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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.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;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.

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.

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.

IntroductionA 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 analysisTeen 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 disseminationThe 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.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

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.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.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%];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.

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.

The radiological findings of COVID-19 are well-described, including its evolution. In an earlier report of admission chest radiographs of patients with COVID-19, we anecdotally noted relative sparing of the left upper zone (LUZ). We subsequently aimed to describe the main chest radiograph findings in another cohort, focusing on zonal predominance. The admission chest radiographs of 111 patients with CO­VID-19 pneumonia requiring intensive care admission were reviewed by 2 thoracic radiologists and categorized according to the predominant pattern into either ground-glass opacities (GGOs), alveolar infiltrates and/or consolidation, or reticular and/or nodular infiltrates or an equal combination of both, and the extent of disease involvement of each of the zones using a modified Radiologic Assessment of Lung Edema (RALE) score. Parenchymal changes were detected in all. In total, 106 radiographs showed GGOs, alveolar infiltrates, and/or consolidation, and 5 had a combination of reticular/nodular infiltrates as well as GGOs, alveolar infiltrates, and/or consolidation. The LUZ had a significant lower grading score than the right upper zone: 1 versus 2 (p < 0.001). Likewise, the upper zones had a significant lower score than the mid and lower zones (p < 0.001). Our findings confirmed the relative sparing of the LUZ in severe COVID-19 pneumonia.

Low-income and middle-income countries (LMICs) bear a disproportionately high burden of the global morbidity and mortality caused by chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease, bronchiectasis, and post-tuberculosis lung disease. CRDs are strongly associated with poverty, infectious diseases, and other non-communicable diseases (NCDs), and contribute to complex multi-morbidity, with major consequences for the lives and livelihoods of those affected. The relevance of CRDs to health and socioeconomic wellbeing is expected to increase in the decades ahead, as life expectancies rise and the competing risks of early childhood mortality and infectious diseases plateau. As such, the World Health Organization has identified the prevention and control of NCDs as an urgent development issue and essential to the achievement of the Sustainable Development Goals by 2030. In this Review, we focus on CRDs in LMICs. We discuss the early life origins of CRDs; challenges in their prevention, diagnosis, and management in LMICs; and pathways to solutions to achieve true universal health coverage.

BackgroundDuring the outbreak of coronavirus disease 2019 (COVID-19), many studies have investigated laboratory biomarkers in management and prognostication of COVID-19 patients, however to date, few have investigated arterial blood gas, acid–base and blood pressure patterns. The aim of the study is to assess the arterial blood gas and acid–base patterns, blood pressure findings and their association with the outcomes of COVID-19 patients admitted to an intensive care unit.MethodsA single-centre retrospective, observational study in a dedicated COVID-19 intensive care unit in Cape Town, South Africa. Admission arterial blood gas, serum electrolytes, renal function and blood pressure readings performed on COVID-19 patients admitted between 26 March and 2 June 2020 were analysed and compared between survivors and non-survivors.ResultsA total of 56 intensive care unit patients had admission arterial blood gas performed at the time of intensive care unit admission. An alkalaemia (pH > 7.45) was observed in 36 (64.3%) patients. A higher arterial pH (median 7.48 [interquartile range: 7.45–7.51] versus 7.46 [interquartile range: 7.40–7.48], P = 0.049) and partial pressure of oxygen in arterial blood (median 7.9 kPa [interquartile range: 7.3–9.6] versus 6.5 kPa [interquartile range: 5.2–7.3], P = 3(median: 28.0 mmol/L [interquartile range: 25.7–28.8] versus 26.3 mmol/L [interquartile range: 24.3–27.9], P = 0.059).ConclusionsThe majority of the study population admitted to intensive care unit had an alkalaemia on arterial blood gas. A higher pH and lower partial pressure of oxygen in arterial blood on arterial blood gas analysis were significantly associated with survival.

Tuberculosis, although curable, frequently leaves the individual with chronic physical and psycho-social impairment, yet these consequences have to-date been largely neglected.\ud The 1st International Post-Tuberculosis Symposium was devoted entirely to impairment after tuberculosis, and covered a number of multi-disciplinary topics. Using the Delphi process, consensus was achieved for the terms “post- tuberculosis”, “post-tuberculosis lung disease/s (PTLD)”, and “post-tuberculosis economic, social and psychological well-being” (Post-TB ESP)”, to overcome the historical challenge of varied terminology in the literature. A minimum case-definition was proposed by consensus for PTLD in adults and children. Lack of sufficient evidence hampered definitive recommendations in most domains, including prevention and treatment of PTLD, but highlighted the dire need for research and priorities were identified. The heterogeneity of respiratory outcomes and previously employed research methodologies complicates the accurate estimation of disease burden. However, consensus was reached proposing a toolkit for future PTLD measurement, and on PTLD patterns to be considered. The importance of extra-pulmonary consequences and progressive impairment throughout the life-course was identified, including tuberculosis recurrence and increased mortality. Patient advocates emphasised the need for addressing the psychological and social impacts post tuberculosis, and called for clinical guidance. Increased awareness and more research addressing post-tuberculosis complications is urgently needed.

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.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 withPatients who died were found to have significantly lower median pH (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.

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 3, 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.

Tuberculous granulomas that develop in response to Mycobacterium tuberculosis (M. tuberculosis) infection are highly dynamic entities shaped by the host immune response and disease kinetics. Within this microenvironment, immune cell recruitment, polarization, and activation are driven not only by coexisting cell types and multicellular interactions but also by M. tuberculosis-mediated changes involving metabolic heterogeneity, epigenetic reprogramming, and rewiring of the transcriptional landscape of host cells. There is an increased appreciation of the in vivo complexity, versatility, and heterogeneity of the cellular compartment that constitutes the tuberculosis (TB) granuloma and the difficulty in translating findings from animal models to human disease. Here, we describe a novel biomimetic in vitro three-dimensional (3D) human lung spheroid granuloma model, resembling early “innate” and “adaptive” stages of the TB granuloma spectrum, and present results of histological architecture, host transcriptional characterization, mycobacteriological features, cytokine profiles, and spatial distribution of key immune cells. A range of manipulations of immune cell populations in these spheroid granulomas will allow the study of host/pathogen pathways involved in the outcome of infection, as well as pharmacological interventions. IMPORTANCE TB is a highly infectious disease, with granulomas as its hallmark. Granulomas play an important role in the control of M. tuberculosis infection and as such are crucial indicators for our understanding of host resistance to TB. Correlates of risk and protection to M. tuberculosis are still elusive, and the granuloma provides the perfect environment in which to study the immune response to infection and broaden our understanding thereof; however, human granulomas are difficult to obtain, and animal models are costly and do not always faithfully mimic human immunity. In fact, most TB research is conducted in vitro on immortalized or primary immune cells and cultured in two dimensions on flat, rigid plastic, which does not reflect in vivo characteristics. We have therefore conceived a 3D, human in vitro spheroid granuloma model which allows researchers to study features of granuloma-forming diseases in a 3D structural environment resembling in vivo granuloma architecture and cellular orientation.

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2-specific (SARS-CoV-2-specific) CD4+ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non-COVID-19 patients. We showed that SARS-CoV-2-specific CD4+ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1-mediated CD4+ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2-specific CD4+ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis-specific CD4+ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2-specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.

CITATION: Abdool-Gaffar, M. S. et al. 2019. Management of chronic obstructive pulmonary disease - A position statement of the South African Thoracic Society: 2019 update. Journal of thoracic disease, 11(11):4408–4427. doi:10.21037/jtd.2019.10.65

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.

ObjectivesTo describe the presentation and outcome of SARS-CoV2 infection in an African setting of high non-communicable co-morbidity and also HIV-1 and tuberculosis prevalence.DesignCase control analysis with cases stratified by HIV-1 and tuberculosis status.SettingA single-centre observational case-control study of adults admitted to a South African hospital with proven SARS-CoV-2 infection or alternative diagnosis.Participants104 adults with RT-PCR-proven SARS-CoV2 infection of which 55 (52.9%) were male and 31 (29.8%) HIV-1 co-infected. 40 adults (35.7% male, 30.9% HIV-1 co-infected) admitted during the same period with no RT-PCR or serological evidence of SARS-CoV2 infection and assigned alternative diagnoses. Additional in vitro data from prior studies of 72 healthy controls and 118 HIV-1 uninfected and infected persons participants enrolled to a prior study with either immune evidence of tuberculosis sensitization but no symptoms or microbiologically confirmed pulmonary tuberculosis.ResultsTwo or more co-morbidities were present in 57.7% of 104 RT-PCR proven COVID-19 presentations, the commonest being hypertension (48%), type 2 diabetes mellitus (39%), obesity (31%) but also HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features could be dominated by either SARS-CoV-2 or tuberculosis: lymphopenia was exacerbated, and some markers of inflammation (D-dimer and ferritin) elevated in singly SARS-CoV-2 infected patients were even further elevated (p < 0.05). HIV-1 and SARS-CoV2 co-infection resulted in lower absolute number and proportion of CD4 lymphocytes, with those in the lowest peripheral CD4 percentage strata exhibiting absent or lower antibody responses against SARS-CoV2. 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.ConclusionsIn this South African setting, HIV-1 and tuberculosis are common co-morbidities in patients presenting with COVID-19. In environments in which tuberculosis is common, SARS-CoV-2 and tuberculosis may co-exist with clinical presentation being typical of either disease. Clinical suspicion of exacerbation of co-existent tuberculosis accompanying SARS-CoV-2 should be high.What is already known on this topic?It has been quite widely thought that Africa has been spared the worst effects of the COVID-19 pandemic. There are very few reported case series and no case-control studies comparing COVID-19 patients admitted to hospital to those admitted for other reasons. However several studies have indicated both HIV-1 and tuberculosis co-infection that are endemic in Africa constitute risk factors for poor outcome. In addition Africa is subject to demographic transition and the prevalence of non-communicable co-morbidities such as type 2 diabetes, hypertension and cardiovascular disease is rising rapidly. No study from Africa has described the clinical impact on the presentation of COVID-19 infection.What this study addsTwo or more co-morbidities were present in over half COVID-19 presentations, including HIV-1 (30%) and active tuberculosis (14%). Patients dually infected by tuberculosis and SARS-CoV-2, presented as either SARS-CoV-2 or tuberculosis. HIV-1 and SARS-CoV2 co-infection resulted in lower absolute number and proportion of CD4 lymphocytes, and those with low CD4 counts had absent or lower antibody responses against SARS-CoV2. Death occurred 29% of all COVID-19 patients and in 40% of patients with coincident SARS-CoV-2 and tuberculosis. Thus in environments in which tuberculosis is common, SARS-CoV-2 and tuberculosis may co-exist with clinical presentation being typical of either disease and clinical suspicion of exacerbation of co-existent tuberculosis accompanying SARS-CoV-2 should be high.

Immunoglobin 4-related disease (IgG4-RD) is an auto-immune, multisystem inflammatory disorder characterised by storiform fibrosis, lymphoplasmacytic infiltration and obliterative phlebitis on histology. Its pathophysiology is not well understood, but is thought to occur due to complex interactions between T helper 2 cells, their cytokines, chemokines, and B lymphocytes that become dysregulated and produce dysfunctional immunoglobulins. Here, we present a case report of a 54-year-old man who was initially suspected of having lung cancer on imaging, but was ultimately diagnosed with IgG4-RD on histological analysis of a pneumonectomy specimen. Treatment with glucocorticoids can establish disease remission, with a small proportion of patients relapsing, if the diagnosis is made before significant fibrosis occurs.

Coronavirus disease 2019 (COVID‐19) and pneumocystis pneumonia (PCP) share many overlapping features and may be clinically indistinguishable on initial presentation in people living with HIV. We present the case of co‐infection with COVID‐19 and PCP in a patient with progressive respiratory failure admitted to our intensive care unit where the dominant disease was uncertain. This case highlights the difficulty in differentiating between the two diseases, especially in a high HIV prevalence setting where PCP is frequently diagnosed using case definitions and clinical experience due to limited access to bronchoscopy, appropriate laboratory testing, and computed tomography scans. In addition, diagnostic testing may yield false‐negative results in both diseases, and clinician awareness to the overlap and pitfalls is essential if COVID‐19 becomes endemic in such settings., We present the case of a 54‐year‐old male with newly diagnosed advanced HIV who presented with clinical, biochemical, and radiological features that were consistent with both pneumocystis pneumonia (PCP) and coronavirus disease 2019 (COVID‐19). He subsequently tested positive for both diseases; however, the contribution of each disease to his progressive respiratory failure is unclear.

An estimated 58 million people have survived tuberculosis since 2000, yet many of them will suffer from post-tuberculosis lung disease (PTLD). PTLD results from a complex interplay between organism, host, and environmental factors and affects long-term respiratory health. PTLD is an overlapping spectrum of disorders that affects large and small airways (bronchiectasis and obstructive lung disease), lung parenchyma, pulmonary vasculature, and pleura and may be complicated by co-infection and haemoptysis. People affected by PTLD have shortened life expectancy and increased risk of recurrent tuberculosis, but predictors of long-term outcomes are not known. No data are available on PTLD in children and on impact throughout the life course. Risk-factors for PTLD include multiple episodes of tuberculosis, drug-resistant tuberculosis, delays in diagnosis, and possibly smoking. Due to a lack of controlled trials in this population, no evidence-based recommendations for the investigation and management of PTLD are currently available. Empirical expert opinion advocates pulmonary rehabilitation, smoking cessation, and vaccinations (pneumococcal and influenza). Exacerbations in PTLD remain both poorly understood and under-recognised. Among people with PTLD, the probability of tuberculosis recurrence must be balanced against other causes of symptom worsening. Unnecessary courses of repeated empiric anti-tuberculosis chemotherapy should be avoided. PTLD is an important contributor to the global burden of chronic lung disease. Advocacy is needed to increase recognition for PTLD and its associated economic, social, and psychological consequences and to better understand how PTLD sequelae could be mitigated. Research is urgently needed to inform policy to guide clinical decision-making and preventative strategies for PTLD.

Summary: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is transmitted mainly by aerosol in particles

Summary 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.

Background : Many individuals who survive TB disease face ongoing disability and elevated mortality risks. However, the impact of post-TB sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of TB, inclusive of post-TB morbidity and mortality. Methods : Lifetime health outcomes were simulated for the cohort developing TB disease globally in 2019, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarize fatal and nonfatal health losses attributable to TB, during the disease episode and afterwards. We estimated post-TB mortality and morbidity based on the decreased lung function caused by pulmonary TB disease. Findings : Globally, we estimated 122 (95% uncertainty interval: 98, 151) million DALYs due to incident TB disease in 2019, with 58 (38, 83) million DALYs attributed to post-TB sequelae, representing 47% (37, 57) of the total burden estimate. The increase in burden from post-TB varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12.1 (10.0, 14.9) DALYs per incident TB case, of which 6.3 (5.6, 7.0) DALYs were from the disease episode and 5.8 (3.8, 8.3) from post-TB. Per-case post-TB burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-TB was spread over the remaining lifetime of TB survivors, with almost one-third (28% (23, 34)) of total DALYs accruing 15 or more years after incident TB. Interpretation : Post-TB sequelae produce a substantial fraction of the disease burden caused by TB. This hitherto unquantified burden has been omitted from most prior policy analyses. Future policy analyses and burden estimates should take better account of post-TB, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue. Funding: NAM and TC acknowledge funding from the NIH (R01AI146555). MQ acknowledges funding from the Bill and Melinda Gates Foundation (INV-001754). AKC acknowledges funding from WEHI philanthropy. JM acknowledges funding from the Medical Research Council MR/S02042X/1). RSW acknowledges funding from Horizon 2020 and EDCTP. RMGJH acknowledges funding from the European Research Council (757699). Declaration of Interest: The authors declare no conflicts of interest.

Background. An outbreak of a novel coronavirus in China in late 2019 has resulted in a global pandemic. The virus (SARS-CoV-2) causes a severe acute respiratory syndrome and had been responsible for >14 000 deaths in South Africa (SA) at the time of writing, 30 August 2020. Autopsies in our setting have not been prioritised owing to the infective risks for staff, resulting in a lack of information on the histopathology of the disease in the SA setting. Postmortem biopsies are relatively quick and easy to perform and reduce the infective risk posed by full autopsies. Objectives. To determine whether postmortem biopsies of lung tissue could be used to determine cause of death in lieu of full autopsies in patients dying from COVID-19. Methods. We performed postmortem biopsies of lung tissue on 4 patients with SARS-CoV-2 confirmed by reverse transcriptase polymerase chain reaction who died in the Tygerberg Hospital (Cape Town, SA) intensive care unit (ICU) in June - July 2020, in order to determine their cause of death. The biopsies were performed in the ICU with the necessary personal protective equipment within 2 hours after death. Clinical information was obtained from the hospital records and the histopathology was reviewed by two consultant histopathologists. Microbiology and electron microscopy were also performed on this tissue. Results. All 4 patients were aged >50 years and had multiple comorbidities. Pulmonary pathology was present in only 3 cases, and the findings were surprisingly heterogeneous. One case demonstrated several findings including diffuse alveolar damage, extensive fibrin thrombi in pulmonary arteries with pulmonary infarction, organising pneumonia and bronchopneumonia. Other findings included type 2 pneumocyte hyperplasia, intra-alveolar macrophages and squamous metaplasia. An organising pneumonia was present in 2 other cases, although these findings were not deemed to be severe enough to be the cause of death. Fibrin thrombi were present in pulmonary arteries of 3 cases. One case showed no significant acute pulmonary pathology. The cause of death could only be determined in 1 case. Conclusions. The pulmonary findings we observed are in keeping with those described in the international literature. However, the pathology was surprisingly heterogeneous between cases, and was only deemed severe enough to be the cause of death in 1 of 4 cases. While lung-targeted, standardised postmortem biopsies may be safe, easy to perform and provide useful insights into the disease, they are not suitable to replace full autopsies in determining cause of death.

Background. South Africa (SA) has a high prevalence of HIV and tuberculosis. Cape Town was the SA metropole most affected in the early stages of the COVID-19 pandemic. Early observational data from Africa may provide valuable insight into what can be expected as the pandemic expands across the continent. Objectives. To describe the prevalence, clinical features, comorbidities and outcome of an early cohort of HIV-positive and HIV-negative patients admitted with COVID-19. Methods. This was a descriptive observational study of an early cohort of adults with COVID-19 pneumonia admitted from 25 March to 11 May 2020. Results. Of 116 patients (mean age 48 years, 61% female) admitted, 24 were HIV-positive (21%). The most common symptoms reported were cough ( n =88; 73%), shortness of breath ( n =78; 69%), fever ( n =67; 59%), myalgia ( n =29; 25%) and chest pain ( n =22; 20%). The most common comorbidities were hypertension ( n =46; 41%), diabetes mellitus ( n =43; 38%), obesity ( n =32; 28%) and HIV ( n =24; 21%). Mortality was associated with older age (mean (standard deviation) 55 (12) years v. 46 (14) years; p

The first critically ill patient admitted to our hospital in Cape Town, South Africa, during the COVID-19 pandemic was co-infected with HIV and SARS-CoV-2. Pneumocystis jirovecii pneumonia (PCP) and other respiratory opportunistic infections share many clinical features with severe COVID-19. Our understanding of the nuances of co-management of HIV and COVID-19 is evolving. We describe the diagnostic and therapeutic challenges presented by this case.

Medical staff caring for COVID-19 patients face mental stress, physical exhaustion, separation from families, stigma, and the pain of losing patients and colleagues. Many of them have acquired SARS-CoV-2 and some have died. In Africa, where the pandemic is escalating, there are major gaps in response capacity, especially in human resources and protective equipment. We examine these challenges and propose interventions to protect healthcare workers on the continent, drawing on articles identified on Medline (Pubmed) in a search on 24 March 2020. Global jostling means that supplies of personal protective equipment are limited in Africa. Even low-cost interventions such as facemasks for patients with a cough and water supplies for handwashing may be challenging, as is ‘physical distancing’ in overcrowded primary health care clinics. Without adequate protection, COVID-19 mortality may be high among healthcare workers and their family in Africa given limited critical care beds and difficulties in transporting ill healthcare workers from rural to urban care centres. Much can be done to protect healthcare workers, however. The continent has learnt invaluable lessons from Ebola and HIV control. HIV counselors and community healthcare workers are key resources, and could promote social distancing and related interventions, dispel myths, support healthcare workers, perform symptom screening and trace contacts. Staff motivation and retention may be enhanced through carefully managed risk ‘allowances’ or compensation. International support with personnel and protective equipment, especially from China, could turn the pandemic’s trajectory in Africa around. Telemedicine holds promise as it rationalises human resources and reduces patient contact and thus infection risks. Importantly, healthcare workers, using their authoritative voice, can promote effective COVID-19 policies and prioritization of their safety. Prioritizing healthcare workers for SARS-CoV-2 testing, hospital beds and targeted research, as well as ensuring that public figures and the population acknowledge the commitment of healthcare workers may help to maintain morale. Clearly there are multiple ways that international support and national commitment could help safeguard healthcare workers in Africa, essential for limiting the pandemic’s potentially devastating heath, socio-economic and security impacts on the continent.

Residual pulmonary impairment is common after treatment for tuberculosis (TB). Lung function data in patients with HIV-associated TB are scarce, especially in the context of paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) and prophylactic prednisone. We aimed to determine the prevalence of lung function abnormalities in patients with HIV-associated TB and CD4 counts ≤100 cells·μL−1 and assess the effect of prophylactic prednisone and the development of paradoxical TB-IRIS on pulmonary impairment. We performed spirometry, 6-min walk test (6MWT) and chest radiography at baseline (week 0) and at weeks 4, 12 and 28 in participants of the PredART trial, which evaluated a 28-day course of prednisone to prevent TB-IRIS in patients with HIV-associated TB commencing antiretroviral therapy. 153 participants underwent spirometry and/or 6MWT at one or more time points. Abnormal spirometry measurements were present in 66% of participants at week 0 and 50% at week 28; low forced vital capacity was the commonest abnormality. Chest radiographs showed little or no abnormalities in the majority of participants. Prednisone use resulted in a 42 m greater 6-min walk distance and a 4.9% higher percentage of predicted forced expiratory volume in 1 s at week 4; these differences were no longer significantly different from week 12 onwards. TB-IRIS did not significantly impair lung function outcome. Residual pulmonary impairment is common in HIV-associated TB. In patients with low CD4 counts, neither prophylactic prednisone as used in our study nor the development of TB-IRIS significantly affected week-28 pulmonary outcome., Post-tuberculosis lung disease is common in patients with HIV-associated TB at high risk of TB-IRIS (CD4 count ≤100 cells·μL−1). Neither TB-IRIS itself, nor prednisone treatment, affected long-term pulmonary outcomes in a South African clinical setting. http://bit.ly/2RjMl9c

Crazy Paving in Pulmonary Alveolar Proteinosis A 34-year-old man presented with dyspnea and a nonproductive cough. A chest CT showed a crazy-paving pattern. Bronchoalveolar lavage was performed, an...

RATIONALE: The utility of heated and humidified high-flow nasal oxygen (HFNO) for severe COVID-19-related hypoxaemic respiratory failure (HRF), particularly in settings with limited access to intensive care unit (ICU) resources, remains unclear, and predictors of outcome have been poorly studied. METHODS: We included consecutive patients with COVID-19-related HRF treated with HFNO and awake proning at two tertiary hospitals in Cape Town, South Africa. The primary outcome was the proportion of patients who were successfully weaned from HFNO, whilst failure comprised intubation or death on HFNO. FINDINGS: The median (IQR) arterial oxygen partial pressure to fraction inspired oxygen ratio (PaO2/FiO2) was 68 (54-92) in 293 enrolled patients. 137/293 (47%) of patients [PaO2/FiO2 76 (63-93)] were successfully treated with HFNO. The median duration of HFNO was 6 (3-9) in those successfully treated versus 2 (1-5) days in those who failed (p

Background Pulmonary tuberculosis (PTB) is associated with many forms of chronic lung disease including the development of chronic airflow obstruction (AFO). However, the nature, evolution and mechanisms responsible for the AFO after PTB are poorly understood. The aim of this study was to examine the progression of changes in lung physiology in patients treated for PTB. Methods Immunocompetent, previously healthy, adult patients receiving ambulatory treatment for a first episode of tuberculosis were prospectively followed up with serial lung physiology and quantitative computed tomography (CT) lung scans performed at diagnosis of tuberculosis, 2, 6, 12 and 18 months during and after the completion of treatment. Results Forty-nine patients (median age 26 years; 37.2% males) were included, and 43 were studied. During treatment, lung volumes improved and CT fibrosis scores decreased, but features of AFO and gas trapping emerged, while reduced diffusing capacity (DLco) seen in a majority of patients persisted. Significant increases in total lung capacity (TLC) by plethysmography were seen in the year following treatment completion (median change 5.9% pred., P45%), and 78.6% had reduced DLco. Conclusion Simple spirometry alone does not fully reveal the residual respiratory impairments resulting after a first episode of PTB. Changes in physiology evolve after treatment completion, and these findings when taken together, suggest emergence of gas trapping after treatment likely caused by progression of small airway pathology during the healing process.

Although chronic airflow limitation (CAL) is an important long-term consequence of tuberculosis (TB), little is known about the disease process. We present what we believe to be the first case of histologically confirmed residual TB-associated obstructive pulmonary disease (TOPD) in a 23-year-old non-smoking man who developed severe CAL after one episode of TB, with no other plausible risk factors. Lung biopsies identified residual post-TB pathology affecting the small airways and vessels throughout his lung; this has not been reported previously. These findings strengthen the argument that TOPD may be a phenotype of CAL distinct from both smoking-related chronic obstructive pulmonary disease and bronchiectasis.

Background. Respiratory diseases account for >10% of the global burden of disease when measured in disability-adjusted life-years. The burden of chronic respiratory diseases (CRDs) increases as the world’s population ages, with a much greater increase in low- to middle-income countries. Objectives. To characterise and quantify the reasons for acute respiratory presentations to the acute care services at a tertiary hospital in Cape Town, South Africa. Methods. A cross-sectional descriptive study was conducted. Casualty registers and electronic record databases were reviewed to determine the diagnoses of consecutive patients attending the casualty unit from May 2019 to January 2020. Results. A total of 1 053 individual patients presented with a primary respiratory diagnosis. Fewer than 10% of admissions were from outside the Cape Town metropole, while >60% were from the subdistrict immediately adjacent to the hospital. Of all patients, 8.3% were readmitted at least once within the 9-month study period. Six hundred and forty-three (61.1%) of the patients presented with non-CRDs. The main reasons for presentation in these patients were pulmonary tuberculosis (PTB) ( n =224; 21.3%), other infections including lower respiratory tract infections, pneumonia and bronchitis ( n =272; 25.8%), and cancer ( n =140; 13.3%). Haemoptysis was seen in 9.8% of all patients, mainly explained by post-tuberculosis lung disease (PTLD) (37.9%) and PTB (36.9%). Of the patients, 410 (38.9%) had an underlying CRD, with chronic pulmonary obstructive disease (COPD) being the most common ( n =192; 18.2%), followed by PTLD ( n =88; 8.5%) and asthma ( n =52; 5.1%). Conclusions. Over a 9-month period, acute respiratory presentations to a tertiary hospital were mainly for primary/secondary level of care indications, highlighting disparity in accessing tertiary services. COPD and PTLD predominated among CRDs, while infections and cancers were common. A high readmission rate was found for several diseases, suggesting the potential for targeted interventions to prevent both admissions and readmissions and reduce acute hospital utilisation costs.

Background. We previously retrospectively validated a 6-point severity-of-illness score aimed at identifying patients at risk of dying of tuberculosis (TB) in the intensive care unit (ICU). Parameters included septic shock, HIV infection with a CD4 count

The coronavirus disease 2019 (COVID-19) pandemic has increased exponentially in numbers with more than 20 million people infected around the globe. It is clear that COVID-19 is not a simple viral pneumonia, but presents with unusual pathophysiological effects. Of special interest is that SARS-CoV-2 utilises the angiotensin-converting enzyme-2 (ACE2) for cell entry and therefore has a direct effect on the renin angiotensin system (RAS). The RAS is primarily responsible for blood pressure control via the classic pathway. Recently numerous other pathological processes have been described due to stimulation of this classic pathway. There is also a protective RAS pathway medicated by ACE2 which may be suppressed in COVID-19. This leads to overstimulation of the classic pathway with adverse cardiovascular and respiratory effects, hypercoagulation, endothelial dysfunction, inflammation and insulin resistance. We hypothesize that overreaction of the renin-angiotensin-aldosterone may account for the myriad of unusual biochemical and clinical abnormalities noted in patients infected with SARS-CoV-2.