Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise.

The current active-latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.

The prevalence of pulmonary hypertension in post-tuberculosis and active tuberculosis populations: a systematic review and meta-analysis.

BACKGROUND: The prevalence of tuberculosis (TB)-associated pulmonary hypertension (PH) has not previously been quantified, resulting in an underappreciated burden of disease. We aimed to estimate the prevalence of PH in post-TB and active TB populations. METHODS: In this systematic review and meta-analysis, we searched PubMed/Medline, Cochrane Library, EBSCOhost, Scopus, African Journals Online and Google Scholar, with no language restriction, for available literature published after 1950. Eligible studies described adult participants (≥16 years), with documented evidence of active or prior TB, diagnosed with PH. Study quality was assessed using a risk of bias tool specifically developed for prevalence studies. Aggregate prevalence estimates with 95% confidence intervals were synthesised using a random-effects meta-analysis model, incorporating the Freeman-Tukey transformation. Subgroup analysis was conducted to ascertain prevalence estimates in specific patient populations. RESULTS: We identified 1452 unique records, of which 34 met our inclusion criteria. 23 studies, with an acceptable risk of bias and where PH was diagnosed at right heart catheterisation or echocardiography, were included in the meta-analysis. In post-TB studies (14/23), the prevalence of PH was 67.0% (95% CI 50.8-81.4) in patients with chronic respiratory failure, 42.4% (95% CI 31.3-54.0) in hospitalised or symptomatic patients and 6.3% (95% CI 2.3-11.8) in nonhealthcare-seeking outpatients (I2=96%). There was a lower estimated prevalence of PH in studies of populations with active TB (9.4%, 95% CI 6.3-13.0), I2=84%). CONCLUSION: Our results highlight the significant burden of PH in post-TB and active TB populations. We emphasise the need for increased recognition of TB-associated PH and additional high-quality prevalence data.

Lung Cancer Presents at a Younger Age and Is Less Likely to be Curable in People Living with HIV.

INTRODUCTION: Globally, lung cancer remains the leading cause of malignancy-related death in men and women. There is increasing evidence that the risk for lung cancer in people living with human immunodeficiency virus (PLHIV) is higher than that of the general population. Given the high burden of PLHIV and lung cancer in Southern Africa, we aimed to compare the characteristics of PLHIV and HIV-negative lung cancer patients with regards to demographics, cell type, performance status, and tumour stage at presentation. METHODS: All patients who presented to a large tertiary hospital over a 7-year period with a confirmed tissue diagnosis of primary lung cancer were included in a prospective registry. The patient demographics, HIV status, as well as the patients' performance status according to the Eastern Cooperative Oncology Group (ECOG) were documented. RESULTS: The cohort consisted of 1,805 patients (mean age 60.0 years) of which 1,129 were male. In total, 133 were PLHIV and 1,292 were confirmed HIV-negative, while the remaining were categorised as HIV-unknown. PLHIV with lung cancer were found to be younger than the HIV-negative group (mean [±SD] 54.6 [9.3] versus 60.3 [10.1], p < 0.001). Notably, not a single PLHIV was diagnosed with resectable non-small cell lung cancer (NSCLC), and only 7 of 133 (6.5%) had potentially curable disease NSCLC (up to stage IIIB) compared to 240 of 1292 HIV-negative patients (27.7%, p < 0.001). CONCLUSION: PLHIV with lung cancer were diagnosed at a significantly younger age and were significantly less likely to have curable NSCLC at presentation.

Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.

An investigation of the correlation of vitamin D status and management outcomes in patients with severe COVID-19 at a South African tertiary hospital.

Background: Severe COVID-19 has a poor prognosis, and biomarkers may predict disease severity. This study aimed to assess the effect of baseline Vitamin D (VitD) inadequacy on outcome of patients with severe COVID-19 admitted to intensive care unit (ICU) in a tertiary hospital in South Africa. Methods: Patients with confirmed SARS-CoV-2 were recruited during wave II of the pandemic in Cape Town. Eighty-six patients were included in the study. They were categorized into three groups "VitD deficient, VitD insufficient and VitD sufficient". We combined the VitD deficient with insufficient group to form "VitD inadequate'' group. Cox regression analysis was done to assess the association between VitD status and mortality. Factors with p< 0.05 in adjusted multivariable cox regression were considered statistically significant. Results: The proportion of VitD inadequacy was 64% (55/86), with significantly higher proportion of hypertension (66%; p 0.012). Kaplan Meir curve showed no significant difference in the probability of survival among the COVID-19 patients admitted in the ICU with or without VitD inadequacy. However, patients with elevated serum creatinine were significantly more at risk of dying (Adjusted Hazard Ratio 1.008 (1.002 - 1.030, p<0.017). Conclusion: Our study found a high prevalence of VitD inadequacy (combined deficiency and insufficiency) in COVID-19 patients admitted to the ICU. This may indicate a possible risk of severe disease. Whilst there was no statistically significant relationship between VitD status and mortality in this cohort, baseline VitD may be an important prognostic biomarker in COVID-19 patients admitted to the ICU, particularly in those with comorbidities that predispose to VitD deficiency.

Rapidly progressive respiratory failure due to antisynthetase syndrome related interstitial lung disease.

A 65-year-old female was admitted with rapidly progressive respiratory failure requiring intubation and mechanical ventilation. She was considered to have an infective exacerbation of underlying interstitial lung disease (ILD). She improved on antibiotics, but the interstitial process progressed rapidly, and she could not be weaned. An antimyositis antibody panel yielded a strongly positive anti-Jo-1 and anti-Ro 52. A diagnosis of antisynthetase syndrome (ASS) associated ILD, a very rare disease with high mortality, was made. She was managed with high-dose corticosteroids and intravenous immunoglobulin therapy and was eventually liberated from mechanical ventilation. This case highlights the importance of considering ASS in an otherwise unexplained rapidly progressive ILD requiring mechanical ventilation.

Effects of tuberculosis and/or HIV-1 infection on COVID-19 presentation and immune response in Africa.

Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p < 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.

A tale of two waves: characteristics and outcomes of COVID-19 admissions during the Omicron-driven fourth wave in Cape Town, South Africa, and implications for the future.

Objectives: The aim of this study was to describe the pattern of admissions during the fourth wave of COVID-19 in order to inform future public health policies. Methods: This was a retrospective descriptive study of an early cohort of all adult patients with SARS-CoV-2 infection admitted to a tertiary hospital in Cape Town, South Africa, at the start of the country's fourth wave. This was compared with an early cohort from the first wave at the same institution. Results: In total, 121 SARS-CoV-2-positive admissions from the fourth wave were included. Thirty-one (25.6%) patients had COVID-19 pneumonia, while 90 (74.4%) had incidental SARS-CoV-2 infection. (In the first wave all 116 patients had COVID-19 pneumonia.) Thirty-two (26.4%) patients self-reported complete or partial COVID-19 vaccination, of whom 12 (37.5%) were admitted with COVID-19 pneumonia. Compared with the first wave, there were fewer intensive- or high-care admissions (18/121 [14.9%] vs 42/116 [36.2%]; p < 0.001) and mortality was lower (12/121 [9.9%] vs 31/116 [26.7%]; p = 0.001). Conclusion: Admissions to the COVID-19 wards during the fourth wave primarily included patients with incidental SARS-CoV-2 infection. There was a reduction in the need for critical care and in-hospital mortality. This changing epidemiology of COVID-19 admissions may be attributed to a combination of natural and/or vaccination-acquired immunity.

The association between acid-base status and clinical outcome in critically ill COVID-19 patients admitted to intensive care unit with an emphasis on high anion gap metabolic acidosis.

OBJECTIVE: The aim of this study was to identify arterial blood gas (ABG) abnormalities, with a focus on a high anion gap (AG) metabolic acidosis and evaluate outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU. METHODS: A retrospective, observational study was conducted in a tertiary hospital in Cape Town during the first and second COVID-19 waves. Age, gender, sodium (Na), potassium (K), chloride (Cl), bicarbonate (HCO3std), pH, partial pressure of carbon dioxide (pCO2), creatinine, estimated glomerular filtration rate (eGFR), lactate levels and ABG results were obtained. The Pearson χ2 test or Fisher exact test and the Wilcoxon rank-sum test were used to compare mortality and survival. To identify factors associated with non-survival, a multivariable model was developed. RESULTS: This study included 465 patients, 226 (48%) of whom were female. The sample population's median (IQR) age was 54.2 (46.1-61.3) years, and 63% of the patients died. ABG analyses found that 283 (61%) of the 465 patients had alkalosis (pH ≥ 7.45), 65 (14%) had acidosis (pH ≤ 7.35) and 117 (25%) had normal pH (7.35-7.45). In the group with alkalosis, 199 (70.3%) had a metabolic alkalosis and in the group with acidosis, 42 (64%) had a metabolic acidosis with an increased AG of more than 17. Non-survivors were older than survivors (56.4 years versus 50.3 years, p < .001). CONCLUSION: Most of the COVID-19 patients admitted to the ICU had an alkalosis, and those with acidosis had a much worse prognosis. Higher AG metabolic acidosis was not associated with patients' characteristics.

Clinical characteristics associated with mortality of COVID-19 patients admitted to an intensive care unit of a tertiary hospital in South Africa.

BACKGROUND: Over 130 million people have been diagnosed with Coronavirus disease 2019 (COVID-19), and more than one million fatalities have been reported worldwide. South Africa is unique in having a quadruple disease burden of type 2 diabetes, hypertension, human immunodeficiency virus (HIV) and tuberculosis, making COVID-19-related mortality of particular interest in the country. The aim of this study was to investigate the clinical characteristics and associated mortality of COVID-19 patients admitted to an intensive care unit (ICU) in a South African setting. METHODS AND FINDINGS: We performed a prospective observational study of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection admitted to the ICU of a South African tertiary hospital in Cape Town. The mortality and discharge rates were the primary outcomes. Demographic, clinical and laboratory data were analysed, and multivariable robust Poisson regression model was used to identify risk factors for mortality. Furthermore, Cox proportional hazards regression model was performed to assess the association between time to death and the predictor variables. Factors associated with death (time to death) at p-value < 0.05 were considered statistically significant. Of the 402 patients admitted to the ICU, 250 (62%) died, and another 12 (3%) died in the hospital after being discharged from the ICU. The median age of the study population was 54.1 years (IQR: 46.0-61.6). The mortality rate among those who were intubated was significantly higher at 201/221 (91%). After adjusting for confounding, multivariable robust Poisson regression analysis revealed that age more than 48 years, requiring invasive mechanical ventilation, HIV status, procalcitonin (PCT), Troponin T, Aspartate Aminotransferase (AST), and a low pH on admission all significantly predicted mortality. Three main risk factors predictive of mortality were identified in the analysis using Cox regression Cox proportional hazards regression model. HIV positive status, myalgia, and intubated in the ICU were identified as independent prognostic factors. CONCLUSIONS: In this study, the mortality rate in COVID-19 patients admitted to the ICU was high. Older age, the need for invasive mechanical ventilation, HIV status, and metabolic acidosis were found to be significant predictors of mortality in patients admitted to the ICU.

Latent class analysis: an innovative approach for identification of clinical and laboratory markers of disease severity among COVID-19 patients admitted to the intensive care unit.

Objective: The aim of this study was to identify clinical and laboratory phenotype distribution patterns and their usefulness as prognostic markers in COVID-19 patients admitted to the intensive care unit (ICU) at Tygerberg Hospital, Cape Town. Methods and results: A latent class analysis (LCA) model was applied in a prospective, observational cohort study. Data from 343 COVID-19 patients were analysed. Two distinct phenotypes (1 and 2) were identified, comprising 68.46% and 31.54% of patients, respectively. The phenotype 2 patients were characterized by increased coagulopathy markers (D-dimer, median value 1.73 ng/L vs 0.94 ng/L; p < 0.001), end-organ dysfunction (creatinine, median value 79 µmol/L vs 69.5 µmol/L; p < 0.003), under-perfusion markers (lactate, median value 1.60 mmol/L vs 1.20 mmol/L; p < 0.001), abnormal cardiac function markers (median N-terminal pro-brain natriuretic peptide (NT-proBNP) 314 pg/ml vs 63.5 pg/ml; p < 0.001 and median high-sensitivity cardiac troponin (Hs-TropT) 39 ng/L vs 12 ng/L; p < 0.001), and acute inflammatory syndrome (median neutrophil-to-lymphocyte ratio 15.08 vs 8.68; p < 0.001 and median monocyte value 0.68 × 109/L vs 0.45 × 109/L; p < 0.001). Conclusion: The identification of COVID-19 phenotypes and sub-phenotypes in ICU patients could help as a prognostic marker in the day-to-day management of COVID-19 patients admitted to the ICU.

Clinical features and outcomes of COVID-19 admissions in a population with a high prevalence of HIV and tuberculosis: a multicentre cohort study.

BACKGROUND: There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB). METHODS: We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed. RESULTS: PWH comprised 270 (19%) of 1434 admissions. There were 47 patients with active tuberculosis (3.3%), of whom 29 (62%) were PWH. Three-hundred and seventy-three patients (26%) died. The mortality in PWH (n = 71, 26%) and HIV-uninfected patients (n = 296, 25%) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38% vs n = 3, 20%; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95%CI 1.02-1.03, p < 0.001), male sex (AHR1.38 (95%CI 1.12-1.72, p = 0.003) and being "overweight or obese" (AHR 1.30 95%CI 1.03-1.61 p = 0.024). HIV (AHR 1.28 95%CI 0.95-1.72, p 0.11) and active TB (AHR 1.50 95%CI 0.84-2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count < 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels. CONCLUSION: In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population.

Diagnosing Tuberculosis: What Do New Technologies Allow Us to (Not) Do?

New tuberculosis (TB) diagnostics are at a crossroads: their development, evaluation, and implementation is severely damaged by resource diversion due to COVID-19. Yet several technologies, especially those with potential for non-invasive non-sputum-based testing, hold promise for efficiently triaging and rapidly confirming TB near point-of-care. Such tests are, however, progressing through the pipeline slowly and will take years to reach patients and health workers. Compellingly, such tests will create new opportunities for difficult-to-diagnose populations, including primary care attendees (all-comers in high burden settings irrespective of reason for presentation) and community members (with early stage disease or risk factors like HIV), many of whom cannot easily produce sputum. Critically, all upcoming technologies have limitations that implementers and health workers need to be cognizant of to ensure optimal deployment without undermining confidence in a technology that still offers improvements over the status quo. In this state-of-the-art review, we critically appraise such technologies for active pulmonary TB diagnosis. We highlight strengths, limitations, outstanding research questions, and how current and future tests could be used in the presence of these limitations and uncertainties. Among triage tests, CRP (for which commercial near point-of-care devices exist) and computer-aided detection software with digital chest X-ray hold promise, together with late-stage blood-based assays that detect host and/or microbial biomarkers; however, aside from a handful of prototypes, the latter category has a shortage of promising late-stage alternatives. Furthermore, positive results from new triage tests may have utility in people without TB; however, their utility for informing diagnostic pathways for other diseases is under-researched (most sick people tested for TB do not have TB). For confirmatory tests, few true point-of-care options will be available soon; however, combining novel approaches like tongue swabs with established tests like Ultra have short-term promise but first require optimizations to specimen collection and processing procedures. Concerningly, no technologies yet have compelling evidence of meeting the World Health Organization optimal target product profile performance criteria, especially for important operational criteria crucial for field deployment. This is alarming as the target product profile criteria are themselves almost a decade old and require urgent revision, especially to cater for technologies made prominent by the COVID-19 diagnostic response (e.g., at-home testing and connectivity solutions). Throughout the review, we underscore the importance of how target populations and settings affect test performance and how the criteria by which these tests should be judged vary by use case, including in active case finding. Lastly, we advocate for health workers and researchers to themselves be vocal proponents of the uptake of both new tests and those - already available tests that remain suboptimally utilized.

Predicting COVID-19 outcomes from clinical and laboratory parameters in an intensive care facility during the second wave of the pandemic in South Africa.

Background: The second wave of coronavirus disease 2019 (COVID-19) in South Africa was caused by the Beta variant of severe acute respiratory syndrome coronavirurus-2. This study aimed to explore clinical and biochemical parameters that could predict outcome in patients with COVID-19. Methods: A prospective study was conducted between 5 November 2020 and 30 April 2021 among patients with confirmed COVID-19 admitted to the intensive care unit (ICU) of a tertiary hospital. The Cox proportional hazards model in Stata 16 was used to assess risk factors associated with survival or death. Factors with P<0.05 were considered significant. Results: Patients who died were found to have significantly lower median pH (P<0.001), higher median arterial partial pressure of carbon dioxide (P<0.001), higher D-dimer levels (P=0.001), higher troponin T levels (P=0.001), higher N-terminal-prohormone B-type natriuretic peptide levels (P=0.007) and higher C-reactive protein levels (P=0.010) compared with patients who survived. Increased standard bicarbonate (HCO3std) was associated with lower risk of death (hazard ratio 0.96, 95% confidence interval 0.93-0.99). Conclusions: The mortality of patients with COVID-19 admitted to the ICU was associated with elevated D-dimer and a low HCO3std level. Large studies are warranted to increase the identification of patients at risk of poor prognosis, and to improve the clinical approach.

Targeted Gene Expression Profiling of Human Myeloid Cells From Blood and Lung Compartments of Patients With Tuberculosis and Other Lung Diseases.

Myeloid-derived suppressor cells (MDSC) have been identified in the peripheral blood and granulomas of patients with active TB disease, but their phenotype-, function-, and immunosuppressive mechanism- spectrum remains unclear. Importantly, the frequency and signaling pathways of MDSC at the site of disease is unknown with no indication how this compares to MDSC identified in peripheral blood or to those of related myeloid counterparts such as alveolar macrophages and monocytes. Most phenotypic and functional markers have been described in oncological studies but have not yet been validated in TB. Using a panel of 43 genes selected from pathways previously shown to contribute to tumor-derived MDSC, we set out to evaluate if the expression of these additional functional markers and properties may also be relevant to TB-derived MDSC. Differential expression was investigated between MDSC, alveolar macrophages and monocytes enriched from bronchoalveolar lavage fluid and peripheral blood of patients with active TB, patients with other lung diseases (OLD). Results demonstrated that anatomical compartments may drive compartment-specific immunological responses and subsequent MDSC immunosuppressive functions, demonstrated by the observation that MDSC and/or monocytes from PB alone can discriminate, via hierarchical clustering, between patients with active TB disease and OLD. Our data show that the gene expression patterns of MDSC in peripheral blood and bronchoalveolar lavage fluid do not cluster according to disease states (TB vs OLD). This suggests that MDSC from TB patients may display similar gene expression profiles to those found for MDSC in cancer, but this needs to be validated in a larger cohort. These are important observations for TB research and may provide direction for future studies aimed at repurposing and validating cancer immunotherapies for use in TB.

Autologous Blood Patch Pleurodesis for the Management of a Persistent Air Leak after Secondary Spontaneous Pneumothorax.

Patients with secondary spontaneous pneumothorax (SSP) complicated by persistent air leak (PAL) and who are poor surgical candidates have limited treatment options. This case series explored autologous blood patch pleurodesis as a possible cost-effective management option. A total of 46 episodes of SSP with PAL were included. The procedure was successful in 33 (71.7%). Of these, 17 (51.5%) resolved within 1 day. The mean duration of intercostal drainage prior to the blood patch was 22 days in the successful group. Pneumothoraces with incomplete lung re-expansion at the time of procedure were successful in 20 of 30 (66.7%). Only human immunodeficiency virus infection was associated with failure (p = 0.03). Adverse events included transient fever (n = 3) that resolved spontaneously, and empyema (n = 3) which were successfully managed with antibiotics and pigtail drainage. We conclude that a large proportion of patients with SSP complicated by PAL who are unfit for surgery may be liberated from intercostal drainage by an autologous blood patch pleurodesis, with minimal adverse effects.

Understanding the biology, morbidity and social contexts of adolescent tuberculosis: a prospective observational cohort study protocol (Teen TB).

INTRODUCTION: A considerable burden of the tuberculosis (TB) epidemic is found in adolescents. The reasons for increased susceptibility to TB infection and higher incidence of TB disease in adolescence, compared with the 5-10 years old age group, are incompletely understood. Despite the pressing clinical and public health need to better understand and address adolescent TB, research in this field remains limited. METHODS AND ANALYSIS: Teen TB is an ongoing prospective observational cohort study that aims to better understand the biology, morbidity and social context of adolescent TB. The study plans to recruit 50 adolescents (10-19 years old) with newly diagnosed microbiologically confirmed pulmonary TB disease and 50 TB-exposed controls without evidence of TB disease in Cape Town, South Africa, which is highly endemic for TB. At baseline, cases and controls will undergo a detailed clinical evaluation, chest imaging, respiratory function assessments and blood collection for viral coinfections, inflammatory cytokines and pubertal hormone testing. At 2 weeks, 2 months and 12 months, TB disease cases will undergo further chest imaging and additional lung function testing to explore the patterns of respiratory abnormalities. At week 2, cases will complete a multicomponent quantitative questionnaire about psychological and social impacts on their experiences and longitudinal, in-depth qualitative data will be collected from a nested subsample of 20 cases and their families. ETHICS AND DISSEMINATION: The study protocol has received ethical approval from the Stellenbosch University Health Research Ethics Committee (N19/10/148). The study findings will be disseminated through peer-reviewed publications, academic conferences and formal presentations to health professionals. Results will also be made available to participants and caregivers.

Lifetime burden of disease due to incident tuberculosis: a global reappraisal including post-tuberculosis sequelae.

BACKGROUND: Many individuals who survive tuberculosis disease face ongoing disability and elevated mortality risks. However, the impact of post-tuberculosis sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of tuberculosis, inclusive of post-tuberculosis morbidity and mortality. METHODS: We constructed a hypothetical cohort of individuals developing tuberculosis in 2019, including pulmonary and extrapulmonary disease. We simulated lifetime health outcomes for this cohort, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarise fatal and non-fatal health losses attributable to tuberculosis, during the disease episode and afterwards. We estimated post-tuberculosis mortality and morbidity based on the decreased lung function caused by pulmonary tuberculosis disease. FINDINGS: Globally, we estimated 122 (95% uncertainty interval [UI] 98-151) million DALYs due to incident tuberculosis disease in 2019, with 58 (38-83) million DALYs attributed to post-tuberculosis sequelae, representing 47% (95% UI 37-57) of the total burden estimate. The increase in burden from post-tuberculosis varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12·1 DALYs (95% UI 10·0-14·9) per incident tuberculosis case, of which 6·3 DALYs (5·6-7·0) were from the disease episode and 5·8 DALYs (3·8-8·3) were from post-tuberculosis. Per-case post-tuberculosis burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-tuberculosis was spread over the remaining lifetime of tuberculosis survivors, with almost a third of total DALYs (28%, 95% UI 23-34) accruing 15 or more years after incident tuberculosis. INTERPRETATION: Post-tuberculosis sequelae add substantially to the overall disease burden caused by tuberculosis. This hitherto unquantified burden has been omitted from most previous policy analyses. Future policy analyses and burden estimates should take better account of post-tuberculosis, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue. FUNDING: National Institutes of Health.