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Rationale: Mycobacterium tuberculosis is transmitted by infectious aerosols, but assessing infectiousness currently relies on sputum microscopy that does not accurately predict the variability in transmission.Objectives: To evaluate the feasibility of collecting cough aerosols and the risk factors for infectious aerosol production from patients with pulmonary tuberculosis (TB) in a resource-limited setting.Methods: We enrolled subjects with suspected TB in Kampala, Uganda and collected clinical, radiographic, and microbiological data in addition to cough aerosol cultures. A subset of 38 subjects was studied on 2 or 3 consecutive days to assess reproducibility.Measurements and Main Results: M. tuberculosis was cultured from cough aerosols of 28 of 101 (27.7%; 95% confidence interval [CI], 19.9-37.1%) subjects with culture-confirmed TB, with a median 16 aerosol cfu (range, 1-701) in 10 minutes of coughing. Nearly all (96.4%) cultivable particles were 0.65 to 4.7 μm in size. Positive aerosol cultures were associated with higher Karnofsky performance scores (P = 0.016), higher sputum acid-fast bacilli smear microscopy grades (P = 0.007), lower days to positive in liquid culture (P = 0.004), stronger cough (P = 0.016), and fewer days on TB treatment (P = 0.047). In multivariable analyses, cough aerosol cultures were associated with a salivary/mucosalivary (compared with purulent/mucopurulent) appearance of sputum (odds ratio, 4.42; 95% CI, 1.23-21.43) and low days to positive (per 1-d decrease; odds ratio, 1.17; 95% CI, 1.07-1.33). The within-test (kappa, 0.81; 95% CI, 0.68-0.94) and interday test (kappa, 0.62; 95% CI, 0.43-0.82) reproducibility were high.Conclusions: A minority of patients with TB (28%) produced culturable cough aerosols. Collection of cough aerosol cultures is feasible and reproducible in a resource-limited setting. [ABSTRACT FROM AUTHOR]

We present a patient with a post-pneumonectomy empyema refractory to surgical debridement and systemic antibiotics. The patient initially presented with a bronchopleural fistula and pneumothorax secondary to tuberculosis (TB) destroyed lung, which required a pneumonectomy with Eloesser flap. Ongoing pleural infection delayed the closure of the Eloesser flap, and thoracoscopic inspection of his chest cavity revealed a green, mucous biofilm-like structure lining the postpneumonectomy pleural cavity. Cultures identified pan-susceptible Pseudomonas aeruginosa. Despite debriding this biofilm-like structure and administering systemic antibiotics, the patient continued to show persistent signs of infection and regrowth of the film. We employed a novel approach to dissolve the biofilm-like structure using intrapleural dornase alfa followed by intrapleural antibiotic washes. After 3 weeks of daily washes, repeat inspection demonstrated the biofilm-like structure had completely resolved. Resolving the pseudomonas biofilm-like structure allowed permanent closure of his chest without further need for systemic antibiotics. At follow up 3 months later, he showed no sequalae. This treatment option can be an important adjunct to improve likelihood of chest closure in patients with post-pneumonectomy empyema that resists standard treatment options due to biofilm formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gustafson, Larrain, Friedman, Repkorwich, Anidi, Forrest, Fennelly and Carr.)

Background: Thymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described as an autoimmune manifestation associated with thymoma presenting with similar clinical, radiographic, histological, and autoantibody features as seen in patients with inherited AIRE deficiency who suffer from Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome., Objectives: To treat two patients with biopsy-proven thymoma-associated pneumonitis with lymphocyte-directed immunomodulation., Methods: Two patients with thymoma were enrolled on IRB-approved protocols at the NIH Clinical Center. We performed history and physical examination; laboratory, radiographic, histologic and pulmonary function evaluations; and measurement of the lung-directed autoantibodies KCNRG and BPIFB1 prior to and at 1- and 6-months following initiation of lymphocyte-directed immunomodulation with azathioprine with or without rituximab., Results: Combination T- and B-lymphocyte-directed immunomodulation resulted in improvement of clinical, functional, and radiographic parameters at 6-month follow-up evaluations in both patients with sustained remission up to 12-36 months following treatment initiation., Conclusion: Lymphocyte-directed immunomodulation remitted autoimmune pneumonitis in two patients with thymoma., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood., Methods: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire -/- Ifng -/- mice and Aire -/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses., Results: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire -/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire -/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients., Conclusions: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Migration to the lungs of an initial upper airway infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other respiratory pathogens can lead to pneumonia, associated with progression from mild to severe symptoms. Chemical pneumonitis or bacterial pneumonia may be caused by the 'macroaspiration' of large volumes of oropharyngeal or gastroesophageal secretions into the lower respiratory tract. 'Microaspiration', i.e. , a similar mechanism but involving much smaller amounts of oropharyngeal secretions, is considered the pathogenetic mechanism for most pneumonias, including that associated with COVID-19. Here, we hypothesize an alternative mechanism: Rather than by microaspiration, these fluids enter the lungs as microdroplets that are generated by snoring and then carried by the inspired airstream. Laboratory measurements indicate that snoring generates (a) comparable numbers and sizes of oral fluid droplets as loud speaking and (b) total fluid quantities that are similar to those reported for microaspiration. Snoring propensity is strongly correlated to known risk factors for severe COVID-19, including male gender, age, obesity, diabetes, obstructive sleep apnea, and pregnancy. Therefore, more research is urgently needed to determine if various methods that decrease snoring can prevent progression to pneumonia after initial infection of the upper airways., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) Community-acquired Pneumonia (CAP) guidelines were developed using systematic reviews to inform every recommendation, as suggested by the Institute of Medicine Standards for Trustworthy Guidelines. Recent studies suggest that an expert consensus-based approach, called the Convergence of Opinion on Recommendations and Evidence (CORE) process, can produce recommendations that are concordant with recommendations informed by systematic reviews., Purpose: The goal of the study was to evaluate the efficacy of the CORE process had it been used to develop the ATS/IDSA CAP guidelines., Methods: Experts in CAP who were not on the guideline panel and had no knowledge of the guideline's systematic reviews or recommendations were recruited to participate in the CORE process, addressing the same questions asked by the guideline panel. Recommendations derived from the CORE process were compared to the guideline recommendations. Concordance of the course of action, strength of recommendation, and quality of evidence were determined., Results: Using a threshold of 70% of experts selecting the same course of action to make a recommendation, the CORE process yielded a recommendation for 20 of 31 (65%) questions. Among the 20 CORE-derived recommendations, 19 (95%) were concordant with the guideline recommendations (kappa agreement 0.88, 95% CI .64-1.00). There was less agreement among the strength of recommendations (58%) and quality of evidence (42%)., Conclusions: If the CORE process had been used, 11 systematic reviews would have been necessary rather than 31, with minimal impact on the recommended courses of action., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: To assess a 0.55-T MRI system for imaging lung disease and to compare image quality with clinical CT scans., Materials and Methods: In this prospective study conducted between November 2018 and December 2019, respiratory-triggered T2-weighted turbo spin-echo MRI at 0.55 T was compared with clinical CT scans in 24 participants (mean age, 59 years ± 16 [standard deviation]; 18 women) with common lung abnormalities. MR images were reviewed and scored by experienced readers. Abnormal findings identified with MRI and CT were compared using the Cohen κ statistic., Results: High-quality structural pulmonary MR images were attained with an average acquisition time of 11 minutes ± 3. MRI generated sufficient image quality to robustly detect bronchiectasis (κ = 0.61), consolidative opacities (κ = 1.00), cavitary lesions (κ = 1.00), effusion (κ = 0.64), mucus plug (κ = 0.68), and solid scattered nodularity (κ = 0.82). Diffuse disease, including ground-glass opacities (κ = 0.57) and tree-in-bud nodules (κ = 0.48), were the findings that were most difficult to discern using MRI, with false readings in four of 18 patients for each feature. Nodule size, which was measured independently at CT and MRI, was strongly correlated ( R 2 = 0.99) for nodules with a measurement of 10 mm ± 5 (range, 5-23 mm)., Conclusion: This initial study indicates that high-performance 0.55-T MRI holds promise in the evaluation of common lung disease.Clinical trials registration no. NCT03331380 Supplemental material is available for this article. Keywords: MRI, Pulmonary, Technology Assessment© RSNA, 2021., Competing Interests: Disclosures of Conflicts of Interest: A.E.C. disclosed no relevant relationships. A.A.M. disclosed no relevant relationships. E.C.J. disclosed no relevant relationships. J.M. disclosed no relevant relationships. K.P.F. disclosed no relevant relationships. K.N.O. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a grant from Beyond Air. Other relationships: disclosed no relevant relationships. M.Y.C. disclosed no relevant relationships., (2021 by the Radiological Society of North America, Inc.)

Context: The monogenic disorder autoimmune polyendocrine syndrome type 1 (APS-1) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) manifests frequently with hypoparathyroidism, which requires treatment with oral supplementation with calcium and active vitamin D analogs. The majority of APS-1/APECED patients also suffer from intestinal malabsorption, which complicates the management of hypoparathyroidism and may lead to refractory severe hypocalcaemia. In such situations, reliance on intravenous calcium carries a high risk of nephrocalcinosis and renal damage., Methods: Here, we report our experience of periprocedural subcutaneous administration of recombinant human parathyroid hormone (rhPTH 1-34) in APS-1/APECED patients. Serum calcium was measured up to five times within the 36-hour period starting the evening before the scheduled procedure and ending the morning following the procedure., Results: Twenty-seven APS-1/APECED patients with hypoparathyroidism (aged 4-67 years) underwent 31 invasive gastrointestinal and/or pulmonary procedures. The patients received an average rhPTH1-34 dose of 9.6 ± 1.4 µg by subcutaneous injection. 92% of the adults and 54% of children in our cohort had evidence of nephrocalcinosis. Mean calcium levels remained stable and ranged from 2.06 to 2.17 mmol/L with minimal fluctuation. None of our patients experienced periprocedural adverse events connected with hypocalcaemia., Conclusion: rhPTH 1-34 is an alternative to conventional therapy in patients with APS-1/APECED and hypoparathyroidism undergoing invasive procedures. Subcutaneous PTH1-34 given directly before and after procedures resulted in well-controlled serum calcium levels maintained in the low-normal range and avoided the need for intravenous calcium which may contribute to renal calcifications and tubular damage., (© 2020 John Wiley & Sons Ltd.)

The global pandemic of COVID-19 has been associated with infections and deaths among health-care workers. This Viewpoint of infectious aerosols is intended to inform appropriate infection control measures to protect health-care workers. Studies of cough aerosols and of exhaled breath from patients with various respiratory infections have shown striking similarities in aerosol size distributions, with a predominance of pathogens in small particles (<5 μm). These are immediately respirable, suggesting the need for personal respiratory protection (respirators) for individuals in close proximity to patients with potentially virulent pathogens. There is no evidence that some pathogens are carried only in large droplets. Surgical masks might offer some respiratory protection from inhalation of infectious aerosols, but not as much as respirators. However, surgical masks worn by patients reduce exposures to infectious aerosols to health-care workers and other individuals. The variability of infectious aerosol production, with some so-called super-emitters producing much higher amounts of infectious aerosol than most, might help to explain the epidemiology of super-spreading. Airborne infection control measures are indicated for potentially lethal respiratory pathogens such as severe acute respiratory syndrome coronavirus 2., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pulmonary infections are important causes of global morbidity and mortality, but diagnostics are often limited by the ability to collect specimens easily, safely, and in a cost-effective manner. We review recent advances in the collection of infectious aerosols from patients with TB and with influenza. Although this research has been focused on assessing the infectious potential of such patients, we propose that these methods have the potential to lead to the use of patient-generated microbial aerosols as noninvasive diagnostic tests of disease and tests of infectiousness., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967&#95;979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Epidemiologic data suggests that only a minority of tuberculosis (TB) patients are infectious. Cough aerosol sampling is a novel quantitative method to measure TB infectiousness., Methods: We analyzed data from three studies conducted in Uganda and Brazil over a 13-year period. We included sputum acid fast bacilli (AFB) and culture positive pulmonary TB patients and used a cough aerosol sampling system (CASS) to measure the number of colony-forming units (CFU) of Mycobacterium tuberculosis in cough-generated aerosols as a measure for infectiousness. Aerosol data was categorized as: aerosol negative (CFU = 0) and aerosol positive (CFU > 0). Logistic regression models were built to identify factors associated with aerosol positivity., Results: M. tuberculosis was isolated by culture from cough aerosols in 100/233 (43%) TB patients. In an unadjusted analysis, aerosol positivity was associated with fewer days of antituberculous therapy before CASS sampling ( p = .0001), higher sputum AFB smear grade ( p = .01), shorter days to positivity in liquid culture media ( p = .02), and larger sputum volume ( p = .03). In an adjusted analysis, only fewer days of TB treatment (OR 1.47 per 1 day of therapy, 95% CI 1.16-1.89; p = .001) was associated with aerosol positivity., Conclusion: Cough generated aerosols containing viable M. tuberculosis, the infectious moiety in TB, are detected in a minority of TB patients and rapidly become non-culturable after initiation of antituberculous treatment. Mechanistic studies are needed to further elucidate these findings.

Background: Mycobacterium tuberculosis cultures of cough-generated aerosols from patients with pulmonary tuberculosis (TB) are a quantitative method to measure infectiousness and to predict secondary outcomes in exposed contacts. However, their reproducibility has not been established., Objective: To evaluate the predictive value of colony-forming units (CFU) of M. tuberculosis in cough aerosols on secondary infection and disease in household contacts in Brazil., Methods: Adult sputum smear+ and culture+ pulmonary TB cases underwent a standard evaluation and were categorized according to aerosol CFU. We evaluated household contacts for infection at baseline and at 8 weeks with TST and IGRA, and secondary disease., Results: We enrolled 48 index TB cases; 40% had negative aerosols, 27% low aerosols (<10 CFU) and 33% high aerosols (≥10 CFU). Of their 230 contacts, the proportion with a TST ≥10 mm at 8 weeks was 59%, 65% and 75%, respectively (p = 0.34). Contacts of high aerosol cases had greater IGRA readouts (median 4.6 IU/mL, IQR 0.02-10) when compared to those with low (0.8, 0.2-10) or no aerosol (0.1, 0-3.7; p = 0.08). IGRA readouts in TST converters of high aerosol cases (median 20 IU/mL, IQR 10-24) were larger than those from aerosol-negative (0.13, 0.04-3; p = o.o2). 8/9 (89%) culture+ secondary TB cases occurred in contacts of aerosol+ cases., Conclusion: Aerosol CFU predicts quantitatively IGRA readouts among household contacts of smear positive TB cases. Our results strengthen the argument of using cough aerosols to guide targeted preventive treatment strategies, a necessary component of current TB elimination projections., Competing Interests: One of our co-authors, Dr. Jones-López, is a co-founder and shareholder of a small startup company created in 2013 to develop and commercialize a molecular assay for tuberculosis diagnosis. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declare that no competing interests exist.

Objectives: Integrating audiological management into the care pathways of clinical specialties that prescribe ototoxic medications for essential, often life-preserving medical care that is critical for early hearing loss identification and remediation. Research shows that successful implementation of a new health service or intervention requires alignment of goals among provider groups, institutional leadership and patients. Thoughtful consideration of the physician's viewpoints about ototoxicity and its implications for treatment planning is, therefore, important for the implementation and enduring success of an ototoxicity monitoring programme (OMP)., Design: This discussion paper uses qualitative methods to explore the perspectives of four physicians on OMP provision in their patient populations., Study Sample: Three pulmonologists and one oncologist completed the written survey or survey-based interview described in this report., Results: Each physician indicated that (i) ototoxicity is a potential problem for their patients; (ii) monitoring hearing is important to ensure good quality of life among their patients and (iii) treatment modification would be considered if an alternative treatment option were available. The physicians differed in their approaches to ototoxicity monitoring, from routine referrals to audiology, to relying on patient self-referral., Conclusion: Physician provider input is needed to optimise monitoring schedules and OMP care coordination with audiology.

Objective: We identified patients with non-tuberculous mycobacterial (NTM) disease in the US Veterans Health Administration (VHA), examined the distribution of diseases by NTM species, and explored the association between NTM disease and the frequency of clinic visits and mortality., Methods: We combined mycobacterial isolate (from natural language processing) with ICD-9-CM diagnoses from VHA data between 2008 and 2012 and then applied modified ATS/IDSA guidelines for NTM diagnosis. We performed validation against a reference standard of chart review. Incidence rates were calculated. Two nested case-control studies (matched by age and location) were used to measure the association between NTM disease and each of 1) the frequency of outpatient clinic visits and 2) mortality, both adjusted by chronic obstructive pulmonary disease (COPD), other structural lung diseases, and immunomodulatory factors., Results: NTM cases were identified with a sensitivity of 94%, a specificity of >99%. The incidence of NTM was 12.6/100k patient-years. COPD was present in 68% of pulmonary NTM. NTM incidence was highest in the southeastern US. Extra-pulmonary NTM rates increased during the study period. The incidence rate ratio of clinic visits in the first year after diagnosis was 1.3 [95%CI 1.34-1.35]. NTM patients had a hazard ratio of mortality of 1.4 [95%CI 1.1-1.9] in the 6 months after NTM identification compared to controls and 1.99 [95%CI 1.8-2.3] thereafter., Conclusions: In VHA, pulmonary NTM disease is commonly associated with COPD, with the highest rates in the southeastern US. After adjustment, NTM patients had more clinic visits and greater mortality compared to matched patients., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: some of the authors had operational roles in Veterans Affairs and were part of the funding agency. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

We used an amoeba model to study the intracellular growth and cytotoxicity of clinical strains of Mycobacterium abscessus subsp. massiliense (Mabsm) isolated from 2 patients (one with cystic fibrosis, the other one with idiopathic bronchiectasis) during the early (smooth colonies) and late stage (rough colonies) of chronic pulmonary infection. Acanthamoeba castellanii were infected with Mabsm (MOI 100) and samples collected every 24 h for 72 h. Results showed Mabsm is able to survive in trophozoites and persist in cysts for at least 7 days. Late Mabsm demonstrated higher cytotoxicity toward A. castellanii when compared to early strains. A. castellanii is a useful in vitro host model to study infection of Mabsm clinical isolates., (Published by Elsevier Masson SAS.)

The transmission of tuberculosis is complex. Necessary factors include a source case with respiratory disease that has developed sufficiently for Mycobacterium tuberculosis to be present in the airways. Viable bacilli must then be released as an aerosol via the respiratory tract of the source case. This is presumed to occur predominantly by coughing but may also happen by other means. Airborne bacilli must be capable of surviving in the external environment before inhalation into a new potential host-steps influenced by ambient conditions and crowding and by M. tuberculosis itself. Innate and adaptive host defenses will then influence whether new infection results; a process that is difficult to study owing to a paucity of animal models and an inability to measure infection directly. This review offers an overview of these steps and highlights the many gaps in knowledge that remain., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Setting: In early studies, Xpert® MTB/RIF accurately detected culture-proven pulmonary tuberculosis (TB). Recent reports have, however, found a lower than expected specificity in previously treated TB patients., Objective: To investigate the diagnostic accuracy of Xpert in presumptive pulmonary TB patients in Southwestern Uganda., Design: We obtained demographic and clinical information and collected three sputum samples from each patient for smear microscopy, Xpert and culture. We estimated Xpert sensitivity and specificity against culture, and stratified the analysis by previous treatment and sputum quality status., Results: We analyzed results from 860 presumptive TB patients, including 109 (13%) with a previous history of anti-tuberculosis treatment; 205 (24%) were culture-positive. Xpert specificity was lower (91.8%, 95%CI 84.9-96.2) in previously treated than in new TB patients (97.5%, 95%CI 96.1-98.5; P = 0.01). In an adjusted analysis, patients with culture-, Xpert+ results were more likely to have been previously treated for TB (OR 8.3, 95%CI 2.1-32.0; P = 0.002), and to have mucosalivary sputum (OR 4.1, 95%CI 1.1-14.6; P = 0.03), but were less likely to self-report fever (OR 0.23, 95%CI 0.1-0.7; P = 0.008) than patients with concordant positive results., Conclusion: Xpert specificity was lower in previously treated patients with suspected TB. The clinical and programmatic impact of culture-, Xpert+ results requires evaluation in future studies.

Background: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies., Methods: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179)., Findings: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid., Interpretation: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing., Funding: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective/background: The aims of this talk are to: (a) provide an overview of our method of collecting, quantifying, and sizing infectious aerosols of Mycobacterium tuberculosis; and (b) to review data indicating that cough aerosol cultures of M. tuberculosis are the best predictors of infection and incident disease among household contacts of persons with active tuberculosis (TB). New infection was defined as tuberculin skin test conversion., Methods: We developed a cough aerosol sampling system by placing two Andersen cascade impactor viability samplers inside a cylinder into which patients cough via connector tubing. We recruited sputum acid fast bacilli (AFB) smear-positive patients from the tuberculosis clinic and wards at Mulago Hospital in Kampala, Uganda. Patients were asked to cough as strongly and frequently as they comfortably could for two 5-min sessions of coughing., Results: In a cohort of 96 sputum culture positive index TB cases, 43 (45%) produced culture-positive cough aerosols. Household contacts of TB patients who produced high aerosols (⩾10colony forming units (CFU)) were more likely to have a new infection compared with contacts with low aerosol CFU (1-9CFU) and aerosol-negative cases (69%, 25%, and 30%, respectively, p=0.009). In adjusted multivariate analyses, high cough aerosols were the only predictor of new TB infection (odds ratio [OR] 4.81; 1.20-19.23). In a follow-up (median 3.9years) of this cohort, 369 (84%) of the contacts could be traced; eight (2%) had developed TB disease. Incident TB disease was associated with larger bacillary load in sputum measured by days to positive in liquid culture (OR 7.9; 0.7-70.5), exposure to a high-aerosol TB case patient (OR 6.0, 1.4-25.2) and marginally to HIV infection in the contact (OR 7.2; 0.7-70.5). Cough aerosol studies of TB patients in Brazil and South Africa are ongoing and appear to be finding similar proportions of cough aerosol cultures among TB patients (personal communication)., Conclusion: Cough aerosol cultures of M. tuberculosis are the best predictors of infectiousness and predict incident TB disease among sputum smear-positive patients in Uganda. We propose that cough aerosol cultures are a better surrogate of inhaled dose than sputum smear., (Copyright © 2016.)

Infectious disease outbreaks and epidemics such as those due to SARS, influenza, measles, tuberculosis, and Middle East respiratory syndrome coronavirus have raised concern about the airborne transmission of pathogens in indoor environments. Significant gaps in knowledge still exist regarding the role of mechanical ventilation in airborne pathogen transmission. This review, prepared by a multidisciplinary group of researchers, focuses on summarizing the strengths and limitations of epidemiologic studies that specifically addressed the association of at least one heating, ventilating and/or air-conditioning (HVAC) system-related parameter with airborne disease transmission in buildings. The purpose of this literature review was to assess the quality and quantity of available data and to identify research needs. This review suggests that there is a need for well-designed observational and intervention studies in buildings with better HVAC system characterization and measurements of both airborne exposures and disease outcomes. Studies should also be designed so that they may be used in future quantitative meta-analyses., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Tuberculosis disease develops in only 5%-10% of humans infected with Mycobacterium tuberculosis The mechanisms underlying this variability remain poorly understood. We recently demonstrated that colony-forming units of M. tuberculosis in cough-generated aerosols are a better predictor of infection than the standard sputum acid-fast bacilli smear. We hypothesized that cough aerosol cultures may also predict progression to tuberculosis disease in contacts., Methods: We conducted a retrospective cohort study of 85 patients with smear-positive tuberculosis and their 369 household contacts in Kampala, Uganda. Index case patients underwent a standard evaluation, and we cultured M. tuberculosis from cough aerosols. Contacts underwent a standard evaluation at enrollment, and they were later traced to determine their tuberculosis status., Results: During a median follow-up of 3.9 years, 8 (2%) of the contacts developed tuberculosis disease. In unadjusted and adjusted analyses, incident tuberculosis disease in contacts was associated with sputum Mycobacterial Growth Indicator Tube culture (odds ratio, 8.2; 95% confidence interval, 1.1-59.2; P = .04), exposure to a high-aerosol tuberculosis case patient (6.0, 1.4-25.2; P = .01), and marginally, human immunodeficiency virus in the contact (6.11; 0.89-41.7; P = .07). We present data demonstrating that sputum and aerosol specimens measure 2 related but different phenomena., Conclusions: We found an increased risk of tuberculosis progression among contacts of high-aerosol case patients. The hypothesis that a larger infectious inoculum, represented by high aerosol production, determines the risk of disease progression deserves evaluation in future prospective studies., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Sputum acid-fast bacilli (AFB) smear microscopy has suboptimal sensitivity but remains the most commonly used laboratory test to diagnose pulmonary tuberculosis (TB). We prospectively evaluated the small membrane filtration (SMF) method that concentrates AFB in a smaller area to facilitate detection to improve the diagnostic performance of microscopy. We enrolled adults with suspicion of pulmonary TB from health facilities in southwestern Uganda. Clinical history, physical examination, and 3 sputum samples were obtained for direct fluorescent AFB smear, SMF, Xpert MTB/RIF, and MGIT culture media. Sensitivity and specificity were estimated for SMF, AFB smear, and Xpert MTB/RIF, using MGIT as the reference standard. The analysis was stratified according to HIV status. From September 2012 to April 2014, 737 participants were included in the HIV-infected stratum (146 [20.5%] were culture positive) and 313 were in the HIV-uninfected stratum (85 [28%] were culture positive). In HIV-infected patients, the sensitivity of a single SMF was 67.4% (95% confidence interval [CI], 59.9% to 74.1%); for AFB, 68.0% (95% CI, 60.6% to 74.6%); and for Xpert MTB/RIF, 91.0% (95% CI, 85.0% to 94.8%). In HIV-uninfected patients, the corresponding sensitivities were 72.5% (95% CI, 62.1% to 80.9%), 80.3% (95% CI, 70.8% to 87.2%), and 93.5% (95% CI, 85.7% to 97.2%). The specificity for all 3 tests in both HIV groups was ≥96%. In this setting, the SMF method did not improve the diagnostic accuracy of sputum AFB. The Xpert MTB/RIF assay performed well in both HIV-infected and -uninfected groups., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Rationale: The diagnosis of latent tuberculosis (TB) infection (LTBI) is complicated by the absence of a gold standard. Discordance between tuberculin skin tests (TST) and interferon gamma release assays (IGRA) occurs in 10-20% of individuals, but the underlying mechanisms are poorly understood., Methods: We analyzed data from a prospective household contact study that included cough aerosol culture results from index cases, environmental and contact factors. We assessed contacts for LTBI using TST and IGRA at baseline and six weeks. We examined TST/IGRA discordance in qualitative and quantitative analyses, and used multivariable logistic regression analysis with generalized estimating equations to analyze predictors of discordance., Measurements and Results: We included 96 TB patients and 384 contacts. Discordance decreased from 15% at baseline to 8% by six weeks. In adjusted analyses, discordance was related to less crowding (p = 0.004), non-cavitary disease (OR 1.41, 95% CI: 1.02-1.96; p = 0.03), and marginally with BCG vaccination in contacts (OR 1.40, 95% CI: 0.99-1.98, p = 0.06)., Conclusions: We observed significant individual variability and temporal dynamism in TST and IGRA results in household contacts of pulmonary TB cases. Discordance was associated with a less intense infectious exposure, and marginally associated with a BCG-mediated delay in IGRA conversion. Cough aerosols provide an additional dimension to the assessment of infectiousness and risk of infection in contacts.

The World Health Organization recommends for tuberculosis retreatment a regimen of isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z), and streptomycin (S) for 2 months, followed by H, R, E, and Z for 1 month and H, R, and E for 5 months. Using data from the National Tuberculosis and Leprosy Program registry, this study determined the long-term outcome under programmatic conditions of patients who were prescribed the retreatment regimen in Kampala, Uganda, between 1997 and 2003. Patients were traced to determine their vital status; 62% (234/377) patients were found dead. Having ≤ 2 treatment courses and not completing retreatment were associated with mortality in adjusted analyses., (© The American Society of Tropical Medicine and Hygiene.)

Experimental animal models of tuberculosis (TB) have convincingly demonstrated that inhaled dose predicts immunopathology and survival. In contrast, the importance of inhaled dose has generally not been appreciated in TB epidemiology, clinical science, or the practice of TB control. Infectiousness of TB patients has traditionally been assessed using microscopy for acid-fast bacilli in the sputum, which should be considered only a risk factor. We have recently demonstrated that cough aerosol cultures from index cases with pulmonary TB are the best predictors of new infection among household contacts. We suggest that cough aerosols of M. tuberculosis are the best surrogates of inhaled dose, and we hypothesize that the quantity of cough aerosols is associated with TB infection versus disease. Although several factors affect the quality of infectious aerosols, we propose that the particle size distribution of cough aerosols is an important predictor of primary upper airway disease and cervical lymphadenitis and of immune responses in exposed hosts. We hypothesize that large droplet aerosols (>5 μ) containing M. tuberculosis deposit in the upper airway and can induce immune responses without establishing infection. We suggest that this may partially explain the large proportion of humans who never develop TB disease in spite of having immunological evidence of M. tuberculosis infection (e.g., positive tuberculin skin test or interferon gamma release assay). If these hypotheses are proven true, they would alter the current paradigm of latent TB infection and reactivation, further demonstrating the need for better biomarkers or methods of assessing TB infection and the risk of developing disease.

Background: Elderly persons have the highest rates of tuberculosis (TB) in the United States compared to all other age groups. A systematic literature review was conducted to determine if older age was a risk factor for hepatotoxicity resulting from treatment with first-line drugs used to treat active (TB) and latent tuberculosis (LTBI)., Methods: A systematic review of MEDLINE, Cochrane Controlled Trial Registry, CINAHL(®), and Science Citation Index Expanded (from 1970 to 2011) was performed to determine the risk of hepatotoxicity, comparing those over 60 with those under 60. A meta-analysis was performed using a random effects model along with log odds ratios and the chi-square test., Findings: Thirty-eight studies (40,034 participants; 1208 cases of hepatotoxicity) met the selection criteria. For active TB, an overall mean effect of 0.277 (p = 0.024, 95% CI: 0.037-0.517) was observed, which is equivalent to an odds ratio of 1.32 (95% CI: 1.04-1.68). For LTBI, an overall mean effect of 1.42 (p < 0.001, 95% CI: 0.794-2.05) was observed, which translates to an odds ratio of 4.14 (95% CI: 2.21-7.74)., Interpretation: Our analysis revealed that patients older than 60 had significantly more risk of hepatotoxicity. These studies suggest that a gentler regimen of treatment for older individuals could benefit health outcomes in this population of TB patients and minimize risks to the public's health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The treatment of infections caused by nontuberculous mycobacteria (NTM) is challenging because multidrug regimens with limited efficacy and considerable toxicity are required. Current treatment of NTM is largely empiric. None of the NTM drugs were specifically developed for the treatment of NTM; the rationale for their use was often extrapolated from the treatment of tuberculosis. This article reviews key features of the drugs that are most commonly used for NTM infections, and provides monitoring parameters. With this information, clinicians can make the most of the limited options available. Considerable research is needed to optimize the treatment of NTM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives . To report a probable interaction between rifampin and carbamazepine, likely leading to a seizure, and to review conflicting reports regarding this interaction. Case Summary . A 55-year-old female was treated with carbamazepine 200 mg 3 times daily for grand mal seizures, with excellent control. A 6-hour postdose carbamazepine concentration was 10.7 µg/mL (therapeutic range = 4-10 µg/mL). After she was diagnosed with pulmonary Mycobacterium avium complex, she received rifampin 300 mg twice daily, ethambutol 800 mg daily, and clarithromycin 500 mg twice daily. At first clinic visit, rifampin was changed to 600 mg daily, and clarithromycin was replaced with azithromycin 250 mg daily. A 4-hour postdose carbamazepine concentration was 7.1 µg/mL. Two weeks later, the patient experienced a seizure (no carbamazepine concentration reported at that time), but admitted to missing doses of carbamazepine. After experiencing 2 more seizures, the patient stopped taking rifampin. Subsequently, the carbamazepine dose was increased to 400 mg twice daily and rifampin was restarted at 600 mg daily. Two follow-up peak carbamazepine concentrations were 4.7 µg/mL and 4.4 µg/mL, with no reported seizures. No additional factors were identified as potential causes of the seizures or the lower carbamazepine concentrations. A Drug Interaction Probability Scale score of 6 indicates a probable interaction. Discussion . Conflicting reports exist regarding the effect of rifampin on carbamazepine concentrations, likely reflecting rifampin's ability to display time-dependent, mixed effects on transporters and cytochrome P450 enzymes. Conclusions . Our case report describes a patient who experienced seizures after the addition of rifampin to her regimen, followed by lower peak concentrations of carbamazepine. Therapeutic drug monitoring in patients receiving both rifampin and carbamazepine is recommended to help clinicians optimize drug therapy., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2014.)

Rationale: Airborne transmission of Mycobacterium tuberculosis results from incompletely characterized host, bacterial, and environmental factors. Sputum smear microscopy is associated with considerable variability in transmission., Objectives: To evaluate the use of cough-generated aerosols of M. tuberculosis to predict recent transmission., Methods: Patients with pulmonary tuberculosis (TB) underwent a standard evaluation and collection of cough aerosol cultures of M. tuberculosis. We assessed household contacts for new M. tuberculosis infection. We used multivariable logistic regression analysis with cluster adjustment to analyze predictors of new infection., Measurements and Main Results: From May 2009 to January 2011, we enrolled 96 sputum culture-positive index TB cases and their 442 contacts. Only 43 (45%) patients with TB yielded M. tuberculosis in aerosols. Contacts of patients with TB who produced high aerosols (≥10 CFU) were more likely to have a new infection compared with contacts from low-aerosol (1-9 CFU) and aerosol-negative cases (69%, 25%, and 30%, respectively; P = 0.009). A high-aerosol patient with TB was the only predictor of new M. tuberculosis infection in unadjusted (odds ratio, 5.18; 95% confidence interval, 1.52-17.61) and adjusted analyses (odds ratio, 4.81; 95% confidence interval, 1.20-19.23). Contacts of patients with TB with no aerosols versus low and high aerosols had differential tuberculin skin test and interferon-γ release assay responses., Conclusions: Cough aerosols of M. tuberculosis are produced by a minority of patients with TB but predict transmission better than sputum smear microscopy or culture. Cough aerosols may help identify the most infectious patients with TB and thus improve the cost-effectiveness of TB control programs.

Background: Lobar or segmental collapse of the lung in mechanically ventilated patients is a common occurrence in the intensive care unit. Management is labor and time intensive and not highly effective., Methods: We conducted a randomized, placebo-controlled, double-blind pilot study to determine whether nebulized Dornase alfa improves radiologic and clinical outcomes in ventilated patients with lobar atelectasis. Drug or placebo was administered twice daily until extubation, death, or transfer. The primary outcome was the total chest x-ray score: secondary outcomes of interest were oxygenation, lung compliance, and rate of extubation over the first 5 days. The groups consisted of 14 intervention patients and 16 control patients., Results: There were no significant differences in "Total Chest X-Ray Score" or compliance over the 5 days of study. There was an improvement in oxygenation for the intervention group at day 5 (P = .03). In addition, this group was less likely to remain intubated over the first 24 hours of the study, a difference that did not persist over the course of the study., Conclusions: Dornase alfa does not improve the appearance of atelectasis on chest radiographs, or the "Total Chest X-Ray Score" over the first 5 days of treatment in mechanically ventilated patients. The intervention group's higher rate of extubation during the first 24 hours as well as its improved oxygenation on day 5 were likely chance findings given the multiple potential confounders for extubation and low study power., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We modified microscopy for acid-fast bacilli to diagnose tuberculosis (TB) using small membrane filters (SMFs) after special processing and prefiltration. With the first specimen obtained from each of 335 persons suspected of having TB, the sensitivity of the new SMF method using fluorescence microscopy (FM) was 89% (95% confidence interval [CI]: 80%, 95%). This was significantly better (P = 0.0001) than the sensitivity of routine FM of centrifuged specimens of 60% (95% CI: 49%, 71%) or that of direct sputum smears of 56% (95% CI: 40%, 72%).

We compared bacillary loads after splitting sputum specimens by chemical (N-acetyl-l-cysteine [NALC]) and mechanical homogenization by vortexing with sterile glass beads. NALC and vortexing with glass beads were equally effective at homogenizing sputum specimens, resulting in an equal distribution of tubercle bacilli in the aliquots.