Genetic Polymorphisms Associated With Susceptibility and Outcome in ARDS

The reported association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the risk for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains controversial despite the publication of four meta-analyses on this topic. Here, we updated the meta-analysis with more studies and additional assessments that include adults and children within the context of the coronavirus disease 2019 (COVID-19) pandemic.

Sixteen articles (22 studies) were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using three genetic models (allele, recessive and dominant), in which ARDS patients were compared with non-ARDS patients (A1) and healthy controls (A2). Mortality outcomes were also assessed (A3). The influence of covariates was examined by meta-regression. Bonferroni correction was performed for multiple pooled associations. Subgroup analyses based on ethnicity (Asians, Caucasians) and life stage (adults, children) were conducted. Heterogeneity was addressed with outlier treatment.

This meta-analysis generated 68 comparisons, 21 of which were significant. Of the 21, four A1 and three A3 highly significant (P^a = 0.00001–0.0008) outcomes withstood Bonferroni correction. For A1, allele and recessive associations were found in overall (OR 0.49, 95% CI 0.39–0.61), Caucasians (OR 0.46, 95% CI 0.35–0.61) and children (ORs 0.49–0.66, 95% CI 0.33–0.84) analyses. For A3, associations were found in overall (dominant: OR 0.45, 95% CI 0.29–0.68) and Asian subgroup (allele/ dominant: ORs 0.31–0.39, 95% CIs 0.18–0.63) analyses. These outcomes were either robust, or statistically powered or both and uninfluenced by covariates.

Significant associations of the ACE I/D polymorphism with the risk of ALI/ARDS were indicated in Caucasians and children as well as in Asians in mortality analysis. These findings were underpinned by high significance, high statistical power and robustness. ACE genotypes may be useful for ALI/ARDS therapy for patients with COVID-19.

Sepsis, pneumonia, and shock are the most common conditions predisposing to acute respiratory distress syndrome (ARDS) and certain host genetic variants have been associated with the development of ARDS. Risk modifiers include abuse of alcohol and tobacco, malnutrition, and obesity. The Lung Injury Prediction Score (LIPS) and the simplified Early Acute Lung Injury Score predict ARDS based on clinical and investigational criteria. Hospital-acquired ARDS may result from a medley factors of which high tidal volume ventilation, high oxygen concentration, and plasma transfusion are most commonly implicated. The Checklist for Lung Injury Prevention (CLIP) has been developed to ensure compliance with evidence-based practice that may affect ARDS occurrence. To date, no pharmacologic intervention has been shown to prevent ARDS

Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury, characterized by acute pulmonary infiltrates, abnormal respiratory system compliance, and moderate to severe hypoxemia. The etiology of ARDS is either direct (e.g., pneumonia) or indirect (e.g., sepsis) insult to the lungs by various inflammatory mediators. The definition of ARDS has evolved over time from the earlier description by Ashbaugh in 1967 to a major revision in 1994 by the North American-European Consensus conference committee (NAECC) to the most recent Berlin definition in 2012. In 2015 a panel of investigators recommended adopting the Berlin definition in children (PARDS, pediatric acute respiratory distress syndrome) with some modifications. The pathophysiology is complex with an inflammatory process starting at the alveolar capillary interface with resultant endothelial and epithelial disruption leading to increased alveolar capillary permeability and flooding of the alveoli with protein rich edema fluid. ARDS is a progressive disease with four stages (exudative, fibroproliferative, fibrosing alveolitis, and recovery stage). Not every patient goes through all stages, and whether children go through similar stages to adults is not clear. Despite significant advancement in critical care, mortality in severe ARDS remains high, especially in immunocompromised children. Mechanical ventilation, while protecting the lungs from iatrogenic injuries using lung protection strategies, is the mainstay of treatment of ARDS. The employment of adjuvant treatment with corticosteroids, prone positioning, exogenous surfactant, or nitric oxide administration has not been proven to be beneficial in randomized trials, and these are used in selected patients according to clinician or center preferences. Extracorporeal membrane oxygenation offers hope in certain patients with refractory ARDS.

To establish the contribution of genetic host factors to the risk of community-acquired pneumonia (CAP) and nosocomial pneumonia (NP) in the population of the Russian Federation.

A total of 796 subjects (CAP: 334 patients, 134 controls; NP: 216 critically ill patients with NP, 105 critically ill patients without NP) were included in two case–control studies. We analyzed 13 polymorphisms in 11 genes (IL-6, TNF-α, MBL2, CCR5, NOS3, CYP1A1 (three sites), GSTM1, GSTT1, ABCB1, ACE, and MTHFR) using a tetra-primer allele-specific PCR method.

Individual single nucleotide polymorphism (SNP) analysis revealed a strong association between CYP1A1 rs2606345 and CAP (p = 3.9 × 10⁻⁵, odds ratio (OR) 0.42, 95% confidence interval (CI) 0.27–0.63). Three genes (CYP1A1, ACE, and IL-6) were identified that account for part of the increase in vulnerability to both diseases, CAP and NP. The carriage of three predisposing genotypes versus protective genotypes increased the CAP risk (p = 0.001, OR 7.01, 95% CI 1.99–24.70) and NP risk (p = 0.028, OR 4.34, 95% CI 1.15–16.45).

Genetic predisposition to CAP and NP is attributed to the cumulative contribution of polymorphisms at the CYP1A1, IL-6, and ACE genes, independently of age, gender, causative pathogen, and the use of mechanical ventilation, in patients in the Russian Federation.