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Twenty percent to 30% of all Sjögren’s patients have some form of pulmonary symptoms. The most common ones involve dry trachea, pleuritic discomfort, cough, and shortness of breath (dyspnea). Over time, approximately 10% of patients develop interstitial changes that may progress to scarring, increased pulmonary pressure, and bronchiectasis. A variety of interstitial lung disease (ILD) have been identified in the context of Sjögren’s. Infrequently, some Sjögren’s patients present with vasculitis or thromboembolic or lymphoproliferative changes. Evaluating the lungs in Sjögren’s includes pulmonary function testing, high-resolution CT scanning, 2-D echocardiography, and sleep studies. Supportive measures such as humidification are useful. If there is evidence for systemic inflammation, disease-modifying agents such as cyclophosphamide, mycophenolate mofetil, antifibrotic agents, or azathioprine are prescribed.

Background/objective Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may involve the kidney, respiratory tract, skin, or central and peripheral nervous system. Reports of interstitial lung disease (ILD) in AAV (AAV-ILD) have been increasing. Methods We reviewed the medical records of all patients with AAV-ILD between January 1, 2007, and December 31, 2017, and compared their pulmonary involvement to patients with idiopathic pulmonary fibrosis (IPF). Results We identified 24 patients with AAV-ILD: 14 with microscopic polyangiitis, 8 with granulomatosis with polyangiitis, and 2 with eosinophilic granulomatosis with polyangiitis. Perinuclear or myeloperoxidase ANCA was present in 16 cases (66.7%), whereas cytoplasmic or proteinase 3 ANCA was positive in 8 (33.3%). Usual interstitial pneumonia (UIP) was seen in 11 (45.8%), probable UIP in 1 (4.2%), indeterminate UIP in 2 (8.3%), and an alternate diagnosis in 10 (41.7%), and was further characterized as chronic hypersensitivity pneumonitis-like pattern seen in 6 (25%), nonspecific interstitial pneumonia-like pattern in 3 (12.5%), and cryptogenic organizing pneumonia-like pattern in 1 (4.2%). Forced vital capacity and diffusing capacity declined over time in patients with AAV-ILD. When compared with the IPF cohort, patients with AAV-ILD had intermediate survival and speed of lung function decline (3-year survival in AAV-ILD group was 94% vs 69% in IPF). Conclusions Antineutrophil cytoplasmic antibody-associated vasculitis ILD is a progressive and potentially fatal condition. Although most cases in the literature are associated with p-ANCA and positive myeloperoxidase, we found that a third of patients had c-ANCA or granulomatosis with polyangiitis. Our cohort adds experience in this rare manifestation of AAV.

Purpose Gastro-oesophageal reflux disease (GORD) is commonly thought to play an important role in chronic cough and patients are often empirically treated with acid suppression therapy. We sought to investigate the response rate to acid suppression treatment in patients with and without heartburn attending two specialist cough clinics. Methods A retrospective review of 558 consecutive patients referred to two specialist cough clinics was performed (UK and USA). Patients who were treated with acid suppression were included and their documented response to treatment was collected. Binary logistic regression was used to ascertain the value of reported heartburn in predicting the response of chronic cough to acid suppression therapy. Results Of 558 consecutive referrals, 238 patients were excluded due to missing data or cough duration of Conclusion In specialist cough clinics, few patients report a response of their chronic cough to acid suppression therapy. Nonetheless, heartburn is a useful predictor substantially increasing the likelihood of benefit.

Objectives Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the most commonly prescribed antihypertensives, with prior studies identifying a possible association between long-term use and increased rates of lung cancer. This study evaluated this potential association in a large population using propensity matching. Methods This was a population-based cohort study in a large healthcare system in three regions of the United States. Pairwise propensity score matching was performed using demographics and comorbidities. All of the adult patients in the healthcare system from January 1, 2000 to April 30, 2018 with at least 1 year of follow-up were included. Results In total, 3,253,811 patients with a median age of 59 (range 18-103) years were included. The ACEI group had a higher freedom from lung cancer versus controls at 15 years (98.47%, 95% confidence interval [CI] 98.41-98.54) versus 98.26%, (95% CI 98.20-98.33), whereas ARBs had similar rates versus controls at all time points. For patients diagnosed as having lung cancer, median all-cause survival was significantly higher in the ACEI (34.7 months, 95% CI 32.8-36.6) and ARB (30.9 months, 95% CI 28.1-33.8) groups than the control group (20.6 months, 95% CI 20.1-21.1). Conclusions This study showed lower rates of lung cancer with ACEI use and no difference in risk with ARBs. In addition, use of these medications was found to be associated with increased survival in those diagnosed as having lung cancer. This study supports the continued use of these medications without concern for increasing the risk of lung cancer.

Introduction In the unprecedented era of COVID-19, ongoing research and evolution of evidence has led to ever-changing guidelines for clinical monitoring and therapeutic options. Formulating treatment protocols requires the understanding and application of the evolving research. Objective The primary objective of this study is to present a systematic evidence-based approach to synthesize the necessary data in order to optimize the management of COVID-19. Methods At Mayo Clinic Florida, we developed a multidisciplinary centralized COVID Treatment Review Panel (TRP) of expert pulmonologists, intensivists, infectious disease specialists, anesthesiologists, hematologists, rheumatologists, and hospitalists that in real-time reviews the latest evidence in peer-reviewed journals, the available clinical trials, and help guide the rapid application of therapeutics or interventions to the patient and the bedside provider. Results/Conclusions The multi-disciplinary team approach of synthesizing clinical data and coordinating care is effective in responding to rapidly evolving and changing evidence. Systematic data collection and evidence-based treatment algorithms enable physicians to rapidly translate the current literature to clinical practice, and improve care and outcomes of patients.

IntroductionNitric Oxide (NO) is an endogenous vasodilator that is synthesized by the vascular endothelium. Due to its vasodilatory effect and short half-life, the use of NO as an exogenous inhaled medication (iNO) to target the pulmonary vasculature, in conditions with increased pulmonary vascular resistance, has been studied.The use of iNO in patients with ARDS secondary to COVID-19 has therapeutic importance in improving oxygenation. It also has potential anti-viral, anti-inflammatory, and anti-thrombotic properties.Herein, we want to share our experience of use of iNO in hypoxemic respiratory failure secondary to COVID 19 pneumonia. We hypothesized that iNO may be beneficial at preventing intubation, decreasing invasive mechanical ventilation duration, and consequently improve outcomes including hospital mortality.MethodsThis is a descriptive hypothesis generating study of patients admitted for COVID-19 pneumonia who received iNO for hypoxemic respiratory failure, at a single tertiary care center. We collected information on patient demographics, co-morbidities, iNO treatment, need for intubation, arterial blood gas analysis, laboratory values, hospital length of stay, and mortality. Patients were divided into two groups based on the timing of iNO administration: group 1 - “pre-intubation” (i.e. iNO started at least 1 day prior to endotracheal intubation, if any) and group 2 - “post-intubation” (i.e. iNO started on the same day as or after endotracheal intubation and mechanical ventilation).ResultA total of 45 (group 1, n=26 [57.8%] vs group2, n=19 [42.2%]) COVID 19 patients who had iNO use. The mean time from hospital admission to iNO administration(days) in group 1 was 2.1 (±1.8) vs 4.2 (±5.9) in group 2. The mean hospital length of stay from the beginning of iNO treatment until discharge or death was 18.3 vs 26.2 days, with 8 deaths (30.8%) vs 9 deaths (47.4%) in group 1 vs group 2, respectively.DiscussionOur study is unable to demonstrate comparably outcomes benefit of iNO. Although there was a trend towards decreased need for invasive mechanical ventilation in group 1[Only 11 (42.3%) patients were intubated out of 26 who received iNO early after hospital admission (2.3 days)], no statistical significance could be achieved because of small sample size.Our study demonstrated that iNO administration pre-intubation did not appear harmful and appears to be safe, complementary to HFNC, signalling the domain where systematic investigation is required to confirm or not the potential for iNO to improve patient outcomes in the management of COVID 19-induced hypoxemic respiratory failure.ConclusionThis study showcases the potential benefit of early pre-intubation use of iNO in COVID patients with hypoxemic respiratory failure. This study could conclusively form the basis for a prospective trial and could have a tremendous impact in improving patient outcomes.HighlightsInhaled nitric oxide can be used in the treatment COVID 19 induced hypoxemic respiratory failure.Inhaled nitric oxide use can lower the burden on overwhelmed medical system.Inhaled nitric oxide use may lower the need for intubation and subsequent invasive mechanical ventilation.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a debilitating and progressive fibrotic interstitial lung disease often resulting in death over several years. Prediction of disease course or survival remains of keen interest for clinicians and patients though a commonly used test or tool remain elusive. Areas covered: We undertook a comprehensive review of the published literature highlighting prognostic indicators and predictors of survival in IPF. Baseline and longitudinal clinical, functional, histopathologic, and radiologic findings have been extensively studied as prognostic predictors, both individually and in composite models. Recent approaches include automated quantifiable radiologic scoring, circulating biomarkers, and genetic polymorphisms or abnormalities. This review highlights individual and composite predictors and their relative utility in clinical practice and research studies. Expert opinion: There is a growing body of knowledge highlighting readily available individual and composite predictors of outcome, though none have come to the forefront for common clinical use. Recent advances include quantitative imaging analysis, circulating serologic markers, and genetic testing, which may be more standardized and less prone to lead-time bias or related complications and comorbidities.

Lung involvement in connective tissue diseases is associated with substantial morbidity and mortality, most commonly in the form of interstitial lung disease, and can occur in any of these disorders. Patterns of interstitial lung disease in patients with connective tissue disease are similar to those seen in idiopathic interstitial pneumonias, such as idiopathic pulmonary fibrosis. It may be difficult to distinguish between the 2 ailments, particularly when interstitial lung disease presents before extrapulmonary manifestations of the underlying connective tissue disease. There are important clinical implications in achieving this distinction. Given the complexities inherent in the management of these patients, a multidisciplinary evaluation is needed to optimize the diagnostic process and management strategies. The aim of this article was to summarize an approach to diagnosis and management based on the opinion of experts on this topic.

Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stays among patients hospitalized for pneumonia. Furthermore, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure (ARF) among patients hospitalized with pneumonia is unknown. Here we describe the ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm, randomized, double-blinded, placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a β-agonist compared with placebo for the prevention of ARF in hospitalized participants with severe pneumonia. The primary outcome is ARF within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation; need for high-flow nasal cannula oxygen therapy or noninvasive ventilation for >36 hours (each alone or combined); or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at 10 academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the U.S. National Heart Lung and Blood Institute. Clinical trial registered with www.clinicaltrials.gov (NCT 04193878).

Objective To report the Mayo Clinic experience with coronavirus disease 2019 (COVID-19) related to patient outcomes. Methods We conducted a retrospective chart review of patients with COVID-19 diagnosed between March 1, 2020, and July 31, 2020, at any of the Mayo Clinic sites. We abstracted pertinent comorbid conditions such as age, sex, body mass index, Charlson Comorbidity Index variables, and treatments received. Factors associated with hospitalization and mortality were assessed in univariate and multivariate models. Results A total of 7891 patients with confirmed COVID-19 infection with research authorization on file received care across the Mayo Clinic sites during the study period. Of these, 7217 patients were adults 18 years or older who were analyzed further. A total of 897 (11.4%) patients required hospitalization, and 354 (4.9%) received care in the intensive care unit (ICU). All hospitalized patients were reviewed by a COVID-19 Treatment Review Panel, and 77.5% (695 of 897) of inpatients received a COVID-19–directed therapy. Overall mortality was 1.2% (94 of 7891), with 7.1% (64 of 897) mortality in hospitalized patients and 11.3% (40 of 354) in patients requiring ICU care. Conclusion Mayo Clinic outcomes of patients with COVID-19 infection in the ICU, hospital, and community compare favorably with those reported nationally. This likely reflects the impact of interprofessional multidisciplinary team evaluation, effective leveraging of clinical trials and available treatments, deployment of remote monitoring tools, and maintenance of adequate operating capacity to not require surge adjustments. These best practices can help guide other health care systems with the continuing response to the COVID-19 pandemic.

Follicular bronchiolitis (FB) and lymphoid interstitial pneumonia (LIP) are a continuum of benign infiltration of the lungs by polyclonal mature lymphocytes. Rarely idiopathic, LIP and FB may represent an expression of systemic immunologic disorders in the lung and are commonly associated with immunodeficiencies, connective tissue diseases, and other autoimmune conditions. This chapter reviews the clinical, radiologic, and pathologic presentation of both entities in this continuum.

Introduction IPF is a chronic, irreversible, and progressive lung disease, with survival from diagnosis of only 2–5 years. It is characterised by excessive extracellular matrix deposition and remodelling within lung tissue, initiated by repetitive alveolar epithelial cell injury. One trigger of injury is believed to be micro-aspiration of gastroesophageal reflux. However, there is limited or no data on objective measures of reflux, and how it relates to oesophageal motility, lung mechanics and pulmonary function. This study used high resolution impedance manometry, 24 hr pH-impedance and pulmonary function testing to address these questions. Methods A prospective cohort study of 32 patients with IPF (aged 53–75 yr; 25 male) assessed between Dec. 2018 and Dec. 2019 at Mayo Clinic, USA and Leeds Teaching Hospital Trust. Results Twenty (63%) patients exhibited dysmotility (Chicago Classification v3.0 (CC)); 14(70%) hypo-contractility (eg ineffective oesophageal motility, fragmented peristalsis, occurring in ≥50% swallows, and absent contractility) and 6(30%) oesophagogastric junction outflow obstruction (EGJOO). Abnormal reflux bolus exposure time was identified in 9(28%) patients, in whom 5/9, and one patient with normal reflux, had an abnormal number of events reaching the proximal oesophagus. 30%(13–48%) (median(IQR)) of all events reached the proximal oesophagus. 4/14 patients with hypo-contractility, 5/12 with normal motility and 0/6 with EGJOO (CC) exhibited abnormal reflux. Interestingly, 4 patients with normal motility (CC) did have ineffective swallows ( Conclusions Ineffective oesophageal motility was associated with increased reflux exposure, with many events reaching the proximal oesophagus, irrespective of whether patients had hypo- or normal motility; likely driven in part by increased GEPG. Furthermore, such motility abnormalities appear to associate with pulmonary dysfunction.

COVID-19 has placed a significant strain upon healthcare resources at a global level and refractory hypoxemia is the leading cause of death among COVID-19 patients. The management of limited resources such as mechanical ventilators has remained a contentious issue both at an individual and institutional level since the beginning of the pandemic. As a result, the COVID-19 pandemic has presented challenges to critical care practitioners to find innovative ways to provide supplemental oxygen therapy to their patients. We present a single-center experience: a case series of five COVID-19 infected patients managed with a novel approach to provide supplemental oxygen and positive end-expiration pressure (PEEP) via the helmet. Three of the five patients responded to therapy, did not require intubation, and survived to discharge. The other two patients continued to deteriorate clinically, required endotracheal intubation, and subsequently expired during their hospitalization. We extrapolated our accumulated experience with non-invasive oxygen support by helmet in COVID-19 patients to a non-COVID-19 postoperative patient who underwent sinus surgery and developed hypoxemic respiratory failure also resulting in avoidance of endotracheal intubation. We conclude that oxygen therapy via a helmet is a safe, cost-effective technique to prevent intubation in carefully selected patients with infectious and non-infectious causes of hypoxic respiratory failure. Our positive experience with the system warrants further large-scale study and possible technique refinement.

BACKGROUND: The clinical benefits of cardiopulmonary rehabilitation are extensive, including improvements in health-related quality of life, emotional condition, physical function, and overall mortality. The COVID-19 pandemic continues to have a negative impact on center-based cardiopulmonary rehabilitation. Justifiable concern exists that the exercise-related increase in pulmonary ventilation within the rehabilitation classes may lead to the generation of infectious respiratory particles. RESEARCH QUESTION: Is cardiopulmonary rehabilitation while wearing a procedural mask a particle-generating procedure? STUDY DESIGN AND METHODS: Data were collected prospectively at a cardiopulmonary rehabilitation facility with all patients wearing a procedural mask. Small (0.3-4.9 µm) and large (5-10 µm) particle generation was quantified using a light-scattering particle counter. Data were analyzed by time, exertion level, and number of participants. RESULTS: A total of 24 distinct patients attended two or more of the cardiopulmonary rehabilitation classes tested. Most of the patients were men (n = 16 [67%]) and were in rehabilitation because of cardiac disease. During the cardiopulmonary rehabilitation class, small and large micrometer-size particles increased with increasing class size. In classes with four patients or more, a significant increase was found from ambient levels in both small (four patients, P < .01; and five patients, P < .01) and large (four patients, P < .01; and five patients, P < .01) particle count that peaked at about 35 to 40 min during each class. INTERPRETATION: Using an airborne particle counter, we found significant exercise-related increases in both small and large micrometer-size particle generation during cardiopulmonary rehabilitation classes, with larger class sizes (ie, more patients), despite participants wearing a procedural mask.

Introduction Gastroesophageal reflux plays a significant role in idiopathic pulmonary fibrosis (IPF). Given the morbidity and mortality associated with IPF, understanding the mechanisms responsible for reflux is essential if patients are to receive optimal treatment and management, especially given the lack of clear benefit of antireflux therapies. Our aim was to understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux-a prerequisite of aspiration), and pulmonary function in patients with IPF. Methods We prospectively recruited 35 patients with IPF (aged 53-75 years; 27 men) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment. Results Twenty-two patients (63%) exhibited dysmotility, 16 (73%) exhibited ineffective esophageal motility (IEM), and 6 (27%) exhibited esophagogastric junction outflow obstruction. Patients with IEM had more severe pulmonary disease (% forced vital capacity: P = 0.032) and more proximal reflux (P = 0.074) than patients with normal motility. In patients with IEM, intrathoracic pressure inversely correlated with the number of proximal events (r = -0.429; P = 0.098). Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus (r = 0.583; P = 0.018), whereas in patients with normal motility, it inversely correlated with the bolus exposure time (r = -0.478; P = 0.098) and number of proximal events (r = -0.542; P = 0.056). % forced vital capacity in patients with IEM inversely correlated with the percentage of reflux events reaching the proximal esophagus (r = -0.520; P = 0.039) and inspiratory LESP (r = -0.477; P = 0.062) and positively correlated with intrathoracic pressure (r = 0.633; P = 0.008). Discussion We have shown that pulmonary function is worse in patients with IEM which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs.

Background Pulmonary disease is a potentially serious yet underdiagnosed complication of Sjogren’s syndrome, the second most common autoimmune rheumatic disease. Approximately 16% of patients with Sjogren’s demonstrate pulmonary involvement with higher mortality and lower quality of life. Research Question Clinical practice guidelines for pulmonary manifestations of Sjogren’s were developed by the Sjogren’s Foundation after identifying a critical need for early diagnosis and improved quality and consistency of care. Study Design and Methods A rigorous and transparent methodology was followed according to American College of Rheumatology guidelines. The Pulmonary Topic Review Group (TRG) developed clinical questions in the PICO (Patient, Intervention, Comparison, Outcome) format and selected literature search parameters. Each article was reviewed by a minimum of two TRG members for eligibility and assessment of quality of evidence and strength of recommendation. Guidelines were then drafted based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale and data extraction tables were submitted to a Consensus Expert Panel for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version. Results The literature search revealed 1,192 articles, of which 150 qualified for consideration in guideline development. Of the original 85 PICO questions posed by the TRG, 52 recommendations were generated. These were then reviewed by the Consensus Expert Panel and 52 recommendations were finalized, with a mean agreement of 97.71% (range, 79%-100%). The recommendations span topics of evaluating Sjogren’s patients for pulmonary manifestations and assessing, managing, and treating upper and lower airway disease, interstitial lung disease, and lymphoproliferative disease. Interpretation Clinical practice guidelines for pulmonary manifestations in Sjogren’s will improve early identification, evaluation, and uniformity of care by primary care physicians, rheumatologists, and pulmonologists. Additionally, opportunities for future research are identified.

STUDY OBJECTIVES: The objectives of this study were to assess the effect of obstructive sleep apnea (OSA) on the risk of acute pulmonary embolism (PE), hospital outcomes including mortality, and PE recurrence. METHODS: We retrospectively enrolled adult patients, admitted to Mayo Clinic Hospital in Rochester, Minnesota, within a 5-year period (2009–2013). We compared frequency of PE, hospital mortality, and secondary outcomes in patients with OSA versus patients without OSA. We assessed risk of PE recurrence in relation to compliance with OSA therapy. RESULTS: Of 25,038 patients, 3,184 (13%) had OSA and 283 (1.1%) experienced PE. Frequency of PE in patients with and without OSA was 2.4% versus 0.9% (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.9–3.3; P < .001). OSA was independently associated with increased risk of PE after adjusting for demographics and comorbidities (OR, 1.44; 95% CI, 1.07–1.9; P = .017). Adjusted hospital mortality was increased in patients with PE (OR, 2.88; 95% CI, 1.7–4.9; P < .001) but not in patients with OSA (OR, 0.98; 95% CI, 0.7–1.4, P = .92). OSA was not a significant determining factor for mortality in patients who experienced a PE (OR, 0.56; 95% CI, 0.1.1–2.78; P = .47), adjusting for demographics, PE severity, and Charlson comorbidity index. Adjusted risk of PE recurrence was greater in patients with OSA compared with patients without OSA (OR, 2.21; 95% CI, 1.05–4.68; P < .04). The patients compliant with OSA therapy had a lower rate of PE recurrence (16% vs 32%; P = not significant). CONCLUSIONS: Although OSA significantly increases risk of acute PE occurrence and recurrences, related hospital mortality was not greater in patients with OSA compared with those without OSA. OSA therapy might have a modifying effect on PE recurrence. CITATION: Secken ZI, Helmi H, Weister TJ, Lee A, Festic E. Acute pulmonary embolism in patients with obstructive sleep apnea: frequency, hospital outcomes, and recurrence. J Clin Sleep Med. 2020;16(7):1029–1036.

Background: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the most commonly prescribed anti-hypertensives with prior studies identifying a possible association between long-term use and increased rates of lung cancer. This study evaluated the potential association between the use of ACEIs and/or ARBs and the development of lung cancer in a large population using propensity matching. Methods: This was a population-based cohort study in a large healthcare system in three regions of the US. All adult patients who entered the Mayo Clinic health system from January 1, 2000 to April 30, 2018 with at least one year of follow-up were included. Pairwise propensity score matching was performed using demographics and comorbidities. Findings: 3,253,811 patients with median age of 59 (range 18-103) years old were included. The ACEI group had a higher freedom from lung cancer versus controls at 5, 10, and 15 years [15 year: 98.47% (CI95: 98.41%-98.54%) vs. 98.26% (CI95: 98.20%-98.33%)] while ARB had similar rates versus controls at all time points. For patients diagnosed with lung cancer, median all-cause survival was significantly higher in the ACEI [34.7 months (CI 95: 32.8-36.6)] and ARB (30.9 months (CI95: 28.1-33.8)] groups than the control group (20.6 months (CI95: 20.1-21.1). Interpretation: This is the largest analysis of lung cancer risk with ACEI and ARBs using patient data from three regions of the United States. This study demonstrates a decreased risk of lung cancer with ACEI use, no difference in risk with ARBs, and no difference in the lung cancer subtypes with ACEI or ARB usage versus controls using propensity score matching. Additionally, ACEI and ARB use was found to be associated with increased survival in those diagnosed with lung cancer. This study supports the continued use of ACEIs without concern for increasing the risk of lung cancer. Funding Statement: Grant Number UL1 TR000135 from the NIH Clinical and Translational Award for the search engine and not awarded to any authors. Declaration of Interests: All authors (SH, MW, RB, YD, AL, CB, ZL, PJ, and NP) report no conflict of interest. Ethics Approval Statement: The Mayo Clinic Institutional Review Board approved this study

Aspiration is a syndrome with variable respiratory manifestations that span acute, life-threatening illnesses, such as acute respiratory distress syndrome, to chronic, sometimes insidious, respiratory disorders such as aspiration bronchiolitis. Diagnostic testing is limited by the insensitivity of histologic testing, and although gastric biomarkers for aspiration are increasingly available, none have been clinically validated. The leading mechanism for microaspiration is thought to be gastroesophageal reflux disease, largely driven by the increased prevalence of gastroesophageal reflux across a variety of respiratory disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, and chronic cough. Failure of therapies targeting gastric acidity in clinical trials, in addition to increasing concerns about both the overuse of and adverse events associated with proton pump inhibitors, raise questions about the precise mechanism and causal link between gastroesophageal reflux and respiratory disease. Our review summarizes key aspiration syndromes with a focus on reflux-mediated aspiration and highlights the need for additional mechanistic studies to find more effective therapies for aspiration syndromes.

Background Clinical differentiation of fibrotic hypersensitivity pneumonitis (f-HP) remains challenging given variable and overlapping presentations with other fibrotic interstitial lung disease (f-ILD). Objective We derived a multivariable model for predicting histopathologic f-HP to better inform multidisciplinary team discussion (MDD) diagnosis, particularly when biopsy may be unsafe or cannot be achieved. Methods Patients with histopathologically-defined f-HP and other overlapping f-ILD were reviewed for distinguishing clinical and radiological variables. Using elastic net logistic regression, a penalized regression approach to minimize overfitting, a clinical model built on non-invasive assessments was derived for the prediction of histopathologic f-HP. This model was then validated in an independently derived external cohort from three sites. Results The derivation and validation cohorts consisted of 248 (84 cHP and 164 other f-ILD) and 157 (82 f-HP and 75 other f-ILD) histopathologically-defined patients, respectively (total study N = 405). Variables retained from the elastic net model included age in years (regression coefficient 0.033), male sex (−1.109), positive exposure history (1.318), percent predicted forced vital capacity (−0.021), radiologic peribronchovascular axial ILD distribution (0.199), mid (−0.22) or lower lobe (−0.839) craniocaudal or patchy (0.287) ILD distribution, upper (1.188) or equivalent upper and lower lobe (0.237) traction bronchiectasis, mosaic attenuation (1.164), and centrilobular nodules (2.045). Bias corrected AUC was 0.84 (standard error = 0.02) for the derivation cohort and 0.80 (CI 0.73–0.87) for the validation cohort. Conclusions This multivariable model demonstrated good predictive performance for delineating histopathologically-defined f-HP from other f-ILD as a means of avoiding or justifying biopsy and supporting MDD diagnostic confidence.

Asthma is a common condition that affects an estimated 24 million children and adults in the United States (prevalence, 8%-10%). Globally, over 300 million people are affected and the number is expected to increase. The age distribution is bimodal, but in most patients, asthma is diagnosed before age 18 years (male to female ratio, 2:1 in children; 1:1 in adults). Susceptibility to asthma is multifactorial with both genetic and environmental factors. The strongest risk factor is atopy, a sensitivity to the development of immunoglobulin E (IgE) to specific allergens. A person with atopy is 3- to 4-fold more likely to have asthma than a person without atopy. Other risk factors include birth weight, prematurity, tobacco use (including secondary exposure), and obesity.

Background The Coronavirus pandemic has a high mortality rate in patients that are mechanically ventilated, which has led to an ever increasing interest in noninvasive forms of oxygenation. The use of these devices has the theoretical risk of increased exposure risk because of possible particulate generation. This study aimed to quantify the particulate generation associated with different oxygen devices. Methods This was a prospective single center study conducted during September 2020 using ten healthy adult volunteers. Testing was conducted in a negative pressure hospital room using a light scattering particle counter. The oxygen devices used were a nasal cannula, an OxyMask™, a non-rebreathing mask, and a high flow system. Particle measurements were obtained at baseline in the room and then with each oxygen delivery device and pre-specified oxygen flow rates. These measurements were obtained different distances from the volunteer with their mouth open. A Wilcoxon/Kruskal-Wallis test was performed on each separate oxygen modality with all flow rates as one model. Results The particle concentrations were slightly non-significantly increased with the OxyMask™ and non-rebreathing mask at the closest distance measured. As the distance increased, these counts decreased closer to ambient levels. The nasal cannula and high flow nasal cannula particle counts were not significantly different from ambient measurements at either distance. Conclusion Nasal cannula, OxyMask™, non-rebreathing mask, and high flow oxygen did not generate any additional aerosols or droplets above a baseline room measurement, but further studies are necessary to determine infectious risk.

Objectives The tricuspid annular plane systolic excursion (TAPSE) is a validated measure of right ventricular function; however, the apical echocardiographic window varies and has limitations in intensive care unit (ICU) patients receiving mechanical ventilation or those with underlying disease and air entrapment. We aimed to evaluate the subcostal echocardiographic assessment of tricuspid annular kick (SEATAK) as an alternative to TAPSE in critically ill patients. Methods To measure SEATAK, we obtained the subcostal inferior vena cava view and used M-mode to measure excursion of the tricuspid annulus (kick). Analysis was performed with JMP for Bland-Altman and Spearman correlations. Results We evaluated 45 patients, 26 (57.8%) of whom were women, with a mean age of 60.8 years. We were not able to obtain the apical view to measure TAPSE in 8.9% of the patients. In contrast, SEATAK was measured in all patients. The mean SEATAK and TAPSE were 1.62 cm and 1.93 cm, respectively, with a mean pairwise difference of −0.26 cm (95% CI: −0.19 to −0.35), with the SEATAK value being lower than TAPSE. The overall correlation was strong and significant (ρ = .86, P=.03). The graphical correlation was maintained between TAPSE and SEATAK and the degree of RVF. Conclusion In patients presenting with RVF in the ICU (or in situations where the apical echocardiographic view is suboptimal for tricuspid annular assessment), SEATAK can be an alternative to TAPSE. Further research is needed to validate and determine the sensitivity and specificity of SEATAK for RVF prognostication.

Objectives: Pulmonary hypertension (PH) is commonly observed in patients with diffuse parenchymal lung disease (DPLD). The purpose of this study was to explore the influence of the 6-minute walk test (6MWT) as a simple, non-invasive tool to assess right ventricular (RV) function in patients with DPLD and to identify the need for an echocardiogram (ECHO) to screen for PH. Methods: We retrospectively reviewed 48 patients with PH secondary to DPLD, who were evaluated in the PH clinic at the Mayo Clinic in Jacksonville, Florida, from January 1999 to December 2014. Results: Fifty-two percent of patients had RV dysfunction. They had a significantly greater right heart pressure by ECHO and mean pulmonary arterial pressure (MPAP) from right heart catheterization (RHC) than those with normal RV function. A reduced 6-minute walk distance (6MWD) did not predict RV dysfunction (OR 0.995; 95% CI 0.980–1.001, p = 0.138). In addition, worsening restrictive physiology, heart rate at one-minute recovery and desaturation were not different between patients with and without RV dysfunction. However, there were inverse correlations between 6MWD and MPAP from RHC (r = -0.41, p = 0.010), 6MWD and RV systolic pressure (r = -0.51, p < 0.001), and 6MWD and MPAP measured by ECHO (r = -0.46, p =0.013). We also found no significant correlation between 6MWD and pulmonary function test parameters. Conclusions: Our single-center cohort of patients with PH secondary to DPLD, PH was found to have an impact on 6MWD. In contrast to our expectations, 6MWD was not useful to predict RV dysfunction. Interestingly, a severe reduction in the 6MWD was related to PH and not to pulmonary function; therefore, it may be used to justify an ECHO to identify patients with a worse prognosis.

Gastro-oesophageal reflux is associated with a wide range of respiratory disorders, including asthma, isolated chronic cough, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and cystic fibrosis. Reflux can be substantial and reach the proximal margins of the oesophagus in some individuals with specific pulmonary diseases, suggesting that this association is more than a coincidence. Proximal oesophageal reflux in particular has led to concern that microaspiration might have an important, possibly even causal, role in respiratory disease. Interestingly, reflux is not always accompanied by typical reflux symptoms, such as heartburn and/or regurgitation, leading many clinicians to empirically treat for possible gastro-oesophageal reflux. Indeed, costs associated with use of acid suppressants in pulmonary disease far outweigh those in typical GERD, despite little evidence of therapeutic benefit in clinical trials. This Review comprehensively examines the possible mechanisms that might link pulmonary disease and oesophageal reflux, highlighting the gaps in current knowledge and limitations of previous research, and helping to shed light on the frequent failure of antireflux treatments in pulmonary disease.

Background There is a need for improved clinical identification of hospitalized patients at risk of aspiration. We evaluated our novel phonetic test in a broad spectrum of patients at risk of aspiration in the ICU or intermediate care unit. Methods We prospectively enrolled 60 hospitalized patients with aspiration risk, between December 2009 and September 2011, who subsequently underwent audio-recorded three-component phonetic bedside evaluation. The recordings were scored by two blinded speech-language pathologists. The institutional dysphagia admission screening test was performed by a bedside nurse. The primary outcomes, dysphagia and aspiration, were assessed by a videofluoroscopic swallowing study, fiber-optic endoscopic evaluation of swallowing, or both. We assessed the short- and long-term clinical outcomes (length of stay, subsequent aspiration pneumonia and respiratory failure, survival) and how these were associated with the phonetic and swallow assessments. Results Statistically significant linear associations with dysphagia were noted for all three individual phonetic components. Also, there were statistically significant linear associations with aspiration for diadochokinesis ( P = .050) and consensus auditory-perceptual evaluation of voice ( P = .025). Diadochokinesis alone predicted dysphagia (area under the curve [AUC], 0.74; P = .001) and aspiration (AUC, 0.67; P = .012). Its predictive ability improved when combined with normalized dysphagia admission screening test results (AUC, 0.79; P = .001). The short- and long-term clinical outcomes were adversely affected by the worse phonetic/swallowing scores, although they were not statistically different. Conclusions Abnormal phonation among ICU and intermediate care unit patients is associated with dysphagia and aspiration. Future investigative efforts should uncover the most effective combination of evaluations for accurate bedside detection of dysphagia and aspiration risk in a broad spectrum of patients.

Goals: To assess the effect of unilateral versus bilateral lung transplantation (LTx) on esophageal motility and gastroesophageal reflux, and the association with the development of obstructive chronic lung allograft dysfunction (o-CLAD). Background: We have shown that esophagogastric junction outflow obstruction, incomplete bolus transit, and proximal reflux are all independent risk factors for the development of chronic allograft failure. However, it remains unclear whether these factors are influenced by the type of surgery and how this relates to allograft failure. Study: Patients post-LTx (n=48, 24 female; aged 20 to 73 y) completed high-resolution impedance manometry and 24-hour pH/impedance. Results: Patients who had undergone unilateral LTx were more likely to exhibit esophagogastric junction outflow obstruction (47% vs. 18%; P=0.046) and less likely to exhibit hypocontractility (0% vs. 21%; P=0.058) than those who had undergone bilateral LTx. Although the proportion of patients exhibiting gastroesophageal reflux was no different between groups (33% vs. 39%; P=0.505), those undergoing bilateral LTx were more likely to exhibit proximal reflux (8% vs. 37%; P=0.067). Univariate Cox proportion hazards regression analysis did not show a difference between unilateral versus bilateral LTx in the development of o-CLAD (hazard ratio=1.17; 95% confidence interval, 0.48-2.85; P=0.723). Conclusion: The type of LTx performed seems to lead to different risk factors for the development of o-CLAD. Physicians should be aware of these differences, as they may need to be taken into account when managing patient’s post-LTx.

Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab. Learning points: Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1). Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1. Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents. Patient Demographics: Geriatric, Male, White, United States Clinical Overview: Pancreas, Diabetes, Insulin, Diabetes mellitus type 1, Diabetic ketoacidosis, Autoimmune disorders, Metastatic carcinoma, Hyperglycaemia, Metabolic acidosis, Hyperkalaemia, Hyponatraemia Diagnosis and Treatment: Diabetes mellitus type 1, Diabetic ketoacidosis, Hyperpnoea, Hyperglycaemia, Metabolic acidosis, Dyspnoea, Abdominal pain, Fatigue, Polyuria, Hyponatraemia, Hyperkalaemia, Glucose (blood), X-ray, Ketones (urine), Glucose (blood, fasting), Haemoglobin A1c, C-peptide (blood), CT scan, Red blood cell count, White blood cell count, White blood cell differential count, Platelet count, Sodium, Potassium, Chloride, Bicarbonate, Urea and electrolytes, Albumin, Magnesium, Calcium (serum), Brain natriuretic peptide, Glucose (urine), Urinalysis, Fluid repletion, Nivolumab, Insulin, Insulin Aspart, Insulin glargine, Aspirin, Lisinopril, Tyrosine-kinase inhibitors Related Disciplines: Oncology Publication Details: Unusual effects of medical treatment, March, 2018 Background Understanding how cancer escapes host immune regulation has led to the development of cancer ‘immunotherapy’. In particular, antibodies such as nivolumab, targeting and inhibiting programmed cell death 1 receptor (PD-1(PDCD1)), can result in the preferential activation of T-cells with specificity for cancer (1). Multiple trials have already demonstrated significant response rates and improved survival with nivolumab in multiple neoplasms including melanoma (2, 3, 4, 5, 6, 7, 8, 9, 10, 11), non-small-cell lung cancer (NSCLC) (2, 3, 4, 12, 13, 14, 15) and renal cell carcinoma (RCC) (2, 3, 4, 16, 17). However, inhibition of the PD-1 pathway results in a reduction of ‘self-tolerance’, with an apparent increase in immune-mediated adverse events (AE). Clinical trials investigating the efficacy of nivolumab in cancers have reported increased rates of autoimmune endocrinopathies, including: hypophysitis (5, 7, 8, 10, 11), adrenal insufficiency (4, 5, 7, 10, 12), thyroid disorders (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18) and hyperglycemia (2, 3, 4, 6, 8, 15, 17). We report a patient presenting critically ill with diabetic ketoacidosis (DKA) after receiving nivolumab. In addition, we provide a review of the literature reporting nivolumab-induced diabetes mellitus (DM). Acute care physicians’ awareness of the acute complications of these novel therapies is essential for the timely management of these critically ill patients.

Objectives Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease that generally results in progressive decline in lung function. Despite advancement of pharmacological therapy for LAM, lung transplantation remains an important option for women with end-stage LAM. Methods Patients with LAM undergoing lung transplantation at the Mayo Clinic campuses in Rochester, Minnesota and Jacksonville, Florida since 1995 were retrospectively reviewed. Results Overall, 12 women underwent lung transplantation. Nine of 12 (75%) underwent double lung transplant. The mean age was 42 ± 8 years at the time of transplant. One patient (8%) had a chylothorax and 7 (58%) had recurrent pneumothoraces, 4 (33%) of which required pleurodesis. All had diffuse, cystic lung disease on chest CT consistent with LAM which was confirmed in the explant of all patients. The average length of ICU and hospital stays were 5 ± 4 and 19 ± 19 days, respectively. Mild to moderate anastomotic ischemia was evident in all patients but resolved with time. No patient was treated with sirolimus pre-transplant. Seven patients received sirolimus post-transplant; however, clinical benefit was documented in only 2 patients, 1 of which was treated for large retroperitoneal cysts with ureteral obstruction and another with persistent chylothorax and retroperitoneal lymphangioleimyomas. Five patients are deceased. The median survival by Kaplan–Meier analysis was 119 months with a median follow-up of 68 months (range 2–225 months). Conclusions Lung transplant remains a viable treatment for patients with end-stage LAM. The role of sirolimus peri-transplantation remains ill-defined.

A mosaic pattern of lung attenuation on chest computed tomography (CT) may be due to various etiologies. There is limited published data on CT results when used to evaluate pulmonary hypertension (PH). We retrospectively studied the frequency of mosaic pattern in patients with PH and the cause of the PH by diagnostic group, as well as the correlation between the mosaic pattern and the following: demographics, severity of the PH, main pulmonary artery (PA) size, PA/aorta (PA/Ao) ratio, pulmonary function tests (PFT), and ventilation perfusion scan results. Overall, 18% of the cohort had CT mosaic pattern (34/189). Mosaic pattern was present in 17/113 (15%) in Group 1 pulmonary arterial hypertension, 5/13 (28%) in Group 2 pulmonary venous hypertension and 8/50 (16%) in Group 3 PH. Conversely, Group 4 chronic thromboembolic PH was more prevalent in 4/8 (50%). Main PA size, PA/Ao ratio, and segmental perfusion defect were positively associated with mosaic pattern. In contrast, factors such as age, gender, body mass index, functional class, hemodynamic data, and PFT values were not associated with mosaic pattern. Mosaic pattern is not specific as an isolated finding for distinguishing the subtype of PH.

In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols.Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock.ICUs of Acute Respiratory Distress Syndrome Network participating hospitals.Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite.Fluid management by protocol.Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite).FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

Objectives: Gastroesophageal reflux is common in patients post-lung transplantation (LTx) and thus considered a risk factor for aspiration and consequently allograft rejection and the development of chronic allograft failure. However, evidence supporting this remains unclear and often contradictory. Our aim was to examine the role played by esophageal motility on gastroesophageal reflux exposure, along with its clearance and that of boluses swallowed, and the relationship to development of obstructive chronic lung allograft dysfunction (o-CLAD). Methods: Patients post-LTx (n=50, 26 female; mean age 55 years (range, 20–73 years)) completed high-resolution impedance manometry and 24-h pH/impedance. Esophageal motility abnormalities were classified based upon the Chicago Classification version 3.0. Results: Esophagogastric junction outflow obstruction alone (EGJOOa) (P=0.01), incomplete bolus transit (IBT) (P=0.006) and proximal reflux (P=0.042) increased the risk for o-CLAD. Patients with EGJOOa were most likely to present with o-CLAD (77%); despite being less likely to exhibit abnormal numbers of reflux events (10%) compared with those with normal motility (o-CLAD: 29%, P