Use of Aerosolized Prostacyclins in Critically Ill Patients and Association With Clinical Outcomes.

Aerosolized prostacyclins are frequently used in patients with severe acute respiratory distress syndrome and refractory hypoxia. Previous studies have shown improvement in oxygenation with use of pulmonary vasodilators such as iloprost and epoprostenol; however, there is no head-to-head comparison between these agents. OBJECTIVES: To compare the effects of inhaled epoprostenol and inhaled iloprost in critically ill patients with refractory hypoxia. DESIGN SETTING AND PARTICIPANTS: We performed a retrospective cohort analysis of patients admitted to the ICUs at the University of Oklahoma Health Sciences Center between 2015 and 2018. Adult patients who received aerosolized epoprostenol or iloprost for more than 4 hours were included in the analysis. MAIN OUTCOMES AND MEASURES: The primary endpoint measured was to compare the change in Pao2/Fio2 ratio between patients treated with iloprost compared with epoprostenol. Secondary outcomes measured were 90-day in-hospital mortality and improvement in vasopressor requirements. RESULTS: A total of 126 patients were included in the study, 95 of whom received iloprost (75%) and 31 patients (25%) received epoprostenol. There were significant improvements in Pao2/Fio2 ratio in both the iloprost and epoprostenol group. Patients in the epoprostenol group appeared to have a higher 90-day mortality compared with the iloprost group. However, our study was not powered to detect a mortality difference and this finding likely represents a sicker population in the epoprostenol group and prescription bias. The use of iloprost was associated with higher vasopressor requirements in the first 12 hours of administration, an association was not observed in the epoprostenol group. CONCLUSIONS AND RELEVANCE: In this retrospective cohort analysis, use of both pulmonary vasodilators was associated with similar improvement in gas exchange. The mortality difference observed likely represents difference in severity of illness. Further studies are needed to corroborate these findings.

Association of Renin Angiotensin Aldosterone System Inhibitors and Outcomes of Hospitalized Patients With COVID-19.

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19. DESIGN: Retrospective observational study. SETTING: Multicenter, international COVID-19 registry. SUBJECTS: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19-1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03-1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81-0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20-1.56]; p < 0.0001). CONCLUSIONS: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients.

Early IFN-ß administration protects cigarette smoke exposed mice against lethal influenza virus infection without increasing lung inflammation.

During influenza A virus (IAV) infection, it is unclear whether type I interferons (IFNs) have defensive antiviral effects or contribute to immunopathology in smokers. We treated nonsmoking (NS) and cigarette smoke (CS)-exposed mice intranasally with early (prophylactic) or late (therapeutic) IFN-ß. We compared the mortality and innate immune responses of the treated mice following challenge with IAV. In NS mice, both early and late IFN-ß administration decreased the survival rate in mice infected with IAV, with late IFN-ß administration having the greatest effect on survival. In contrast, in CS-exposed mice, early IFN-ß administration significantly increased survival during IAV infection while late IFN-ß administration did not alter mortality. With regards to inflammation, in NS mice, IFN-ß administration, especially late administration, significantly increased IAV-induced inflammation and lung injury. Early IFN-ß administration to CS-exposed mice did not increase IAV-induced inflammation and lung injury as occurred in NS mice. Our results demonstrate, although IFN-ß administration worsens the susceptibility of NS mice to influenza infection with increased immunopathology, early IFN-ß administration to CS-exposed mice, which have suppression of the intrinsic IFN response, improved outcomes during influenza infection.

Interlobular Septal Thickening in a Young Man With Dyspnea.

CASE PRESENTATION: A 30-year-old man with a history of childhood asthma, a 15-pack-year smoking history, and methamphetamine abuse was intubated and started on mechanical ventilation because of acute hypoxic respiratory failure after experiencing progressive dyspnea and a nonproductive cough over the previous year. During the previous 3 months, he had multiple clinic visits, with chest radiographs showing diffuse, bilateral, reticulonodular opacities and small bilateral pleural effusions and was treated for community-acquired pneumonia. Testing for COVID pneumonia was negative, and he failed to respond to antimicrobial therapy. Physical examination on admission showed diffuse fine crackles bilaterally on lung auscultation. Admission laboratory test results were unremarkable.

Long-term cigarette smoke exposure dysregulates pulmonary T cell response and IFN-γ protection to influenza virus in mouse.

BACKGROUND: Influenza is a highly contagious, acute, febrile respiratory infection caused by a negative-sense, single-stranded RNA virus, which belongs in the Orthomyxoviridae family. Cigarette smoke (CS) exposure worsens influenza infection in terms of frequency and severity in both human and animal models. METHODS: C57BL/6 mice with or without CS exposure for 6 weeks were inoculated intranasally with a single, non-lethal dose of the influenza A virus (IAV) A/Puerto Rico/8/1934 (PR8) strain. At 7 and 10 days after infection, lung and mediastinal lymph nodes (MLN) cells were collected to determine the numbers of total CD4 + and CD8 + T cells, and IAV-specific CD4 + and CD8 + T cells, using flow cytometry. Bronchoalveolar lavage fluid (BALF) was also collected to determine IFN-γ levels and total protein concentration. RESULTS: Although long-term CS exposure suppressed early pulmonary IAV-antigen specific CD8 + and CD4 + T cell numbers and IFN-γ production in response to IAV infection on day 7 post-infection, CS enhanced numbers of these cells and IFN-γ production on day 10. The changes of total protein concentration in BALF are consistent with the changes in the IFN-γ amounts between day 7 and 10, which suggested that excessive IFN-γ impaired barrier function and caused lung injury at the later stage of infection. CONCLUSIONS: Our results demonstrated that prior CS exposure caused a biphasic T cell and IFN-γ response to subsequent infection with influenza in the lung. Specifically, the number of IAV antigen-specific T cells on day 10 was greatly increased by CS exposure even though CS decreased the number of the same group of cells on day 7. The result suggested that CS affected the kinetics of the T cell response to IAV, which was suppressed at an early stage and exaggerated at a later stage. This study is the first to describe the different effect of long-term CS on T cell responses to IAV at early and late stages of infection in vivo.

Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is primarily caused by cigarette smoking. Increased numbers of mucus-producing secretory ("goblet") cells, defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. Primary human bronchial epithelial cells (HBECs) from nonsmokers and smokers with COPD were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using 1) the NOTCH/γ-secretase inhibitor dibenzazepine (DBZ), 2) lentiviral overexpression of the NICD3 (NOTCH3-intracellular domain), or 3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by quantitative PCR, Western blotting, immunostaining, and RNA sequencing. We found that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Overexpression of NICD3 increased the expression of goblet cell-associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a novel potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

Endobronchial Lipoma: Case Report and Literature Review.

Endobronchial lipomas are rare benign tumors that can cause bronchial obstruction resulting in significant symptoms and post-obstructive parenchymal damage. Accurate diagnosis and treatment are essential to avoid unnecessary morbidity and mortality in these patients. We describe one case of endobronchial lipoma at our institution and include a literature review of endobronchial lipoma cases reported during the time period 2003-2018. Treatment has shifted towards bronchoscopic management and away from surgery for the majority of patients; 64.3% of patients in this review had their lipoma resected bronchoscopically, compared to 30% or less in reviews as recent as 2003. Notably, in cases reported since 2010, 72.7% of cases were managed bronchoscopically. Recurrence rates are low following both bronchoscopic and surgical resection.

Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes.

Bacillus anthracis, the causative agent of inhalation anthrax, is a serious concern as a bioterrorism weapon. The vegetative form produces two exotoxins: Lethal toxin (LT) and edema toxin (ET). We recently characterized and compared six human airway and alveolar-resident phagocyte (AARP) subsets at the transcriptional and functional levels. In this study, we examined the effects of LT and ET on these subsets and human leukocytes. AARPs and leukocytes do not express high levels of the toxin receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). Less than 20% expressed surface TEM8, while less than 15% expressed CMG2. All cell types bound or internalized protective antigen, the common component of the two toxins, in a dose-dependent manner. Most protective antigen was likely internalized via macropinocytosis. Cells were not sensitive to LT-induced apoptosis or necrosis at concentrations up to 1000 ng/mL. However, toxin exposure inhibited B. anthracis spore internalization. This inhibition was driven primarily by ET in AARPs and LT in leukocytes. These results support a model of inhalation anthrax in which spores germinate and produce toxins. ET inhibits pathogen phagocytosis by AARPs, allowing alveolar escape. In late-stage disease, LT inhibits phagocytosis by leukocytes, allowing bacterial replication in the bloodstream.

IRF7 Is Required for the Second Phase Interferon Induction during Influenza Virus Infection in Human Lung Epithelia.

Influenza A virus (IAV) infection is a major cause of morbidity and mortality. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of IAV in most cell types, and leads to the activation of interferon (IFN). We investigated mechanisms of RIG-I and IFN induction by IAV in the BCi-NS1.1 immortalized human airway basal cell line and in the A549 human alveolar epithelial cell line. We found that the basal expression levels of RIG-I and regulatory transcription factor (IRF) 7 were very low in BCi-NS1.1 cells. IAV infection induced robust RIG-I and IRF7, not IRF3, expression. siRNA against IRF7 and mitochondrial antiviral-signaling protein (MAVS), but not IRF3, significantly inhibited RIG-I mRNA expression and IFN induction by IAV infection. Most importantly, even without virus infection, IFN-ß alone induced RIG-I, and siRNA against IRF7 did not inhibit RIG-I induction by IFN-ß. Similar results were found in the alveolar basal epithelial A549 cell line. RIG-I and IRF7 expression in humans is highly inducible and greatly amplified by IFN produced from virus infected cells. IFN induction can be separated into two phases, that initially induced by the virus with basal RIG-I (the first phase), and that induced by the subsequent virus with amplified RIG-I from the first phase IFN (the second phase). The de novo synthesis of IRF7 is required for the second phase IFN induction during influenza virus infection in human lung bronchial and alveolar epithelial cells.

An unusual case of unilateral pulmonary edema with contralateral bronchial obstruction.

A 61 year-old man presented with progressive shortness of breath. Computed tomography scan of the chest showed diffuse ground glass infiltrates and dilated pulmonary vessels in the right lung in addition to bilateral pulmonary masses with obstruction of the left main pulmonary bronchus. The patient underwent bronchoscopy with destruction of the tumor obstructing the left main pulmonary bronchus, resulting in clinical improvement and resolution of the right pulmonary infiltrates. We hypothesize that the patient developed right pulmonary edema secondary to hypoxic vasoconstriction of the left lung. This case suggests a rare mechanism of unilateral pulmonary edema and supports inclusion of pulmonary edema in the differential diagnosis of unilateral pulmonary infiltrates in the setting of contralateral bronchial obstruction.

Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: use of restraining therapies--American College of Critical Care Medicine Task Force 2001-2002.

OBJECTIVE: To develop clinical practice guidelines for the use of restraining therapies to maintain physical and psychological safety of adult and pediatric patients in the intensive care unit. PARTICIPANTS: A multidisciplinary, multispecialty task force of experts in critical care practice was convened from the membership of the American College of Critical Care Medicine (ACCM), the Society of Critical Care Medicine (SCCM), and the American Association of Critical Care Nurses (AACN). EVIDENCE: The task force members reviewed the published literature (MEDLINE articles, textbooks, etc.) and provided expert opinion from which consensus was derived. Relevant published articles were reviewed individually for validity using the Cochrane methodology (http://hiru.mcmaster.ca/cochrane/ or www.cochrane.org). CONSENSUS PROCESS: The task force met as a group and by teleconference to identify the pertinent literature and derive consensus recommendations. Consideration was given to both the weight of scientific information within the literature and expert opinion. Draft documents were composed by a task force steering committee and debated by the task force members until consensus was reached by nominal group process. The task force draft then was reviewed, assessed, and edited by the Board of Regents of the ACCM. After steering committee approval, the draft document was reviewed and approved by the SCCM Council. CONCLUSIONS: The task force developed nine recommendations with regard to the use of physical restraints and pharmacologic therapies to maintain patient safety in the intensive care unit.

Microbiological, biological, and chemical weapons of warfare and terrorism.

Microbiological, biological, and chemical toxins have been employed in warfare and in terrorist attacks. In this era, it is imperative that health care providers are familiar with illnesses caused by these agents. Botulinum toxin produces a descending flaccid paralysis. Staphylococcal enterotoxin B produces a syndrome of fever, nausea, and diarrhea and may produce a pulmonary syndrome if aerosolized. Clostridium perfringens epsilon-toxin could possibly be aerosolized to produce acute pulmonary edema. Ricin intoxication can manifest as gastrointestinal hemorrhage after ingestion, severe muscle necrosis after intramuscular injection, and acute pulmonary disease after inhalation. Nerve agents inhibit acetylcholinesterase and thus produce symptoms of increased cholinergic activity. Ammonia, chlorine, vinyl chloride, phosgene, sulfur dioxide, and nitrogen dioxide, tear gas, and zinc chloride primarily injure the upper respiratory tract and the lungs. Sulfur mustard (and nitrogen mustard) are vesicant and alkylating agents. Cyanide poisoning ranges from sudden-onset headache and drowsiness to severe hypoxemia, cardiovascular collapse, and death. Health care providers should be familiar with the medical consequences of toxin exposure, and understand the pathophysiology and management of resulting illness.