Gastroesophageal reflux disease (GERD) is a prevalent comorbidity of chronic respiratory diseases including idiopathic pulmonary fibrosis (IPF), non-IPF interstitial lung disease, asthma, chronic obstructive pulmonary disease (COPD) and refractory chronic cough. Prevalence of symptoms of reflux and/ or refractory respiratory symptoms, along with concerns that refluxed gastric contents into the esophagus may micro-aspirate into the lungs causing injury and potentially accelerate disease progression, have resulted in high usage of empirical anti-reflux treatments. However, empirical treatment of reflux (medical or mechanical) is frequently ineffective without obvious explanation for the lack of respiratory improvement. This review provides novel and updated understanding of the pathophysiological mechanisms that link upper gut dysfunction, reflux (both distal and proximal), lung structure, lung mechanics and breathing patterns, including the potential role of the vagally mediated esophageal-bronchial reflex and the bi-directional nature of these interactions in individual respiratory diseases. We also highlight the need for a consensus between gastrointestinal and respiratory communities and propose a framework for diagnosing and managing GERD in respiratory disease.

Background:Sex and age have long been known to affect lung function. Several biological variables and anatomical factors may contribute to sex- and age-related differences in pulmonary metrics. Objective:We hypothesized that a machine learning model could be trained to predict a person's lung age and self-reported sex using pulmonary function test data. Methods:We retrospectively analyzed complete pulmonary function tests from 6392 healthy adults across 3 Mayo Clinic regions. Four models of increasing complexity were trained using gradient-boosted machines to predict chronological age and biological sex. Model interpretability was assessed using Shapley additive explanation values and partial dependence plots. Quantile regression was used to estimate reference percentiles for predicted lung age. Results:The best-performing age model (model 4, inclusive of time-series features) achieved a root mean square error of 7.01 years (95% CI 6.73-7.30) and a mean absolute error of 5.55 years (95% CI 5.32-5.80). The best-performing sex classification model (model 4) achieved an area under the curve of 0.981 (95% CI 0.975-0.988), sensitivity of 91.7% (95% CI 89.0%-93.9%), and specificity of 95.6% (95% CI 93.9%-97%). Key predictors for lung age included residual volume as a percentage of total lung capacity (TLC), forced expiratory volume in 1 second, and alveolar volume. For sex classification, peak expiratory flow, height, and age were among the most influential features. Age-stratified evaluation showed the overestimation of lung age in younger adults and underestimation in older adults. Predicted lung age increased broadly with chronological age, and quantile regression provided normative reference ranges. Conclusions:Applying artificial intelligence to pulmonary function data allows the prediction of a patient's sex and estimation of lung age. The ability of an artificial intelligence algorithm to determine physiological lung age, with further validation, may serve as a measure of overall respiratory health.

BACKGROUND:Solid organ transplant (SOT) recipients are at risk for Pneumocystis jirovecii pneumonia (PCP), yet how their clinical phenotype and outcomes compare with other immunocompromised patients without HIV remains poorly defined. METHODS:We conducted a multicenter retrospective cohort study of adults with proven or probable PCP from 2017 to 2025, including 95 SOT recipients and 588 non-SOT, non-HIV immunocompromised patients. The primary outcome was 90-day mortality, secondary outcomes included new renal failure requiring dialysis, and 30-day mortality. Outcomes were analyzed using inverse probability weighting (IPW) with winsorization to adjust for baseline differences. RESULTS:In unadjusted analysis, SOT recipients had lower 90-day mortality (hazard ratio [HR]: 0.62, 95% CI 0.39-0.97, p = 0.037). After IPW with winsorization of extreme weights, SOT status remained associated with lower 90-day mortality (HR: 0.32, 95% CI 0.13-0.76, p = 0.009), and 30-day mortality (HR: 0.35, 95% CI: 0.14-0.92, p = 0.034). SOT recipients had higher odds of renal failure requiring dialysis in unadjusted analysis (OR: 3.49, 95% CI 1.94-6.14, p < 0.001), which persisted after IPW adjustment (OR: 1.62, 95% CI: 1.04-2.51, p = 0.032). CONCLUSIONS:Despite higher rates of renal failure requiring dialysis, SOT recipients with PCP experienced significantly improved short- and intermediate-term survival compared with other non-HIV immunocompromised patients, underscoring the need for further investigation into transplant-associated contributors to PCP outcomes.

Microplastics may pose health risks, particularly for chronic lung diseases. Clarifying the link between circulating microplastics and pulmonary disease is vital for shaping research and interventions. The objective of this study was to evaluate whether microplastics in peripheral blood are associated with COPD or IPF vs. no lung disease. In this pilot prospective case-control study, participants were grouped as control (n = 10), COPD (n = 9), or IPF (n = 10). Relevant comorbidities and exposures were obtained from records and questionnaires. All underwent standardized blood collection (PlasticTox©). Samples were analyzed for total microplastic concentration, stratified by size (<10 µm, 10–30 µm, 30–70 µm). The primary outcome was to show a difference in total microplastic burden between lung disease and controls. Secondary measures were to determine size-specific concentrations and associations with demographic variables and smoking history. Among 29 participants (median age 70 (IQR 64–80); 14 women (48.3%)), COPD/IPF groups had significantly higher total microplastic concentrations vs. controls (median 26.0 vs. 3.5 particles/100 µL; p < 0.01). Particle burdens <10 µm and 10–30 µm were particularly elevated (both p < 0.01). After adjusting for smoking, only the <10 µm fraction remained independently associated with lung disease (adjusted odds ratio 1.94 (95% CI, 1.23–7.04)). In this pilot exploratory study, individuals with COPD or IPF showed greater circulating microplastic levels than controls. These findings should be interpreted as hypothesis-generating, and larger analytically validated studies are needed to clarify directionality, causal mechanisms, contamination control, and the clinical relevance of circulating microplastic burden.

Background:Spirometry can be performed in an office setting or remotely using portable spirometers. Although basic spirometry is used for diagnosis of obstructive lung disease, clinically relevant information such as restriction, hyperinflation, and air trapping require additional testing, such as body plethysmography, which is not as readily available. We hypothesize that spirometry data contains information that can allow estimation of static lung volumes in certain circumstances by leveraging machine learning techniques. Objective:The aim of the study was to develop artificial intelligence-based algorithms for estimating lung volumes and capacities using spirometry measures. Methods:This study obtained spirometry and lung volume measurements from the Mayo Clinic pulmonary function test database for patient visits between February 19, 2001, and December 16, 2022. Preprocessing was performed, and various machine learning algorithms were applied, including a generalized linear model with regularization, random forests, extremely randomized trees, gradient-boosted trees, and XGBoost for both classification and regression cohorts. Results:A total of 121,498 pulmonary function tests were used in this study, with 85,017 allotted for exploratory data analysis and model development (ie, training dataset) and 36,481 tests reserved for model evaluation (ie, testing dataset). The median age of the cohort was 64.7 years (IQR 18-119.6), with a balanced distribution between genders, consisting 48.2% (n=58,607) female and 51.8% (n=62,889) male patients. The classification models showed a robust performance overall, with relatively low root mean square error and mean absolute error values observed across all predicted lung volumes. Across all lung volume categories, the models demonstrated strong discriminatory capacity, as indicated by the high area under the receiver operating characteristic curve values ranging from 0.85 to 0.99 in the training set and 0.81 to 0.98 in the testing set. Conclusions:Overall, the models demonstrate robust performance across lung volume measurements, underscoring their potential utility in clinical practice for accurate diagnosis and prognosis of respiratory conditions, particularly in settings where access to body plethysmography or other lung volume measurement modalities is limited.

Background and Aims:Gastroesophageal reflux (GER) is common and thought to contribute to disease progression in patients with respiratory disease. Delayed gastric emptying (DGE) can increase GER in patients with GER disease, but its effect in patients with respiratory disease, and how differing lung structure (eg, scarring, inflammation) and mechanics (eg, decreased thoracic pressure in restrictive disease, increased abdominal pressure in obstructive disease) influences this is unknown. Our aim was to understand these interrelationships and association with pulmonary function in patients with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and non-IPF interstitial lung disease (non-IPF ILD). Methods:We prospectively recruited 22 COPD (aged 34-75 years), 33 IPF (45-74 years), and 19 non-IPF ILD (37-74 years) patients who underwent gastric emptying studies, high resolution impedance manometry, 24-hr pH-impedance, and pulmonary function testing, as part of routine lung transplantation assessment. Results:Gastric emptying was delayed in a total of 20(27%) patients; 5(23%) with COPD, 8(24%) with IPF and 7(37%) with non-IPF ILD. Notably, all 7 non-IPF ILD patients with DGE had nonspecific interstitial pneumonia (NSIP; ie, 70% of NSIP patients; P < .02 compared with other groups). DGE irrespective of disease type was not associated with increased acid exposure time, total bolus exposure time or number of reflux events. Furthermore, DGE was not associated with higher intra-abdominal pressure, specific esophageal dysmotility, or worse pulmonary function in any of the respiratory diseases. Conclusion:Significantly more NSIP patients have DGE compared with other respiratory diseases. Irrespective of this, DGE had little effect on GER or pulmonary function in any of the respiratory diseases.

Background:Pneumocystis jirovecii pneumonia (PCP) is increasingly seen in patients who are non-HIV immunocompromised hosts, yet modern risk factors and outcomes are poorly recognized and defined. Methods:A retrospective review was conducted of adult patients who met criteria for proven or probable PCP from 2017 to 2024 across a large academic multicenter health system. The primary outcome was mortality among cohorts, defined by etiology of immunosuppression through univariate and age-adjusted logistic regression. Secondary analyses included trends in annual diagnoses and testing patterns. Results:A total of 701 patients met criteria for inclusion, representing one of the largest clinically characterized cohorts of PCP to date. The median age was 65 years (IQR, 54-73) and 62% were male. The most common risk groups were hematologic malignancy (32.2%), solid tumor cancers receiving chemotherapy (22.4%), and autoimmune disease with immunosuppression (17.7%). Annual PCP diagnoses increased at a rate of 15.8% (95% CI, 8.9%-23.2%) in parallel with increased testing. Only 5.4% of patients were receiving prophylaxis at the time of diagnosis. Overall mortality was 20% (95% CI, 17%-23%) and highest in cirrhosis (adjusted odds ratio, 6.24; 95% CI, 2.84-13.69; P < .001). Conclusions:PCP in the current era affects a broad range of patients who are immunocompromised, with high associated mortality and low rates of prophylaxis. Patients with solid tumors and those with cirrhosis are at particularly high risk of mortality. These findings highlight the need to reassess and redefine PCP prophylaxis guidelines in specific populations and our understanding of who is at risk.

INTRODUCTION:Gastroesophageal reflux is common in respiratory disease, but the interplay between gastrointestinal mechanisms that expose individuals to reflux and potentially aspiration, and lung mechanics and function remain incompletely understood. Our aim was to investigate this in patients with chronic obstructive pulmonary disease (COPD) and non-idiopathic pulmonary fibrosis (IPF) interstitial lung disease (non-IPF ILD), and compare with our published findings in IPF. METHODS:Fifty-seven patients with COPD (aged: 34-75 years) and 64 with non-IPF ILD (22-75 years) who underwent high-resolution impedance manometry and 24-hour pH impedance together with pulmonary function assessment were compared with 35 IPF patients (51-84 years). RESULTS:COPD patients were less likely to exhibit ineffective esophageal motility (IEM) and/or absent contractility ( P = 0.009; P = 0.028), and tended to exhibit esophagogastric junction outflow obstruction (EGJOO) and/or hypercontractility ( P = 0.09, P = 0.14) than IPF and non-IPF ILD patients. Notably, integrated relaxation pressure correlated with esophageal length index (ELI) ( P = 0.048) and inspiratory LESP ( P = 0.003), with latter 2 correlating with each other ( P < 0.001). EGJOO patients tended to have fewer proximal reflux events and reduced pulmonary function, with the latter inversely correlating with ELI ( P < 0.05). Non-IPF ILD patients were less likely to exhibit EGJOO than COPD patients ( P = 0.27), and less likely to exhibit IEM ( P = 0.07) than IPF patients. However, those with IEM or EGJOO exhibited greater proportions of reflux events reaching the proximal esophagus than those with normal motility ( P < 0.03), which in contrast to IPF, seemed not to associate with worse pulmonary function. DISCUSSION:Associations between esophageal motility, and lung mechanics and function, and consequently reflux, are very disease-specific.

Abstract Background Metaplastic breast carcinoma (MBC) is an unusual malignancy that presents a diagnostic challenge due to the presence of varying cytomorphologies that can be seen in benign and malignant tumors. We posit that metastatic disease to the breast, itself an uncommon entity, should be considered in the differential diagnosis of MBC. We report a unique case of metastatic non-small cell lung cancer (NSCLC) with an actionable driver mutation that presented as a symptomatic breast mass and was initially considered to represent MBC. Report A 74-year-old woman with a 22-pack-year smoking history presented to the breast clinic complaining of a palpable left breast mass that had grown rapidly over the previous month. Ultrasound-guided biopsy of the breast mass revealed high-grade poorly differentiated carcinoma. On immunohistochemical (IHC) evaluation, tumor cells were strongly positive for epithelial markers CAM5.2 and keratin AE1/AE3, weakly positive for breast cancer (BC) marker TRPS1, and negative for BC marker GATA3, squamous cell carcinoma markers p63 and CK5, and melanoma marker SOX10. Metaplastic triple-negative BC was diagnosed. However, concern remained for metastasis from a non-breast primary tumor due to the patient’s constitutional symptoms such as fatigue, night sweats, and 60-pound unintentional weight loss over the previous year, as well as interval development of a suspicious nodular rash on her right upper extremity. An FDG-PET-CT was obtained and demonstrated a hypermetabolic left lung consolidation (maximum SUV 33.3) measuring 7.2 cm, pulmonary nodules, and extensive thoracic lymphadenopathy. Due to rising suspicion for a primary lung tumor, additional IHC staining on the original breast biopsy was requested. Tumor cells were positive for TTF-1, consistent with metastatic lung adenocarcinoma. Tissue next-generation sequencing (NGS) identified a MET exon 14 skipping mutation, making the patient eligible for treatment with capmatinib, a first-line kinase inhibitor targeted therapy for metastatic NSCLC. At the time of this report, the patient has completed a course of palliative stereotactic body radiation therapy to the left lung and started capmatinib 400 mg BID, which she is tolerating well. Her first restaging scans after treatment initiation will be obtained one week after the time of this report. Conclusion In the absence of heightened suspicion for a non-breast primary tumor, our patient had initially received a diagnosis of triple-negative MBC. This diagnosis would have exposed her to increased treatment-related toxicities from cytotoxic chemotherapy and poor prognosis from MBC without survival benefit from targeted therapy for NSCLC. We advocate for the use of supplemental body imaging, expert and comprehensive IHC evaluation, and multidisciplinary discussion in cases of MBC and undifferentiated breast malignancy to facilitate accurate diagnosis and treatment. Citation Format: Tanmayi Pai, Marte Wasserman, Jason Lewis, Miglena Komforti, James Jakub, Augustine Lee, Yanyan Lou, Pooja Advani, Rohit Rao. Metastatic Lung Cancer Masquerading as Metaplastic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-08.

Rationale: Global Lung Function Initiative (GLI) Global spirometry reference equations were recently derived to offer a "race-neutral" interpretation option. The impact of transitioning from the race-specific GLI-2012 to the GLI Global reference equations is unknown. Objectives: Describe the direction and magnitude of changes in predicted lung function measurements in a population of diverse race and ethnicity using GLI Global in place of GLI-2012 reference equations. Methods: In this multicenter cross-sectional study using a large pulmonary function laboratory database, 109,447 spirometry tests were reanalyzed using GLI Global reference equations and compared with the existing GLI-2012 standard, stratified by self-reported race and ethnicity. Measurements and Main Results: Mean FEV1 and FVC percent predicted increased in the White and Northeast Asian groups and decreased in the Black, Southeast Asian, and mixed/other race groups. The prevalence of obstruction increased by 9.7% in the White group, and prevalences of possible restriction increased by 51.1% and 37.1% in the Black and Southeast Asian groups, respectively. Using GLI Global in a population with equal representation of all five race and ethnicity groups altered the interpretation category for 10.2% of spirometry tests. Subjects who self-identified as Black were the only group with a relative increase in the frequency of abnormal spirometry test results (32.9%). Conclusions: The use of GLI Global reference equations will significantly impact spirometry interpretation. Although GLI Global offers an innovative approach to transition from race-specific reference equations, it is important to recognize the continued need to place these data within an appropriate clinical context.

Background Social media has become a vital tool for health care providers to quickly share information. However, its lack of content curation and expertise poses risks of misinformation and premature dissemination of unvalidated data, potentially leading to widespread harmful effects due to the rapid and large-scale spread of incorrect information. Objective We aim to determine whether social media had an undue association with the prescribing behavior of hydroxychloroquine, using the COVID-19 pandemic as the setting. Methods In this retrospective study, we gathered the use of hydroxychloroquine in 48 hospitals in the United States between January and December 2020. Social media data from X/Twitter was collected using Brandwatch, a commercial aggregator with access to X/Twitter’s data, and focused on mentions of “hydroxychloroquine” and “Plaquenil.” Tweets were categorized by sentiment (positive, negative, or neutral) using Brandwatch’s sentiment analysis tool, with results classified by date. Hydroxychloroquine prescription data from the National COVID Cohort Collaborative for 2020 was used. Granger causality and linear regression models were used to examine relationships between X/Twitter mentions and prescription trends, using optimum time lags determined via vector auto-regression. Results A total of 581,748 patients with confirmed COVID-19 were identified. The median daily number of positive COVID-19 cases was 1318.5 (IQR 1005.75-1940.3). Before the first confirmed COVID-19 case, hydroxychloroquine was prescribed at a median rate of 559 (IQR 339.25-728.25) new prescriptions per day. A day-of-the-week effect was noted in both prescriptions and case counts. During the pandemic in 2020, hydroxychloroquine prescriptions increased significantly, with a median of 685.5 (IQR 459.75-897.25) per day, representing a 22.6% rise from baseline. The peak occurred on April 2, 2020, with 3411 prescriptions, a 397.6% increase. Hydroxychloroquine mentions on X/Twitter peaked at 254,770 per day on April 5, 2020, compared to a baseline of 9124 mentions per day before January 21, 2020. During this study’s period, 3,823,595 total tweets were recorded, with 10.09% (n=386,115) positive, 37.87% (n=1,448,030) negative, and 52.03% (n=1,989,450) neutral sentiments. A 1-day lag was identified as the optimal time for causal association between tweets and hydroxychloroquine prescriptions. Univariate analysis showed significant associations across all sentiment types, with the largest impact from positive tweets. Multivariate analysis revealed only neutral and negative tweets significantly affected next-day prescription rates. Conclusions During the first year of the COVID-19 pandemic, there was a significant association between X/Twitter mentions and the number of prescriptions of hydroxychloroquine. This study showed that X/Twitter has an association with the prescribing behavior of hydroxychloroquine. Clinicians need to be vigilant about their potential unconscious exposure to social media as a source of medical knowledge, and health systems and organizations need to be more diligent in identifying expertise, source, and quality of evidence when shared on social media platforms.

BACKGROUND:For many patients with lung disease the only proven intervention to improve survival and quality of life is lung transplantation (LTx). Esophageal dysmotility and gastroesophageal reflux (GER) are common in patients with respiratory disease, and often associate with worse prognosis following LTx. Which, if any patients, should be excluded from LTx based on esophageal concerns remains unclear. Our aim was to understand the effect of LTx on esophageal motility diagnosis and examine how this and the other physiological and mechanical factors relate to GER and clearance of boluses swallowed.METHODS:We prospectively recruited 62 patients with restrictive (RLD) and obstructive (OLD) lung disease (aged 33-75 years; 42 men) who underwent high resolution impedance manometry and 24-h pH-impedance before and after LTx.KEY RESULTS:RLD patients with normal motility were more likely to remain normal (p = 0.02), or if having abnormal motility to change to normal (p = 0.07) post-LTx than OLD patients. Esophageal length (EL) was greater in OLD than RLD patients' pre-LTx (p < 0.001), reducing only in OLD patients' post-LTx (p = 0.02). Reduced EL post-LTx associated with greater contractile reserve (r = 0.735; p = 0.01) and increased likelihood of motility normalization (p = 0.10). Clearance of reflux improved (p = 0.01) and associated with increased mean nocturnal baseline impedance (p < 0.001) in RLD but not OLD. Peristaltic breaks and thoraco-abdominal pressure gradient impact both esophageal clearance of reflux and boluses swallowed (p < 0.05).CONCLUSIONS AND INFERENCES:RLD patients are more likely to show improvement in esophageal motility than OLD patients post-LTx. However, the effect on GER is more difficult to predict and requires other GI, anatomical and pulmonary factors to be taken into consideration.

OBJECTIVE:Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long-term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. METHODS:We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow-up. RESULTS:Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6-37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52-72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. CONCLUSION:We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow-up, and adverse events, including infection, were observed.

Rationale: Hospital readmission within 30 days poses challenges for healthcare providers, policymakers, and patients because of its impact on care quality, costs, and outcomes. Patients with interstitial lung disease (ILD) are particularly affected by readmission, which is associated with increased morbidity and mortality and reduced quality of life. Because small sample sizes have hindered previous studies, this study seeks to address this gap in knowledge by examining a large-scale dataset. Objective: To determine the rate and probability of 30-day all-cause readmission and secondary outcomes in patients with coronavirus disease (COVID-19) or ILD admitted to the hospital. Methods: This study is a nested cohort study that used the PearlDiver patient records database. Adult patients (age ⩾18 yr) who were admitted to hospitals in 28 states in the United States with COVID-19 or ILD diagnoses were included. We defined and analyzed two separate cohorts in this study. The first cohort consisted of patients with COVID-19 and was later divided into two groups with or without a history of ILD. The second cohort consisted of patients with ILD and was later divided into groups with COVID-19 or with a non-COVID-19 pneumonia diagnosis at admission. We also studied two other subcohorts of patients with and without idiopathic pulmonary fibrosis within the second cohort. Propensity score matching was employed to match confounders between groups. The Kaplan-Meier log rank test was applied to compare the probabilities of outcomes. Results: We assessed the data of 2,286,775 patients with COVID-19 and 118,892 patients with ILD. We found that patients with COVID-19 with preexisting ILD had an odds ratio of 1.6 for 30-day all-cause readmission. Similarly, an odds ratio of 2.42 in readmission rates was observed among hospitalized individuals with ILD who contracted COVID-19 compared with those who were hospitalized for non-COVID-19 pneumonia. Our study also found a significantly higher probability of intensive care admission among patients in both cohorts. Conclusions: Patients with ILD face heightened rates of hospital readmissions, particularly when ILD is combined with COVID-19, resulting in adverse outcomes such as decreased quality of life and increased healthcare expenses. It is imperative to prioritize preventive measures against COVID-19 and establish effective postdischarge care strategies for patients with ILD.