The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

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.).

Snoring-generated fluid droplets as a potential mechanistic link between sleep-disordered breathing and pneumonia.

The soft palate and back of the throat represent vulnerable early infection sites for SARS-CoV-2, influenza, streptococci, and many other pathogens. We demonstrate that snoring causes aerosolization of pharyngeal fluid that covers these surfaces, which previously has escaped detection because the inspired airstream carries the micron-sized droplets into the lung, inaccessible to traditional aerosol detectors. While many of these droplets will settle in the lower respiratory tract, a fraction of the respirable smallest droplets remains airborne and can be detected in exhaled breath. We distinguished these exhaled droplets from those generated by the underlying breathing activity by using a chemical tracer, thereby proving their existence. The direct transfer of pharyngeal fluids and their pathogens into the deep lung by snoring represents a plausible mechanistic link between the previously recognized association between sleep-disordered breathing and pneumonia incidence.

Snoring may transmit infectious aerosols from the upper to the lower respiratory tract.

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.

T2-weighted Lung Imaging Using a 0.55-T MRI System.

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. NCT03331380Supplemental material is available for this article. Keywords: MRI, Pulmonary, Technology Assessment© RSNA, 2021.

Community-acquired Pneumonia Guideline Recommendations-Impact of a Consensus-based Process versus Systematic Reviews.

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.

Impact of periprocedural subcutaneous parathyroid hormone on control of hypocalcaemia in APS-1/APECED patients undergoing invasive procedures.

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.

Particle sizes of infectious aerosols: implications for infection control.

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.

Microbial Aerosols: New Diagnostic Specimens for Pulmonary Infections.

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.

Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance.

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_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.

Host Determinants of Infectiousness in Smear-Positive Patients With Pulmonary Tuberculosis.

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.

Cough-aerosol cultures of Mycobacterium tuberculosis in the prediction of outcomes after exposure. A household contact study in Brazil.

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.

Epidemiology of nontuberculous mycobacterial infections in the U.S. Veterans Health Administration.

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.

Survival of pathogenic Mycobacterium abscessus subsp. massiliense in Acanthamoeba castellanii.

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.

Ototoxicity monitoring through the eyes of the treating physician: Perspectives from pulmonology and medical oncology.

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.

Tuberculosis Infectiousness and Host Susceptibility.

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.