Alveolar macrophages from EVALI patients and e-cigarette users: a story of shifting phenotype.

Exposure to e-cigarette vapors alters important biologic processes including phagocytosis, lipid metabolism, and cytokine activity in the airways and alveolar spaces. Little is known about the biologic mechanisms underpinning the conversion to e-cigarette, or vaping, product use-associated lung injury (EVALI) from normal e-cigarette use in otherwise healthy individuals. We compared cell populations and inflammatory immune populations from bronchoalveolar lavage fluid in individuals with EVALI to e-cigarette users without respiratory disease and healthy controls and found that e-cigarette users with EVALI demonstrate a neutrophilic inflammation with alveolar macrophages skewed towards inflammatory (M1) phenotype and cytokine profile. Comparatively, e-cigarette users without EVALI demonstrate lower inflammatory cytokine production and express features associated with a reparative (M2) phenotype. These data indicate macrophage-specific changes are occurring in e-cigarette users who develop EVALI.

E-Cigarette or Vaping Product Use-associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report.

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.

Climate Change for the Pulmonologist: A Focused Review.

Climate change adversely impacts global health. Increasingly, temperature variability, inclement weather, declining air quality, and growing food and clean water supply insecurities threaten human health. Earth's temperature is projected to increase up to 6.4 °C by the end of the 21st century, exacerbating the threat. Public and health care professionals, including pulmonologists, perceive the detrimental effects of climate change and air pollution and support efforts to mitigate its effects. In fact, evidence is strong that premature cardiopulmonary death is associated with air pollution exposure via inhalation through the respiratory system, which functions as a portal of entry. However, little guidance is available for pulmonologists in recognizing the effects of climate change and air pollution on the diverse range of pulmonary disorders. To educate and mitigate risk for patients competently, pulmonologists must be armed with evidence-based findings of the impact of climate change and air pollution on specific pulmonary diseases. Our goal is to provide pulmonologists with the background and tools to improve patients' health and to prevent adverse outcomes despite climate change-imposed threats. In this review, we detail current evidence of climate change and air pollution impact on a diverse range of pulmonary disorders. Knowledge enables a proactive and individualized approach toward prevention strategies for patients, rather than merely treating ailments reactively.

Common things are common, but what is common? Incorporating probability information into differential diagnosis.

The well-known clinical axiom declaring that 'common things are common' attests to the pivotal role of probability in diagnosis. Despite the popularity of this and related axioms, there is no operationalized definition of a common disease, and no practicable way of incorporating actual disease frequencies into differential diagnosis. In this essay, we aim to disambiguate the definition of a common (or rare) disease and show that incidence-not prevalence-is the proper metric of disease frequency for differential diagnosis. We explore how numerical estimates of disease frequencies based on incidence can be incorporated into differential diagnosis as well as the inherent limitations of this method. These concepts have important implications for diagnostic decision making and medical education, and hold promise as a method to improve diagnostic accuracy.

Prospectively Assessed Long-Term Outcomes of Patients with E-Cigarette- or Vaping-associated Lung Injury.

Rationale: E-cigarette- or vaping-associated lung injury (EVALI) was first identified in 2019. The long-term respiratory, cognitive, mood disorder, and vaping behavior outcomes of patients with EVALI remain unknown. Objectives: To determine the long-term respiratory, cognitive, mood disorder, and vaping behavior outcomes of patients with EVALI. Methods: We prospectively enrolled patients with EVALI from two health systems. We assessed outcomes at 1 year after onset of EVALI using validated instruments measuring cognitive function, depression, anxiety, post-traumatic stress, respiratory disability, coronavirus disease (COVID-19) infection, pulmonary function, and vaping behaviors. We used multivariable regression to identify risk factors of post-EVALI vaping behaviors and to identify whether admission to the intensive care unit (ICU) was associated with cognitive, respiratory, or mood symptoms. Results: Seventy-three patients completed 12-month follow-up. Most patients were male (66.7%), young (mean age, 31 ± 11 yr), and White (85%) and did not need admission to the ICU (59%). At 12 months, 39% (25 of 64) had cognitive impairment, whereas 48% (30 of 62) reported respiratory limitations. Mood disorders were common, with 59% (38 of 64) reporting anxiety and/or depression and 62% (39 of 63) having post-traumatic stress. Four (6.4%) of 64 reported a history of COVID-19 infection. Despite the history of EVALI, many people continued to vape. Only 38% (24 of 64) reported quitting all vaping and smoking behaviors. Younger age was associated with reduced vaping behavior after EVALI (odds ratio, 0.93; P = 0.02). ICU admission was not associated with cognitive impairment, dyspnea, or mood symptoms. Conclusions: Patients with EVALI, despite their youth, commonly have significant long-term respiratory disability; cognitive impairment; symptoms of depression, anxiety, post-traumatic stress; and persistent vaping.

Pulmonary and Critical Care Considerations for e-Cigarette, or Vaping, Product Use-Associated Lung Injury.

BACKGROUND: In 2019, the United States experienced a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). More than one-half of these patients required admission to an ICU. RESEARCH QUESTION: What are the recent literature and expert opinions which inform the diagnosis and management of patients with critical illness with EVALI? STUDY DESIGN AND METHODS: To synthesize information critical to pulmonary/critical care specialists in the care of patients with EVALI, this study examined data available from patients hospitalized with EVALI between August 2019 and January 2020; reviewed the clinical course and critical care experience with those patients admitted to the ICU; and compiled opinion of national experts. RESULTS: Of the 2,708 patients with confirmed or probable EVALI requiring hospitalization as of January 21, 2020, a total of 1,604 (59.2%) had data available on ICU admission; of these, 705 (44.0%) were admitted to the ICU and are included in this analysis. The majority of ICU patients required respiratory support (88.5%) and in severe cases required intubation (36.1%) or extracorporeal membrane oxygenation (6.7%). The majority (93.0%) of these ICU patients survived to discharge. Review of the clinical course and expert opinion provided insight into: imaging; considerations for bronchoscopy; medical treatment, including use of empiric antibiotics, antiviral agents, and corticosteroids; respiratory support, including considerations for intubation, positioning maneuvers, and extracorporeal membrane oxygenation; and patient outcomes. INTERPRETATION: Review of the clinical course of patients with EVALI requiring ICU admission and compilation of expert opinion provided critical insight into pulmonary/critical care-specific considerations for this patient population. Because a large proportion of patients hospitalized with EVALI required ICU admission, it is important to remain prepared to care for patients with EVALI.

A 64-Year-Old Man With Multifocal Infiltrates.

CASE PRESENTATION: A 64-year-old previously healthy man presented with 8 weeks of progressive dyspnea on exertion and cough. Prior to presentation, the patient was able to bicycle > 60 miles per week and work full-time in a home improvement store. He was up-to-date with age-appropriate cancer screening and immunizations, and home medications included famotidine for reflux and nonsteroidal antiinflammatories for osteoarthritis, both as-needed. He had no significant respiratory exposure, aside from previous work as an electrician. His symptoms began in mid-February 2020 amid the coronavirus disease 2019 pandemic, although he had no known exposure to the virus.

Diagnosis of EVALI: General Approach and the Role of Bronchoscopy.

A 23-year-old man arrives at the ED with a 3-week history of dyspnea, dry cough, fevers, and night sweats. Two weeks previously, he was evaluated in an outpatient clinic and given a course of azithromycin for presumed infectious pneumonia. His symptoms did not improve, and he was seen 1 week later in an urgent care center and given a prescription for doxycycline, which he has been taking without improvement. He states that he feels miserable, has severe nausea and vomiting, and has not eaten in several days. His only medical history is childhood asthma. He reports no surgeries and takes no medications. He has no risk factors for HIV, does not smoke combustible cigarettes or use IV drugs, and has not recently traveled. Examination shows a room air saturation of 89%, a temperature of 38.3°C, and a respiratory rate of 22 breaths/min. Results of his examination are normal, and there are no rales or wheezing heard in the lungs. Chest radiograph shows bilateral, consolidative opacities. WBC count is 14,000, with left shift. Results of biochemistries are normal. Erythrocyte sedimentation rate is 104, and procalcitonin is 0.08. Urine toxicology screen is positive for tetrahydrocannabinol (THC). Asked specifically about vaping and e-cigarette use, he reports that he recently began using THC "carts" that his friend gets from an unknown supplier. What is the diagnosis and what additional steps are necessary to confirm it? Is bronchoscopy indicated?

Clinical, Bronchoscopic, and Imaging Findings of e-Cigarette, or Vaping, Product Use-Associated Lung Injury Among Patients Treated at an Academic Medical Center.

Importance: e-Cigarette, or vaping, product use-associated lung injury (EVALI) has caused more than 2800 illnesses and 68 deaths in the United States. Better characterization of this novel illness is needed to inform diagnosis and management. Objective: To describe the clinical features, bronchoscopic findings, imaging patterns, and outcomes of EVALI. Design, Setting, and Participants: This case series of 31 adult patients diagnosed with EVALI between June 24 and December 10, 2019, took place at an academic medical center in Salt Lake City, Utah. Exposures: e-Cigarette use, also known as vaping. Main Outcomes and Measures: Symptoms, laboratory findings, bronchoscopic results, imaging patterns, and clinical outcomes. Results: Data from 31 patients (median [interquartile range] age, 24 [21-31] years) were included in the study. Patients were primarily men (24 [77%]) and White individuals (27 [87%]) who used e-cigarette products containing tetrahydrocannabinol (THC) (29 [94%]). Patients presented with respiratory (30 [97%]), constitutional (28 [90%]), and gastrointestinal (28 [90%]) symptoms. Serum inflammatory markers were elevated in all patients. Bronchoscopy was performed in 23 of 28 inpatients (82%) and bronchoalveolar lavage (BAL) revealed the presence of lipid-laden macrophages (LLMs) in 22 of 24 cases (91%). BAL samples tested positive for Pneumocystis jirovecii (3 patients [13%]), rhinovirus (2 patients [8%]), human metapneumovirus and Aspergillus (1 patient each [4%]); all except human metapneumovirus were determined to be false-positives or clinically inconsequential. The exclusive or dominant computed tomography (CT) pattern was organizing pneumonia in 23 of 26 cases (89%). Patients received antibiotics (26 [84%]) and corticosteroids (24 [77%]), and all survived; 20 patients (65%) seen in follow-up showed marked improvement, but residual symptoms (13 [65%]), radiographic opacities (8 [40%]), and abnormal pulmonary function tests (8 of 18 [44%]) were common. Conclusions and Relevance: In this case series, patients with EVALI characteristically presented with a flu-like illness with elevated inflammatory markers, LLMs on BAL samples, and an organizing pneumonia pattern on CT imaging. Bronchoscopic testing for infection had a high incidence of false-positive results. Patients had substantial residual abnormal results at early follow-up. These data suggest a limited role for bronchoscopy in typical presentations of EVALI without risk factors for alternative diagnoses and the need for careful longitudinal follow-up.

Sporadic Obliterative Bronchiolitis: Case Series and Systematic Review of the Literature.

OBJECTIVE: To describe the clinical characteristics and outcomes of patients diagnosed with obliterative bronchiolitis (OB) not associated with transplantation or point-source exposures to inhaled toxins. PATIENTS AND METHODS: We compiled all confirmed diagnoses of OB at our institution and analyzed their demographic characteristics, treatments, and outcomes as defined by pulmonary function tests (PFTs) and transplant-free mortality. The study period ranged from July 2007 to August 2017. Histological diagnosis was confirmed by a pathologist, and high-resolution chest computed tomography (CT) scans were reviewed and scored by chest radiologists. We also performed a systematic literature review of sporadic OB series. RESULTS: We identified 19 confirmed cases at our institution and 9 publications in the literature containing 104 patients. In both our series and the literature, patients were disproportionately middle-aged Caucasian women. The disease was idiopathic in 42% and was associated with connective tissue diseases and inhalational exposures in 31% and 15%, respectively. Chest CT showed expiratory air trapping in all patients. Patients were treated with corticosteroids, steroid-sparing agents, and macrolides in 77%, 46%, and 22%, respectively. Over a median follow-up in our series of 1703 days (range, 11-3206 days), PFTs did not change significantly. In all series combined, mortality incidence from any cause was 82/1000 patient-years (95% CI, 65-102). Of 14 patients who died, 3 deaths were due to respiratory failure and 5 were potentially related to complications of immunosuppressive therapy. CONCLUSION: Sporadic OB is a rare disease that is uniformly associated with air trapping on high-resolution chest CT. The diagnosis should be established with surgical biopsy if possible. The illness is not typically progressive.

Probing Changes in Lung Physiology in COPD Using CT, Perfusion MRI, and Hyperpolarized Xenon-129 MRI.

RATIONALE AND OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is highly heterogeneous and not well understood. Hyperpolarized xenon-129 (Xe129) magnetic resonance imaging (MRI) provides a unique way to assess important lung functions such as gas uptake. In this pilot study, we exploited multiple imaging modalities, including computed tomography (CT), gadolinium-enhanced perfusion MRI, and Xe129 MRI, to perform a detailed investigation of changes in lung morphology and functions in COPD. Utility and strengths of Xe129 MRI in assessing COPD were also evaluated against the other imaging modalities. MATERIALS AND METHODS: Four COPD patients and four age-matched normal subjects participated in this study. Lung tissue density measured by CT, perfusion measures from gadolinium-enhanced MRI, and ventilation and gas uptake measures from Xe129 MRI were calculated for individual lung lobes to assess regional changes in lung morphology and function, and to investigate correlations among the different imaging modalities. RESULTS: No significant differences were found for all measures among the five lobes in either the COPD or age-matched normal group. Strong correlations (R > 0.5 or < -0.5, p < 0.001) were found between ventilation and perfusion measures. Also gas uptake by blood as measured by Xe129 MRI showed strong correlations with CT tissue density and ventilation measures (R > 0.5 or < -0.5, p < 0.001) and moderate to strong correlations with perfusion measures (R > 0.4 or < -0.5, p < 0.01). Four distinctive patterns of functional abnormalities were found in patients with COPD. CONCLUSION: Xe129 MRI has high potential to uniquely identify multiple changes in lung physiology in COPD using a single breath-hold acquisition.

Validation of claims-based algorithms for pulmonary arterial hypertension.

Administrative claims studies do not adequately distinguish pulmonary arterial hypertension (PAH) from other forms of pulmonary hypertension (PH). Our aim is to develop and validate a set of algorithms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and electronic medical records (EMR), to identify patients with PAH. From January 2012 to August 2015, the EMRs of patients with ICD-9-CM codes for PH with an outpatient visit at the University of Texas Medical Branch were reviewed. Patients were divided into PAH or non-PAH groups according to EMR encounter diagnosis. Patient demographics, echocardiography, right heart catheterization (RHC) results, and PAH-specific therapies were assessed. RHC measurements were reviewed to categorize cases as hemodynamically determined PAH or not PAH. Weighted sensitivity, specificity, and positive and negative predictive values were calculated for the developed algorithms. A logistic regression analysis was conducted to determine how well the algorithms performed. External validation was performed at the University of Virginia Health System. The cohort for the development algorithms consisted of 683 patients with PH, PAH group (n = 191) and non-PAH group (n = 492). A hemodynamic diagnosis of PAH determined by RHC was recorded in the PAH (26%) and non-PAH (3%) groups. The positive predictive value for the algorithm that included ICD-9-CM and PAH-specific medications was 66.9% and sensitivity was 28.2% with a c-statistic of 0.66. The positive predictive value for the EMR-based algorithm that included ICD-9-CM, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medication was 69.4% and a c-statistic of 0.87. A validation cohort of 177 patients with PH examined from August 2015 to August 2016 using EMR-based algorithms yielded a similar positive predictive value of 62.5%. In conclusion, claims-based algorithms that included ICD-9-CM codes, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medications better-identified patients with PAH than ICD-9-CM codes alone.

A case of massive hemoptysis following transesophageal echocardiogram.

INTRODUCTION: Tracheal intubation leading to injury of the airway is a rare complication of transesophageal echocardiography (TEE). Tracheal trauma is not a described complication of TEE, and safety literature for this procedure remains silent on the matter. We describe the case of a patient on systemic anticoagulation and antiplatelet therapy who underwent TEE and suffered massive hemoptysis requiring bronchial artery embolization (BAE). CASE PRESENTATION: An elderly patient was admitted to the hospital with recently diagnosed atrial fibrillation and shortness of breath. The patient underwent a TEE with successful synchronized cardioversion on hospital day #2. Later that day the patient experienced respiratory distress and hemoptysis and was intubated. Oropharyngeal and gastrointestinal sources of bleeding were excluded. A bronchoscopy revealed active bleeding from an ulceration in the bronchus intermedius (BI) of the right lung. A 7 French Arndt endobronchial blocker (Cook Medical, Bloomington, Indiana) was placed and anticoagulation reversed. Bleeding stopped for two days, but then returned on hospital day #5, requiring BAE to the right bronchial artery. The procedure was successful, the patient was successfully extubated, and was discharged over the next 10 days. DISCUSSION: Massive hemoptysis and respiratory compromise as a result of tracheal trauma is not described in the TEE literature. This patient proved to be a difficult esophageal intubation secondary to a newly discovered Zenker's diverticulum. The risk for bleeding in this patient was higher secondary to anticoagulation with warfarin and antiplatelet therapy with ticagrelor. As in all cases of massive hemoptysis, key aspects of care in this case involved localization of bleeding, reversal of anticoagulation, and definitive management such as BAE. CONCLUSIONS: Tracheal trauma is not a described complication of TEE, but clinicians should be mindful of this possible complication in patients receiving anticoagulation. Typical management for massive hemoptysis was successful in this patient.