RATIONALE:Hyperinflammatory and hypoinflammatory phenotypes previously identified in sepsis and ARDS may enable precision therapies, but their clinical relevance and translational modeling in severe pneumonia remain incompletely characterized. OBJECTIVES:To examine biomarker-defined hyperinflammatory and hypoinflammatory phenotypes in critically ill patients with pneumonia (pulmonary sepsis), test whether the biomarkers that define these phenotypes identify subgroups and outcomes in a mouse model of bacterial pneumonia, and determine whether the mouse phenotypes respond differently to therapeutic interventions. METHODS:We performed latent class analysis (LCA) in a cohort of 548 ICU patients with pulmonary sepsis to identify inflammatory phenotypes and test the association of these phenotypes with clinical outcomes using validated classifier models. We developed a mouse model of pneumococcal pneumonia which recapitulates key aspects of these phenotypes and tested responses to dexamethasone and IL-6 receptor blockade. MEASUREMENTS AND MAIN RESULTS:Two phenotypes were identified in patients with pulmonary sepsis: a hyperinflammatory phenotype with more lung injury and increased mortality, and a hypoinflammatory phenotype with more favorable outcomes. Despite uniform pathogen exposure and baseline conditions, LCA identified two phenotypes in the mice with divergent trajectories (lung injury and mortality). Therapeutic benefit from anti-inflammatory interventions was observed exclusively in the more inflamed mice. CONCLUSIONS:By integrating clinical data from human studies and experimental findings in a clinically relevant mouse model, this study provides a translational framework for developing phenotype-targeted therapies for critical illness, with the goal of improving patient outcomes.

BACKGROUND:Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The primary objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in a mouse model. A secondary objective was to identify shared transcriptomic features of pneumococcal pneumonia and steroid treatment in the mouse model and clinical samples. METHODS:We carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. We also studied lower respiratory tract gene expression from a cohort of 15 mechanically ventilated patients (10 with Streptococcus pneumoniae and 5 controls) to compare with the transcriptional studies in the mice. RESULTS:In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Transcriptomic analyses identified effects of steroid therapy in mice that were also observed in the clinical samples. CONCLUSIONS:In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The transcriptional studies in patients suggest that the mouse model replicates some of the features of pneumonia in patients with Streptococcus pneumoniae and steroid treatment. Overall, these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.

Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.

Neutrophils are the first leukocytes to be recruited to sites of inflammation in response to chemotactic factors released by activated macrophages and pulmonary epithelial and endothelial cells in bacterial pneumonia, a common cause of acute respiratory distress syndrome (ARDS). Although neutrophilic inflammation facilitates the elimination of pathogens, neutrophils also may cause bystander tissue injury. Even though the presence of neutrophils in alveolar spaces is a key feature of acute lung injury and ARDS especially from pneumonia, their contribution to the pathogenesis of lung injury is uncertain. The goal of this study was to elucidate the role of neutrophils in a clinically relevant model of bacterial pneumonia. We investigated the effect of reducing neutrophils in a mouse model of pneumococcal pneumonia treated with antibiotics. Neutrophils were reduced with anti-lymphocyte antigen 6 complex locus G6D (Ly6G) monoclonal antibody 24 h before and immediately preceding infection. Mice were inoculated intranasally with Streptococcus pneumoniae and received ceftriaxone 12 h after bacterial inoculation. Neutrophil reduction in mice treated with ceftriaxone attenuated hypoxemia, alveolar permeability, epithelial injury, pulmonary edema, and inflammatory biomarker release induced by bacterial pneumonia, even though bacterial loads in the distal air spaces of the lung were modestly increased as compared with antibiotic treatment alone. Thus, when appropriate antibiotics are administered, lung injury in the early phase of bacterial pneumonia is mediated in part by neutrophils. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense. NEW & NOTEWORTHY Neutrophil accumulation is a key feature of ARDS, but their contribution to the pathogenesis is still uncertain. We investigated the effect of reducing neutrophils in a clinically relevant mouse model of pneumococcal pneumonia treated with antibiotics. When appropriate antibiotics were administered, neutrophil reduction with Ly6G antibody markedly attenuated lung injury and improved oxygenation. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.

Background: Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. Methods: A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would 1) identify patients with the currently accepted conceptual framework for ARDS, 2) facilitate rapid ARDS diagnosis for clinical care and research, 3) be applicable in resource-limited settings, 4) be useful for testing specific therapies, and 5) be practical for communication to patients and caregivers. Results: The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia; 3) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and 4) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices. Conclusions: We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.

E-cigarette use has rapidly increased as an alternative means of nicotine delivery by heated aerosolization. Recent studies demonstrate nicotine-containing e-cigarette aerosols can have immunosuppressive and pro-inflammatory effects, but it remains unclear how e-cigarettes and the constituents of e-liquids may impact acute lung injury and the development of acute respiratory distress syndrome caused by viral pneumonia. Therefore, in these studies, mice were exposed one hour per day over nine consecutive days to aerosol generated by the clinically-relevant tank-style Aspire Nautilus aerosolizing e-liquid containing a mixture of vegetable glycerin and propylene glycol (VG/PG) with or without nicotine. Exposure to the nicotine-containing aerosol resulted in clinically-relevant levels of plasma cotinine, a nicotine-derived metabolite, and an increase in the pro-inflammatory cytokines IL-17A, CXCL1, and MCP-1 in the distal airspaces. Following the e-cigarette exposure, mice were intranasally inoculated with influenza A virus (H1N1 PR8 strain). Exposure to aerosols generated from VG/PG with and without nicotine caused greater influenza-induced production in the distal airspaces of the pro-inflammatory cytokines IFN-γ, TNFα, IL-1β, IL-6, IL-17A, and MCP-1 at 7 days post inoculation (dpi). Compared to the aerosolized carrier VG/PG, in mice exposed to aerosolized nicotine there was a significantly lower amount of Mucin 5 subtype AC (MUC5AC) in the distal airspaces and significantly higher lung permeability to protein and viral load in lungs at 7 dpi with influenza. Additionally, nicotine caused relative downregulation of genes associated with ciliary function and fluid clearance and an increased expression of pro-inflammatory pathways at 7 dpi. These results show that (1) the e-liquid carrier VG/PG increases the pro-inflammatory immune responses to viral pneumonia and that (2) nicotine in an e-cigarette aerosol alters the transcriptomic response to pathogens, blunts host defense mechanisms, increases lung barrier permeability, and reduces viral clearance during influenza infection. In conclusion, acute exposure to aerosolized nicotine can impair clearance of viral infection and exacerbate lung injury, findings that have implications for the regulation of e-cigarette products.

Although vitamin E acetate (VEA) is suspected to play a causal role in the development of electronic-cigarette, or vaping, product use-associated lung injury (EVALI), the underlying biological mechanisms of pulmonary injury are yet to be determined. In addition, no study has replicated the systemic inflammation observed in humans in a murine EVALI model, nor investigated potential additive toxicity of viral infection in the setting of exposure to vaping products. To identify the mechanisms driving VEA-related lung injury and test the hypothesis that viral infection causes additive lung injury in the presence of aerosolized VEA, we exposed mice to aerosolized VEA for extended times, followed by influenza infection in some experiments. We used mass spectrometry to evaluate the composition of aerosolized VEA condensate and the VEA deposition in murine or human alveolar macrophages. Extended vaping for 28 days versus 15 days did not worsen lung injury but caused systemic inflammation in the murine EVALI model. Vaping plus influenza increased lung water compared with virus alone. Murine alveolar macrophages exposed to vaped VEA hydrolyzed the VEA to vitamin E with evidence of oxidative stress in the alveolar space and systemic circulation. Aerosolized VEA also induced cell death and chemokine release and reduced efferocytotic function in human alveolar macrophages in vitro. These findings provide new insights into the biological mechanisms of VEA toxicity.

Electronic cigarettes (e-cigarettes) are designed to simulate combustible cigarette smoking and to aid in smoking cessation. Although the number of e-cigarette users has been increasing, the potential health impacts and biological effects of e-cigarettes are still not fully understood. Previous research has focused on the biological effects of e-cigarettes on lung cancer cell lines and distal airway epithelial cells; however, there have been few published studies on the effect of e-cigarettes on primary lung alveolar epithelial cells. The primary purpose of this study was to investigate the direct effect of e-cigarette aerosol on primary human lung alveolar epithelial type 2 (AT2) cells, both alone and in the presence of viral infection. The Melo-3 atomizer caused direct AT2 cell toxicity, whereas the more popular Juul pod's aerosol did not have a detectable cytotoxic effect on AT2 cells. Juul nicotine aerosol also did not increase short-term susceptibility to viral infection. However, 3 days of exposure upregulated genes central to the generation of reactive oxygen species, lipid peroxidation, and carcinogen metabolism and downregulated key innate immune system genes related to cytokine and chemokine signaling. These findings have implications for the potentially injurious impact of long-term use of popular low-power e-cigarette pods on the human alveolar epithelium. Gene expression data might be an important endpoint for evaluating the potential harmful effects of vaping devices that do not cause overt toxicity.

Rationale: Cigarette smoke exposure is associated with an increased risk of developing acute respiratory distress syndrome (ARDS) in trauma, transfusion, and nonpulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if patients with ARDS have differences in underlying biology based on smoking status. Objectives: To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. Methods: We studied a prospective cohort of 592 patients with sepsis from 2009 to 2017. Plasma cotinine and urine NNAL [urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. Measurements and Main Results: Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Among patients with sepsis and ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. Patients with ARDS with cigarette smoke exposure had lower plasma levels of IL-8 (P = 0.01) and sTNFR-1 (soluble tumor necrosis factor 1; P = 0.01) compared with those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. Conclusions: Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and nonpulmonary sepsis. Among patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared with nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.

RATIONALE Cigarette smoke exposure is associated with an increased risk of developing ARDS in trauma, transfusion, and non-pulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if ARDS patients have differences in underlying biology based on smoking status. OBJECTIVES To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. METHODS We studied a prospective cohort of 592 septic patients from 2009 - 2017. Plasma cotinine and urine NNAL were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. MEASUREMENTS AND MAIN RESULTS Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Amongst septic patients with ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. ARDS patients with cigarette smoke exposure had lower plasma levels of IL-8 (p = 0.01) and sTNFR-1 (p = 0.01) compared to those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. CONCLUSIONS Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and non-pulmonary sepsis. Amongst patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared to nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.

Influenza remains a major cause of death and disability with limited treatment options. Studies of acute lung injury have identified angiopoietin-2 (Ang-2) as a key prognostic marker and a potential mediator of Acute respiratory distress syndrome. However, the role of Ang-2 in viral pneumonia remains poorly defined. This study characterized the time course of lung Ang-2 expression in severe influenza pneumonia and tested the therapeutic potential of Ang-2 inhibition. We inoculated adult mice with influenza A (PR8 strain) and measured angiopoietin-1 (Ang-1), Ang-2, and Tie2 expressions during the evolution of inflammatory lung injury over the first 7 days post-infection (dpi). We tested a peptide-antibody inhibitor of Ang-2, L1-7, administered at 2, 4, and 6 dpi and measured arterial oxygen saturation, survival, pulmonary edema, inflammatory cytokines, and viral load. Finally, we infected primary human alveolar type II epithelial (AT2) cells grown in air-liquid interface culture with influenza and measured Ang-2 RNA expression. Influenza caused severe lung injury between 5 and 7 dpi in association with increased Ang-2 lung RNA and a dramatic increase in Ang-2 protein in bronchoalveolar lavage. Inhibition of Ang-2 improved oxygenation and survival and reduced pulmonary edema and alveolar-capillary barrier permeability to protein without major effects on inflammation or viral load. Finally, influenza increased the expression of Ang-2 RNA in human AT2 cells. The increased Ang-2 levels in the airspaces during severe influenza pneumonia and the improvement in clinically relevant outcomes after Ang-2 antagonism suggest that the Ang-1/Ang-2 Tie-2 signaling axis is a promising therapeutic target in influenza and potentially other causes of viral pneumonia.

Resolution of the acute respiratory distress syndrome (ARDS) from pneumonia requires repair of the injured lung endothelium and alveolar epithelium, removal of neutrophils from the distal airspaces of the lung, and clearance of the pathogen. Previous studies have demonstrated the importance of specialized proresolving mediators (SPMs) in the regulation of host responses during inflammation. Although ARDS is commonly caused by Streptococcus pneumoniae, the role of lipoxin A4 (LXA4) and resolvin D1 (RvD1) in pneumococcal pneumonia is not well understood. In the present experimental study, we tested the hypothesis that endogenous SPMs play a role in the resolution of lung injury in a clinically relevant model of bacterial pneumonia. Blockade of formyl peptide receptor 2 (ALX/FPR2), the receptor for LXA4 and RvD1, with the peptide WRW4 resulted in more pulmonary edema, greater protein accumulation in the air spaces, and increased bacteria accumulation in the air spaces and the blood. Inhibition of this receptor was also associated with decreased levels of proinflammatory cytokines. Even in the presence of antibiotic treatment, WRW4 inhibited the resolution of lung injury. In summary, these experiments demonstrated two novel findings: LXA4 and RvD1 contribute to the resolution of lung injury due to pneumococcal pneumonia, and the mechanism of their benefit likely includes augmenting bacterial clearance and reducing pulmonary edema via the restoration of lung alveolar-capillary barrier permeability.

Background: We reported that permeability of cultured microvascular endothelial cells is increased by incubation in e-cigarette (e-cig) users’ serum relative to that from smokers or non-users. It is unclear whether this is a direct effect of aerosol chemicals that reach the circulation, or an indirect response mediated by the e-cig users’ pulmonary epithelium. Hypothesis: Vaping increases microvascular endothelial permeability indirectly by signaling from alveolar epithelium. Methods: E-cig aerosol condensates were derived from e-liquids with and without nicotine (12 mg/mL free base), each containing menthol, vanillin, ethyl maltol, or cinnamaldehyde (2 mg/mL). Cell permeability was measured in human lung microvascular endothelial cells (HMVEC-Ls) using electric cell-substrate impedance sensing. Human Type II lung alveolar epithelial cells (ATII) were grown in serum-free air-liquid interface and exposed to e-cig aerosols with 0, 18, or 36 mg/mL nicotine (free base and salt), or air, 1 h/day for 3 days in an exposure chamber inside a CO 2 incubator. Results: Incubation of HMVEC-Ls with 0.3% v/v e-cig aerosol condensates from most e-liquids, with and without nicotine, decreased cell permeability (in contrast to the increased permeability that we reported from incubation with e-cig user serum). The exception was menthol + nicotine, which increased permeability (but reduced viability). When HMVEC-Ls were instead incubated with supernatant collected from ATII cells after exposure to e-cig aerosols, permeability was increased when supernatants were from exposure to aerosol with 36 mg/ml nicotine salt, but not 36 or 18 mg/mL freebase nicotine. Supernatants from similarly exposed ATII cells contained higher levels of the proinflammatory proteins MCP-1, IL-8, GROα, and MIP-1β when aerosol contained 36 mg/mL freebase nicotine (3/6 wells) or nicotine salt (5/6), but not 18 mg/ml nicotine (0/6). Conclusion: HVMEC-L permeability was not directly increased by e-cig aerosol condensate, but was increased by supernatant of alveolar epithelial cells exposed to high-nicotine aerosol, potentially mediated by elevated ATII cytokine production, indicating a potential indirect mechanism by which vaping increases pulmonary microvascular permeability.

Electronic-cigarette, or vaping, product use-associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, BAL analysis, histology, and inflammatory cytokines; in vitro outcomes included cell death, cytokine release, cellular uptake of VEA, and gene-expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared with control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.

In The Lancet Respiratory Medicine, Kollengode Ramanathan and colleagues1Ramanathan K Antognini D Combes A et al.Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases.Lancet Respir Med. 2020; (published online March 20.)https://doi.org/10.1016/S2213-2600(20)30121-1Summary Full Text Full Text PDF PubMed Scopus (389) Google Scholar provide excellent recommendations for the use of extracorporeal membrane oxygenation (ECMO) for patients with respiratory failure from acute respiratory distress syndrome (ARDS) secondary to coronavirus disease 2019 (COVID-19). The authors describe pragmatic approaches to the challenges of delivering ECMO to patients with COVID-19, including training health-care personnel, resolving equipment and facilities issues, implementing systems for infection control and personal protection, providing overall support for health-care staff, and mitigating ethical issues. They also address some of the anticipated challenges with local and regional surges in COVID-19 ARDS cases; although there has been an increase in hospitals with the capacity to provide ECMO, the potential demand might exceed the available resources. Furthermore, some health-care systems offer advanced therapies such as ECMO but lack a coordinated local, regional, or national referral protocol. Given the practical constraints on substantially increasing the global availability of ECMO services in the next few months, it is important to emphasise the other evidence-based treatment options that can be provided for patients with severe ARDS from COVID-19 (figure).2Fielding-Singh V Matthay MA Calfee CS Beyond low tidal volume ventilation: treatment adjuncts for severe respiratory failure in acute respiratory distress syndrome.Crit Care Med. 2018; 46: 1820-1831Crossref PubMed Scopus (36) Google Scholar Before endotracheal intubation, it is important to consider a trial of high-flow nasal oxygen for patients with moderately severe hypoxaemia. This procedure might avoid the need for intubation and mechanical ventilation because it provides high concentrations of humidified oxygen, low levels of positive end-expiratory pressure, and can facilitate the elimination of carbon dioxide.4Frat J-P Thille AW Mercat A et al.High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure.N Engl J Med. 2015; 372: 2185-2196Crossref PubMed Scopus (1563) Google Scholar WHO guidelines support the use of high-flow nasal oxygen in some patients, but they urge close monitoring for clinical deterioration that could result in the need for emergent intubations because such procedures might increase the risk of infection to health-care workers.5WHOInfection prevention and control during health care when novel coronavirus (nCoV) infection is suspected: interim guidance.https://apps.who.int/iris/rest/bitstreams/1266296/retrieveDate: 2020Date accessed: March 13, 2020Google Scholar For patients with COVID-19 who require endotracheal intubation, use of low tidal volume (6 mL/kg per predicted bodyweight) with a plateau airway pressure of less than 30 cm H2O, and increasing the respiratory rate to 35 breaths per min as needed, is the mainstay of lung-protective ventilation. If the hypoxaemia progresses to a PaO2:FiO2 ratio of less than 100–150 mm Hg, there are several therapeutic options. The level of positive end-expiratory pressure can be increased by 2–3 cm H2O every 15–30 min to improve oxygen saturation to 88–90%, with the goal of maintaining a plateau airway pressure of less than 30 cm H2O. Lower driving pressures (plateau airway pressure minus positive end-expiratory pressure) with a target of 13–15 cm H2O can also be used. If the patient is not responding to adjustment of the level of positive end-expiratory pressure, additional strategies might stabilise them. Recruitment manoeuvres probably have little value,6Sahetya SK Brower RG Lung recruitment and titrated PEEP in moderate to severe ARDS: is the door closing on the open lung?.JAMA. 2017; 318: 1327-1329Crossref PubMed Scopus (42) Google Scholar but moderate pressures of approximately 30 cm H2O for 20–30 s can be applied in the presence of a physician to monitor haemodynamics. If there is no improvement in oxygenation or driving pressure, or if the patient develops hypotension or barotrauma, the recruitment manoeuvres should be discontinued. If there is considerable dyssynchrony with positive pressure ventilation, accompanied by increased plateau airway pressures and refractory hypoxaemia, then deep sedation should be used followed by prompt institution of neuromuscular blockade with cisatracurium. Additionally, prone positioning should be instituted, unless there is a specific contraindication, and can be initiated along with the interventions already described. For persistent refractory hypoxaemia even with prone positioning, neuromuscular blockade, and efforts to optimise positive end-expiratory pressure therapy, there are additional options. Inhaled 5–20 ppm NO might improve oxygenation. Insertion of an oesophageal balloon to measure transpulmonary pressures to set an optimal positive end-expiratory pressure can be considered in patients with moderate-to-severe obesity, although a 2019 trial in patients with ARDS did not show the benefit of this procedure in most patients.7Beitler JR Sarge T Banner-Goodspeed VM et al.Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure-guided strategy vs an empirical high PEEP-FiO2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial.JAMA. 2019; 321: 846-857PubMed Google Scholar Fluid management is important to consider as a measure to reduce pulmonary oedema.8Wiedemann HP Wheeler AP Bernard GR et al.Comparison of two fluid-management strategies in acute lung injury.N Engl J Med. 2006; 354: 2564-2575Crossref PubMed Scopus (2847) Google Scholar In the absence of shock, fluid conservative therapy is recommended to achieve a negative fluid balance of 0·5 to 1·0 L per day. In the presence of shock, fluid balance might be achieved with renal replacement therapy, especially if there is associated acute kidney injury and oliguria. Antibiotics should be considered since secondary bacterial infections have been reported in patients with COVID-19.9Huang C Wang Y Li Y et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Summary Full Text Full Text PDF PubMed Scopus (32861) Google Scholar Glucocorticoids should be avoided in view of the evidence that they can be harmful in cases of viral pneumonia and ARDS from influenza.10Ni Y-N Chen G Sun J Liang B-M Liang Z-A The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis.Critical Care. 2019; 23: 99Crossref PubMed Scopus (276) Google Scholar Rescue therapy with high-dose vitamin C can also be considered.11Fowler AA Truwit JD Hite RD et al.Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial.JAMA. 2019; 322: 1261-1270Crossref PubMed Scopus (566) Google Scholar Finally, ECMO should be considered using the inclusion and exclusion criteria of the EOLIA trial.3Combes A Hajage D Capellier G et al.Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.N Engl J Med. 2018; 378: 1965-1975Crossref PubMed Scopus (1426) Google Scholar Since treatment of severe ARDS from COVID-19 is an ongoing challenge, it is important to learn from the patients who have been treated to gain an understanding of the disease's epidemiology, biological mechanisms, and the effects of new pharmacological interventions. Currently, there are some research groups working to coordinate and disseminate key information, including information on patients who have been treated with ECMO for COVID-19, although an accurate estimate of the number of such patients is not currently available. The Extracorporeal Life Support Organization is an international non-profit consortium that plans to maintain a registry of patients to facilitate an improved understanding of how ECMO is being used for patients with COVID-19. MAM reports grants from the National Institutes of Health—the National Heart, Lung and Blood Institute, the US Food and Drug Administration, the US Department of Defense, Bayer Pharmaceuticals, Genentech-Roche, and personal fees from Gen1e Life Sciences, outside of the submitted work. JMA has done been part of the electronic medical records committee of the Society of Critical Care Medicine, outside of the submitted work. JEG declares no competing interests. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseasesWHO interim guidelines recommend offering extracorporeal membrane oxygenation (ECMO) to eligible patients with acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). The number of patients with COVID-19 infection who might develop severe ARDS that is refractory to maximal medical management and require this level of support is currently unknown. Available evidence from similar patient populations suggests that carefully selected patients with severe ARDS who do not benefit from conventional treatment might be successfully supported with venovenous ECMO. Full-Text PDF

Electronic cigarettes (e-cigarettes) are alternative, non-combustible tobacco products that generate an inhalable aerosol containing nicotine, flavors, propylene glycol, and vegetable glycerin. Vaping is now a multibillion dollar industry that appeals to current smokers, former smokers, and young people who have never smoked. E-cigarettes reached the market without either extensive preclinical toxicology testing or long term safety trials that would be required of conventional therapeutics or medical devices. Their effectiveness as a smoking cessation intervention, their impact at a population level, and whether they are less harmful than combustible tobacco products are highly controversial. Here, we review the evidence on the effects of e-cigarettes on respiratory health. Studies show measurable adverse biologic effects on organ and cellular health in humans, in animals, and in vitro. The effects of e-cigarettes have similarities to and important differences from those of cigarettes. Decades of chronic smoking are needed for development of lung diseases such as lung cancer or chronic obstructive pulmonary disease, so the population effects of e-cigarette use may not be apparent until the middle of this century. We conclude that current knowledge of these effects is insufficient to determine whether the respiratory health effects of e-cigarette are less than those of combustible tobacco products.

Editorial FocusElectronic Cigarettes: Not All Good News?High-power vaping injures the human lungJeffrey E. GottsJeffrey E. GottsDepartment of Medicine, Cardiovascular Research Institute, University of California, San Francisco, CaliforniaPublished Online:17 Apr 2019https://doi.org/10.1152/ajplung.00099.2019This is the final version - click for previous versionMoreSectionsPDF (42 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Electronic cigarettes aerosolize e-liquids, mixtures of vegetable glycerin (VG), propylene glycol (PG), nicotine, and flavorings, with a heated metal coil. Since their introduction in the early 21st century, e-cigarettes have increased dramatically in popularity and have undergone technological evolution in multiple directions, becoming a multibillion-dollar industry. The variety of devices and e-liquids available in vape shops and online is extraordinary, presenting formidable challenges to scientists, health care practitioners, and policymakers.Most of the research testing for potential negative health effects of e-cigarettes has been performed using cell culture and rodent models (3, 13). These studies have demonstrated that e-cigarette aerosol can produce inflammation in the lung and have negative effects on endothelial, epithelial, and immune lung cells (4, 9, 10, 12, 16). Survey studies in humans have been suggestive of acute airway inflammation although spirometry has not yielded consistent evidence of airflow obstruction (13). More recent studies have identified inflammatory changes in the sputum (14) and bronchial epithelium (8) of vapers. To date, no experimental human study has produced evidence of e-cigarette-mediated impairment of gas exchange.In this issue of the American Journal of Physiology-Lung Cellular and Molecular Physiology, Chaumont and colleagues (2) report the results of two small controlled studies of the acute pulmonary effects of e-cigarette aerosol generated by a high-power (60 W), low-resistance (0.4 Ω, i.e., sub-ohm) atomizer. In the first study, healthy young occasional smokers underwent each of three exposure conditions separated by a week in a within-subjects design: sham vaping, VG/PG, and VG/PG/nicotine 3 mg/ml. Puffing topography was tightly controlled during each session lasting ~15 min, and outcomes included transcutaneous tension of O2 (TcpO2), CO2 (TcpCO2), and pulmonary function testing before and after the exposure. Remarkably, TcpO2 dropped by 15 mmHg and 20 mmHg 10 min after exposure to the aerosol from VG/PG or VG/PG/nicotine, respectively. Expiratory gas flow at low lung volumes and the ratio of FEV1 to FVC were also significantly decreased by VG/PG compared with sham vaping. Finally, the level of CC16, a protein secreted into the airspace by Clara cells near terminal bronchioles, was significantly increased in the serum of both aerosol-exposed groups. Remarkably, the level of CC16 in the serum was predictive of the drop in TcpO2 after vaping VG/PG.In the second study, 24 smokers undergoing coronary angiography (average age 54, mean 34 pack-years smoking) were randomized to sham vaping or VG/PG, and outcomes included TcpO2, TcpCO2, pulse oximetry, and arterial blood gas analysis. Nicotine was not used in this study due to the concern for negative cardiac effects. As in the first study, vaping VG/PG at 60 W compared with sham vaping decreased TcpO2. The presence of arterial catheters permitted serial blood gas analysis and calculation of the alveolar-arterial oxygen gradient, which was increased by VG/PG compared with sham vaping 5 min after the exposure.Strengths of the experimental approach include standardization of the atomizer, e-liquids, and puffing topography and inclusion of multiple clinically important end points. The use of transcutaneous oximetry in the first study permitted repetitive noninvasive measurement of oxygen flux with higher sensitivity than pulse oximetry. Although this technology makes several assumptions, the use of arterial blood sampling in the second study provides strong corroboration of the oximetry results. Limitations of the experimental design include the use of a single, short duration exposure, the exclusion of flavoring compounds, the lack of blinding of the subjects, and the focus on a single type of atomizer. However, taken in aggregate the results of these two small studies strongly suggest that e-cigarette aerosol with or without nicotine generated from high-power vaping conditions causes acute injury to the small airways of the lung, resulting in impaired gas exchange. Although the experimental design addressed a fairly limited question, the authors are to be congratulated on raising the bar for controlled experimental human studies in this field.E-cigarettes aerosolize nicotine either by using a high power/high coil temperature with a low concentration of e-liquid nicotine (3 mg/ml in the case of the 60 W device in these experiments) or by using a low power/low coil temperature with a high concentration of e-liquid nicotine. Under higher coil temperatures, atomizers release greater quantities of volatile carbonyl compounds with known toxicity, including formaldehyde (11). The use of very high power (125 W) with sub-ohm devices was recently shown to liberate large amounts of carbon monoxide, with important interactions with the type of metal used in the coil (5). Thus the finding that high-power vaping is toxic to the human lung is consistent with a rapidly growing body of cell culture and animal studies. Accordingly, a reasonable hypothesis would be that lower power atomizers are likely to have less pulmonary toxicity.Until recently the delivery of nicotine to users with the low-power devices was limited by unpleasant sensations in the throat caused by high nicotine concentrations. However, it is now known that lowering the pH of the e-liquid with so-called "nicotine salts," as JUUL has achieved with the addition of benzoic acid, markedly increases the tolerance of vapers to very high e-liquid nicotine concentrations, at and above 50 mg/ml. Although it is commonly believed that nicotine itself is not toxic to the lung, direct evidence of the safety of inhaled nicotine in humans is lacking. Indeed, there is a substantial literature implicating nicotine in disrupting lung development in animal models and humans (6). More recently, researchers have demonstrated that adult mice exposed for several months to nicotine-containing (but not nicotine-free) e-liquid aerosols had increased airway and alveolar cell death and airspace enlargement (7). Similar results have also been reported in rats (15) with nicotine-containing aerosol. Earlier this year in the Journal of Physiology, Ahmad and colleagues (1) described a novel exposure system to aerosolize nicotine in saline (rather than in vg/pg) at 50 or 100 mg/ml, reporting that just 15 min of nose-only exposure increased alveolar-capillary permeability, lung edema, and inflammatory lung cytokines. Thus animal studies in multiple species are consistent with nicotine having direct pulmonary toxicity.The tradeoff between nicotine concentration and coil power is central to the ongoing debate over regulating these devices. If regulatory agencies lower the maximum nicotine concentration, many users will switch to higher power devices, likely increasing their exposure to toxic compounds. Meanwhile, the safety of e-liquids with very high nicotine concentrations in various salt formulations remains unknown. Against the backdrop of rapid product evolution and the explosion of youth use, the scientific community must focus on the rigorous and timely study of the cardiovascular, respiratory, and other health effects caused by these devices in all their variety.GRANTSThis work was supported by National Heart, Lung, and Blood Institute Grant U54 HL-147127.DISCLAIMERSThe content is solely the responsibility of the author and does not necessarily represent the official views of the NIH or the Food and Drug Administration.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.AUTHOR CONTRIBUTIONSJ.E.G. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.REFERENCES1. Ahmad S, Zafar I, Mariappan N, Husain M, Wei C-C, Vetal N, Eltoum IA, Ahmad A. Acute pulmonary effects of aerosolized nicotine. Am J Physiol Lung Cell Mol Physiol 316: L94–L104, 2019. doi:10.1152/ajplung.00564.2017. Link | ISI | Google Scholar2. Chaumont M, van de Borne P, Bernard A, Van Muylem A, Deprez G, Ullmo J, Starczewska E, Briki R, de Hemptinne Q, Zaher W, Debbas N. Fourth generation e-cigarette vaping induces transient lung inflammation and gas exchange disturbances: results from two randomized clinical trials. Am J Physiol Lung Cell Mol Physiol. In press. doi:10.1152/ajplung.00492.2018. Link | ISI | Google Scholar3. Chun LF, Moazed F, Calfee CS, Matthay MA, Gotts JE. Pulmonary toxicity of e-cigarettes. Am J Physiol Lung Cell Mol Physiol 313: L193–L206, 2017. doi:10.1152/ajplung.00071.2017. Link | ISI | Google Scholar4. Clapp PW, Lavrich KS, van Heusden CA, Lazarowski ER, Carson JL, Jaspers I. Cinnamaldehyde in flavored e-cigarette liquids temporarily suppresses bronchial epithelial cell ciliary motility by dysregulation of mitochondrial function. Am J Physiol Lung Cell Mol Physiol 316: L470–L486, 2019. doi:10.1152/ajplung.00304.2018. Link | ISI | Google Scholar5. El-Hellani A, Al-Moussawi S, El-Hage R, Talih S, Salman R, Shihadeh A, Saliba NA. Carbon monoxide and small hydrocarbon emissions from sub-ohm electronic cigarettes. Chem Res Toxicol 32: 312–317, 2019. doi:10.1021/acs.chemrestox.8b00324. Crossref | PubMed | ISI | Google Scholar6. England LJ, Aagaard K, Bloch M, Conway K, Cosgrove K, Grana R, Gould TJ, Hatsukami D, Jensen F, Kandel D, Lanphear B, Leslie F, Pauly JR, Neiderhiser J, Rubinstein M, Slotkin TA, Spindel E, Stroud L, Wakschlag L. Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products. Neurosci Biobehav Rev 72: 176–189, 2017. doi:10.1016/j.neubiorev.2016.11.013. Crossref | PubMed | ISI | Google Scholar7. Garcia-Arcos I, Geraghty P, Baumlin N, Campos M, Dabo AJ, Jundi B, Cummins N, Eden E, Grosche A, Salathe M, Foronjy R. Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner. Thorax 71: 1119–1129, 2016. doi:10.1136/thoraxjnl-2015-208039. Crossref | PubMed | ISI | Google Scholar8. Ghosh A, Coakley RC, Mascenik T, Rowell TR, Davis ES, Rogers K, Webster MJ, Dang H, Herring LE, Sassano MF, Livraghi-Butrico A, Van Buren SK, Graves LM, Herman MA, Randell SH, Alexis NE, Tarran R. Chronic e-cigarette exposure alters the human bronchial epithelial proteome. Am J Respir Crit Care Med 198: 67–76, 2018. doi:10.1164/rccm.201710-2033OC. Crossref | PubMed | ISI | Google Scholar9. Glynos C, Bibli S-I, Katsaounou P, Pavlidou A, Magkou C, Karavana V, Topouzis S, Kalomenidis I, Zakynthinos S, Papapetropoulos A. Comparison of the effects of e-cigarette vapor with cigarette smoke on lung function and inflammation in mice. Am J Physiol Lung Cell Mol Physiol 315: L662–L672, 2018. doi:10.1152/ajplung.00389.2017. Link | ISI | Google Scholar10. Hwang JH, Lyes M, Sladewski K, Enany S, McEachern E, Mathew DP, Das S, Moshensky A, Bapat S, Pride DT, Ongkeko WM, Crotty Alexander LE. Electronic cigarette inhalation alters innate immunity and airway cytokines while increasing the virulence of colonizing bacteria. J Mol Med (Berl) 94: 667–679, 2016. doi:10.1007/s00109-016-1378-3. Crossref | PubMed | ISI | Google Scholar11. Kosmider L, Sobczak A, Fik M, Knysak J, Zaciera M, Kurek J, Goniewicz ML. Carbonyl compounds in electronic cigarette vapors: effects of nicotine solvent and battery output voltage. Nicotine Tob Res 16: 1319–1326, 2014. doi:10.1093/ntr/ntu078. Crossref | PubMed | ISI | Google Scholar12. Larcombe AN, Janka MA, Mullins BJ, Berry LJ, Bredin A, Franklin PJ. The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice. Am J Physiol Lung Cell Mol Physiol 313: L67–L79, 2017. doi:10.1152/ajplung.00203.2016. Link | ISI | Google Scholar13. National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Public Health Consequences of E-Cigarettes, edited by Eaton DL, Kwan LY, Stratton K. Washington, DC: National Academies Press. https://www.ncbi.nlm.nih.gov/books/NBK507171/ [10 Nov. 2018].Google Scholar14. Reidel B, Radicioni G, Clapp PW, Ford AA, Abdelwahab S, Rebuli ME, Haridass P, Alexis NE, Jaspers I, Kesimer M. E-cigarette use causes a unique innate immune response in the lung, involving increased neutrophilic activation and altered mucin secretion. Am J Respir Crit Care Med 197: 492–501, 2018. doi:10.1164/rccm.201708-1590OC. Crossref | PubMed | ISI | Google Scholar15. Reinikovaite V, Rodriguez IE, Karoor V, Rau A, Trinh BB, Deleyiannis FW, Taraseviciene-Stewart L. The effects of electronic cigarette vapour on the lung: direct comparison to tobacco smoke. Eur Respir J 51: 1701661, 2018. doi:10.1183/13993003.01661-2017. Crossref | PubMed | ISI | Google Scholar16. Schweitzer KS, Chen SX, Law S, Van Demark M, Poirier C, Justice MJ, Hubbard WC, Kim ES, Lai X, Wang M, Kranz WD, Carroll CJ, Ray BD, Bittman R, Goodpaster J, Petrache I. Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures. Am J Physiol Lung Cell Mol Physiol 309: L175–L187, 2015. doi:10.1152/ajplung.00411.2014. Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. E. Gotts, Dept. of Medicine, Cardiovascular Research Institute, UCSF, Moffitt, Room M-917, 505 Parnassus Ave., San Francisco, CA 94143-0624 (e-mail: Jeffrey.[email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation CollectionsAJP-Lung CollectionsElectronic Cigarettes: Not All Good News? Related ArticlesFourth generation e-cigarette vaping induces transient lung inflammation and gas exchange disturbances: results from two randomized clinical trials 17 Apr 2019American Journal of Physiology-Lung Cellular and Molecular PhysiologyCited ByImpact of e-cigarette aerosol on primary human alveolar epithelial type 2 cellsKatherine D. Wick,* Xiaohui Fang,* Mazharul Maishan, Shotaro Matsumoto, Natasha Spottiswoode, Aartik Sarma, Camille Simoneau, Manisha Khakoo, Chaz Langelier, Carolyn S. Calfee, Jeffrey E. Gotts, and Michael A. Matthay9 August 2022 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 323, No. 2VAPIng into ARDS: Acute Respiratory Distress Syndrome and Cardiopulmonary FailurePharmacology & Therapeutics, Vol. 232Toxicology of flavoring- and cannabis-containing e-liquids used in electronic delivery systemsPharmacology & Therapeutics, Vol. 224World No Tobacco Day 2020Claudio Nardiello and Rory E. Morty30 April 2020 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 318, No. 5Asthma without bordersY. S. Prakash30 April 2020 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 318, No. 5Vaping is a risk factor for spontaneous pneumothorax: Two casesJournal of Pediatric Surgery Case Reports, Vol. 50 Press Release E-cigarette Use during Pregnancy Creates Lung Dysfunction in Babies - December 8, 2022 More from this issue > Volume 316Issue 5May 2019Pages L703-L704 Copyright & PermissionsCopyright © 2019 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00099.2019PubMed30838866History Received 28 February 2019 Accepted 28 February 2019 Published online 17 April 2019 Published in print 1 May 2019 Metrics

Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly. the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate. alveolar macrophages in the airspaces, and probably by interstitial pathways. Together. these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.