss and to identify the most-at-risk patients through effect-modification analysis. A P-value < 0.05 was statistically significant. RESULTS: All 353 patients had normal baseline hearing, 46 % were HIV co-infected. Cumulative incidence of any hearing loss was 58 %, which was mostly bilateral (83 %), and mild (32 %), moderate (23 %), moderate-severe (16 %), severe (10 %), or profound (15 %). Patients using amikacin had a greater risk of developing the more severe forms of hearing loss than those using kanamycin (adjusted odds ratio (OR) = 4.0, 95 % CI: 1.5-10.8). Patients co-infected with HIV (OR = 3.4, 95 % CI: 1.1-10.6), males (OR = 4.5, 95 %1.5-13.4) and those with lower baseline body weight (40-59 kg, OR = 2.8, 95 % CI: 1.1-6.8), were most-at-risk of developing hearing loss. CONCLUSION: Amikacin use in the long-term MDR-TB treatment led to a higher risk of occurrence of the more severe forms of hearing loss compared to kanamycin use. Males, patients with low baseline body weight and those co-infected with HIV were most-at-risk. MDR-TB treatment programmes should consider replacing amikacin with kanamycin and strengthen the routine renal, serum therapeutic drug levels and audiometric monitoring in the most-at-risk patients treated with aminoglycosides.

Barriers to access to antiretroviral treatment for HIV-positive tuberculosis patients in Windhoek, Namibia.

SETTING: Namibia faces a high burden of tuberculosis (TB) and HIV-infection. In 2011, 50% of the TB patients were co-infected with HIV. While all patients co-infected with TB and HIV are eligible for antiretroviral treatment (ART), only 54% were reported to have received ART according to national data. OBJECTIVE: To explore the perspective of healthcare professionals on barriers to access to ART for HIV-positive TB patients. DESIGN: Nine semi-structured qualitative interviews were conducted with healthcare professionals from TB and HIV services in Windhoek in 2012 to investigate access barriers to ART for HIV-positive TB patients in Namibia. RESULTS: Many barriers known from other African countries were also present in Namibia. The barriers rated as most important were: staff shortage (health system level); limited training (healthcare worker level); and fear of stigma and discrimination (patient/community level). Direct treatment costs and limited availability of antiretroviral medication were not observed as barriers. Interference with TB treatment and ART by some Pentecostal churches was revealed as an important barrier that has not yet received sufficient attention. CONCLUSION: The study identified access barriers to ART for HIV-positive TB patients and their relevance in Namibia. The findings provide evidence for tailored interventions to increase ART-uptake among HIV-positive TB patients.

Characteristics of multidrug-resistant tuberculosis in Namibia.

BACKGROUND: To describe the epidemiology and possible risk factors for the development of multidrug-resistant tuberculosis (MDR-TB) in Namibia. METHODS: Using medical records and patient questionnaires, we conducted a case-control study among patients diagnosed with TB between January 2007 and March 2009. Cases were defined as patients with laboratory-confirmed MDR-TB; controls had laboratory-confirmed drug-susceptible TB or were being treated with WHO Category I or Category II treatment regimens. RESULTS: We enrolled 117 MDR-TB cases and 251 TB controls, of which 100% and 2% were laboratory-confirmed, respectively. Among cases, 97% (113/117) had been treated for TB before the current episode compared with 46% (115/251) of controls (odds ratio [OR] 28.7, 95% confidence interval [CI] 10.3-80.5). Cases were significantly more likely to have been previously hospitalized (OR 1.9, 95% CI 1.1-3.5) and to have had a household member with MDR-TB (OR 5.1, 95% CI 2.1-12.5). These associations remained significant when separately controlled for being currently hospitalized or HIV-infection. CONCLUSIONS: MDR-TB was associated with previous treatment for TB, previous hospitalization, and having had a household member with MDR-TB, suggesting that TB control practices have been inadequate. Strengthening basic TB control practices, including expanding laboratory confirmation, directly observed therapy, and infection control, are critical to the prevention of MDR-TB.