Non-communicable Lung Disease in Sub Saharan Africa: a Community-based Cross-sectional Study of Adults in Urban Malawi

Rationale Non-communicable diseases (NCD) are major causes of morbidity and mortality in sub-Saharan Africa (sSA). Valid burden of disease estimates are lacking for non-communicable lung disease in sSA. Objectives We performed a community-based survey to determine the prevalence of chronic lung disease amongst adults ≥18 years in Malawi, using ATS standard spirometry, internationally validated respiratory symptom and exposure questionnaires, and including assessment of HIV-status. Methods An age and gender stratified random sample of 2000 adults was taken from the population of Chilomoni district of Blantyre, Malawi. Fieldworkers collected questionnaire data, conducted HIV-testing and performed pre/post bronchodilator spirometry on eligible participants. Survey-weighted population prevalence estimates of respiratory symptoms and spirometric abnormalities were computed, and bivariate and multivariable regression were used to identify associated variables. Results Questionnaire data, HIV status and BOLD standard spirometry were obtained from 1059, 937 and 749 participants respectively. Current respiratory symptoms, exposure to biomass and ever smoking were reported by 11.8%, 85.2% and 10.4% respectively. HIV prevalence was 24.2%. Moderate-severe airway obstruction was seen in 3.6%. The prevalence of spirometric restriction was 38.6% using NHANES reference ranges and 9.0% using local reference ranges. Age was positively associated with obstruction while low BMI was associated with restriction. Conclusions Over 40% of the Malawian adults in our urban population-representative sample had abnormal lung function (mostly restrictive) in the context of widespread exposure to biomass smoke and high HIV prevalence. These findings have potentially major pubic health implications for Malawi and the broader sSA region

The two homologous chaperonin 60 proteins of Mycobacterium tuberculosis have distinct effects on monocyte differentiation into osteoclasts.

Mycobacterium tuberculosis produces two homologous chaperonin (Cpn)60 proteins, Cpn60.1 and Cpn60.2 (Hsp65). Both proteins stimulate human and murine monocyte cytokine synthesis but, unlike Cpn60 proteins from other microbial species, fail to stimulate the breakdown of cultured murine bone. Here, we have examined the mechanism of action of these proteins on bone remodelling and osteoclastogenesis, induced in vitro in murine calvarial explants and the murine monocyte cell line RAW264.7. Additionally, we have determined their effect on bone remodelling in vivo in an animal model of arthritis. Recombinant Cpn60.1 but not Cpn60.2 inhibited bone breakdown both in vitro, in murine calvaria and in vivo, in experimental arthritis. Analysis of the mechanism of action of Cpn60.1 suggests that this protein works by directly blocking the synthesis of the key osteoclast transcription factor, nuclear factor of activated T cells c1. The detection of circulating immunoreactive intact Cpn60.1 in a small number of patients with tuberculosis but not in healthy controls further suggests that the skeleton may be affected in patients with tuberculosis. Taken together, these findings reveal that M. tuberculosis Cpn60.1 is a potent and novel inhibitor of osteoclastogenesis both in vitro and in vivo and a potential cure for bone-resorptive diseases like osteoporosis

Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis

BACKGROUND: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis. METHODS: Malawian adults with a first presentation of microbiologically-confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid, and alveolar cells. Population pharmacokinetic modelling generated estimates of drug exposure (Cmax and AUC) from individual-level post-hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics. RESULTS: One-hundred-and-fifty-seven patients (58% HIV co-infected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug monitoring targets. Rifampicin concentrations were low in all three compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in epithelial lining fluid and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6 (95% CI: 11.2-18.0) and 49.8-fold (95% CI: 34.2-65.3) higher in lining fluid than plasma respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cells:plasma ratio 15.0, 95% CI 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response. CONCLUSIONS: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens

Post-tuberculosis lung health: perspectives from the first International symposium

Tuberculosis, although curable, frequently leaves the individual with chronic physical and psycho-social impairment, yet these consequences have to-date been largely neglected. 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

High intrapulmonary rifampicin and isoniazid concentrations are associated with rapid sputum bacillary clearance in patients with pulmonary tuberculosis

This work was supported by a Wellcome Trust Clinical PhD Fellowship [grant number 105392/B/14/Z to A.D.M. and L69AGB to JM]. ELC was supported by Wellcome [200901/Z/16/Z]. The Malawi-Liverpool-Wellcome Clinical Research Programme is supported by a strategic award from the Wellcome Trust [206545/Z/17/Z]. We also acknowledge infrastructural support for bioanalysis from the Liverpool Biomedical Research Centre funded by Liverpool Health Partners.Background Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modelling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. Methods Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0 to 8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (AUC and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. Results Among 157 participants (58% HIV co-infected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavourable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. Conclusions Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.Publisher PDFPeer reviewe

Symptomatic, biochemical and radiographic recovery in patients with Covid-19

Background: The symptoms, radiography, biochemistry and healthcare utilisation of patients with COVID-19 following discharge from hospital have not been well described. Methods: Retrospective analysis of 401 adult patients attending a clinic following an index hospital admission or emergency department attendance with COVID-19. Regression models were used to assess the association between characteristics and persistent abnormal chest radiographs or breathlessness. Results: 75.1% of patients were symptomatic at a median of 53 days post discharge and 72 days after symptom onset and chest radiographs were abnormal in 47.4%. Symptoms and radiographic abnormalities were similar in PCR-positive and PCR-negative patients. Severity of COVID-19 was significantly associated with persistent radiographic abnormalities and breathlessness. 18.5% of patients had unscheduled healthcare visits in the 30 days post discharge. Conclusions: Patients with COVID-19 experience persistent symptoms and abnormal blood biomarkers with a gradual resolution of radiological abnormalities over time. These findings can inform patients and clinicians about expected recovery times and plan services for follow-up of patients with COVID-19