Gene Therapy for Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome that leads to acute respiratory failure and accounts for over 70,000 deaths per year in the United States alone, even prior to the COVID-19 pandemic. While its molecular details have been teased apart and its pathophysiology largely established over the past 30 years, relatively few pharmacological advances in treatment have been made based on this knowledge. Indeed, mortality remains very close to what it was 30 years ago. As an alternative to traditional pharmacological approaches, gene therapy offers a highly controlled and targeted strategy to treat the disease at the molecular level. Although there is no single gene or combination of genes responsible for ARDS, there are a number of genes that can be targeted for upregulation or downregulation that could alleviate many of the symptoms and address the underlying mechanisms of this syndrome. This review will focus on the pathophysiology of ARDS and how gene therapy has been used for prevention and treatment. Strategies for gene delivery to the lung, such as barriers encountered during gene transfer, specific classes of genes that have been targeted, and the outcomes of these approaches on ARDS pathogenesis and resolution will be discussed.

Airway Closure and Expiratory Flow Limitation in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is mostly characterized by the loss of aerated lung volume associated with an increase in lung tissue and intense and complex lung inflammation. ARDS has long been associated with the histological pattern of diffuse alveolar damage (DAD). However, DAD is not the unique pathological figure in ARDS and it can also be observed in settings other than ARDS. In the coronavirus disease 2019 (COVID-19) related ARDS, the impairment of lung microvasculature has been pointed out. The airways, and of notice the small peripheral airways, may contribute to the loss of aeration observed in ARDS. High-resolution lung imaging techniques found that in specific experimental conditions small airway closure was a reality. Furthermore, low-volume ventilator-induced lung injury, also called as atelectrauma, should involve the airways. Atelectrauma is one of the basic tenet subtending the use of positive end-expiratory pressure (PEEP) set at the ventilator in ARDS. Recent data revisited the role of airways in humans with ARDS and provided findings consistent with the expiratory flow limitation and airway closure in a substantial number of patients with ARDS. We discussed the pattern of airway opening pressure disclosed in the inspiratory volume-pressure curves in COVID-19 and in non-COVID-19 related ARDS. In addition, we discussed the functional interplay between airway opening pressure and expiratory flow limitation displayed in the flow-volume curves. We discussed the individualization of the PEEP setting based on these findings.

Comparison of deep vein thrombosis risks in acute respiratory distress syndrome Caused by COVID-19 and Bacterial Pneumonia: A Retrospective Cohort Study

Background: High incidence of deep vein thrombosis (DVT) has been observed in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 and those by bacterial pneumonia. However, it is also important to differentiate between these two groups of patients. Study Design and Methods: We performed a retrospective cohort study to investigate the difference of DVT between the two independent cohorts of ARDS and eventually enrolled 240 patients, 105 of whom with ARDS caused by COVID-19 and 135 by bacterial pneumonia. We analyzed demographics and clinical characteristics for patients with and without DVT in these two cohorts and explored the main differences and similarities between them.Results: The 28-days incidence of DVT in COVID-19 cohort was higher than that in bacterial pneumonia cohort (57.1% vs 41.5%, P=0.016). Taking death as competitive risk, Fine-Gray test showed no significant difference in 28-day cumulative incidence of DVT between these two groups (P=0.220). Fine-Gray competing risk analysis showed an association between CK (creatine kinase isoenzyme)-MB levels, PaO2 (partial pressure of arterial oxygen)/FiO2 (fraction of inspired oxygen) ratios, D-dimer levels and DVT in COVID-19 cohort and an association between serum creatinine levels, IMV, and DVT in bacterial pneumonia cohort. The sensitivity and specificity of corresponding receiver operating characteristic curve originating from the combination of CK-MB levels, PaO2/FiO2 ratios and D-dimer levels ≥ 0.5 µg/mL was not inferior to those of the Padua prediction score and the Wells score for screening for DVT in COVID-19 cohort.Conclusions: Compared with patients with ARDS caused by bacterial pneumonia, the incidence of DVT is higher by logistic model in patients with ARDS caused by COVID-19, and the risk factors for DVT are completely different. Our novel prediction model can aid early identifying patients with high risk for DVT.

Duration of invasive mechanical ventilation prior to extracorporeal membrane oxygenation is not associated with survival in acute respiratory distress syndrome caused by coronavirus disease 2019

Background Duration of invasive mechanical ventilation (IMV) prior to extracorporeal membrane oxygenation (ECMO) affects outcome in acute respiratory distress syndrome (ARDS). In coronavirus disease 2019 (COVID-19) related ARDS, the role of pre-ECMO IMV duration is unclear. This single-centre, retrospective study included critically ill adults treated with ECMO due to severe COVID-19-related ARDS between 01/2020 and 05/2021. The primary objective was to determine whether duration of IMV prior to ECMO cannulation influenced ICU mortality. Results During the study period, 101 patients (mean age 56 [SD ± 10] years; 70 [69%] men; median RESP score 2 [IQR 1–4]) were treated with ECMO for COVID-19. Sixty patients (59%) survived to ICU discharge. Median ICU length of stay was 31 [IQR 20.7–51] days, median ECMO duration was 16.4 [IQR 8.7–27.7] days, and median time from intubation to ECMO start was 7.7 [IQR 3.6–12.5] days. Fifty-three (52%) patients had a pre-ECMO IMV duration of > 7 days. Pre-ECMO IMV duration had no effect on survival (p = 0.95). No significant difference in survival was found when patients with a pre-ECMO IMV duration of < 7 days (< 10 days) were compared to ≥ 7 days (≥ 10 days) (p = 0.59 and p = 1.0). Conclusions The role of prolonged pre-ECMO IMV duration as a contraindication for ECMO in patients with COVID-19-related ARDS should be scrutinised. Evaluation for ECMO should be assessed on an individual and patient-centred basis.

Evaluation of Continuous Inhaled Epoprostenol in the Treatment of Acute Respiratory Distress Syndrome, Including Patients With SARS-CoV-2 Infection

Background Acute respiratory distress syndrome (ARDS) management is primarily supportive. Pulmonary vasodilators, such as inhaled epoprostenol (iEPO), have been shown to improve PaO2:FiO2 (PF) and are used as adjunctive therapy. Objective To identify the positive response rate and variables associated with response to iEPO in adults with ARDS. A positive response to iEPO was defined as a 10% improvement in PF within 6 hours. Methods This retrospective study included adults with ARDS treated with iEPO. The primary endpoint was the variables associated with a positive response to iEPO. Secondary endpoints were positive response rate and the change in PF and SpO2:FiO2 within 6 hours. Statistical analysis included multivariable regression. Results Three hundred thirty-one patients were included. As baseline PF increased, the odds of responding to iEPO decreased (odds ratio [OR], 0.752, 95% CI, 0.69-0.819, p < 0.001). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related ARDS (OR 0.478, 95% CI, 0.281-0.814, p = 0.007) was associated with decreased odds of a positive response to iEPO. The total population had a 68.3% positive response rate to iEPO. SARS-CoV-2-related ARDS and non-SARS-CoV-2-related ARDS had a 59.5% and 72.7% positive response rate, respectively. iEPO significantly improved PF (71 vs 95, P < 0.001) in the whole population. Conclusion and Relevance iEPO was associated with a positive effect in a majority of moderate-to-severe ARDS patients, including patients with SARS-CoV-2-related ARDS. Lower baseline PF and non-SARS-CoV-2-related ARDS were significantly associated with a positive response to iEPO. The ability to predict which patients will respond to iEPO can facilitate better utilization.

Effects of Transthoracic Echocardiography on the Prognosis of Patients with Acute Respiratory Distress Syndrome: A Propensity Score Matched Analysis of the MIMIC-III Database

Introduction: Acute respiratory distress syndrome (ARDS) has high mortality and is mainly related to the circulatory failure.Therefore, real-time monitoring of cardiac function and structural changes has important clinical significance.Transthoracic echocardiography (TTE) is a simple and noninvasive real-time cardiac examination which is widely used in intensive care unit (ICU) patients.The purpose of this study was to analyze the effect of TTE on the prognosis of ICU patients with ARDS.Methods: The data of ARDS patients were retrieved from the MIMIC-III v1.4 database and patients were divided into the TTE group and non-TTE group. Then, the baseline data were compared between the two groups, and the effect of TTE on the prognosis of ARDS patients was analyzed through multivariate logistic analysis and the propensity score (PS).Results: A total of 1,346 ARDS patients were enrolled, including 519 (38.6%) cases in the TTE group and 827 (61.4%) cases in the non-TTE group. Compared with the non-TTE group, the 28-day mortality of patients in the TTE group was greatly improved (OR=0.64 95%CI: 0.48-0.86, P=0.003). The length of ICU stay in the TTE group was significantly shorter than that in the non-TTE group (17d vs.14d, P=0.0001). The infusion volume in the TTE group was significantly less than that of the non-TTE group (6.2L vs.5.5L on day 1, P=0.0012). Importantly, the patients in the TTE group were weaned ventilators earlier than those in the non-TTE group (ventilator-free days within 28 d: 21 d vs. 19.8 d, respectively, P = 0.071).Conclusion: TTE can lower the risk of 28-d mortality in patients with ARDS.

The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome

Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of Coronavirus Disease 2019 (COVID-19) and an increase in complications including Acute Respiratory Distress Syndrome (ARDS). Due to the lack of therapeutic options for Acute Respiratory Distress Syndrome, recent attention has focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help define effective therapeutic strategies. Interleukin 8 (IL-8) is a pro-inflammatory cytokine that has a role in neutrophil activation and has been identified within the pathogenesis and progression of this disease. The aim of this review is to highlight the role of IL-8 as a biomarker and prognostic factor in modulating the hyperinflammatory response in ARDS. The crucial role of IL-8 in lung inflammation and disease pathogenesis might suggest IL-8 as a possible new therapeutic target to efficiently modulate the hyperinflammatory response in ARDS.