Hospitalization Outcomes for COVID-19 in Patients with Interstitial Lung Disease: A Potential Role for Aerodigestive Pathophysiology?

To the Editor:

We congratulate Drake and colleagues for their timely, international multicenter study of outcomes of hospitalization for coronavirus disease (COVID-19) in people with interstitial lung disease (ILD) (1). This found that 161 people with ILD were at increased risk of death compared with 322 propensity score–matched control subjects. The comparison group, people without ILD, or other chronic lung disease, was obtained from the valuable ISARIC 4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterization Consortium) cohort. People with ILD and COVID-19 had higher mortality (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.17–2.18; P = 0.003) compared with control subjects, with the greatest risk in idiopathic pulmonary fibrosis (IPF) (HR, 1.74; 95% CI, 1.16–2.60; P = 0.007). Furthermore, obese people with ILD had an elevated risk of death (HR, 2.27; 95% CI, 1.39−3.71).

Gastroesophageal reflux disease (GERD) is linked with obesity and is an important comorbidity in many chronic lung diseases (2) including ILD (3) before and after lung transplantation. The link between IPF and GERD has been identified as a research priority. GERD appears to be common in IPF, the largest ILD subgroup studied by Drake and colleagues, and GERD may be associated with adverse IPF outcomes.

GERD treatment in IPF ranges from conservative clinical strategies such as antacid strategies to consideration of surgical fundoplication (3). Conditional recommendations for treatment are incorporated into IPF current guidelines, and treatment with proton pump inhibitors (PPIs) is very common (3).

Excess lower respiratory tract infections are described as a concern in people prescribed PPIs. Prospective data are limited in ILD, but in a rare pilot randomized study of omeprazole therapy in IPF, there was a small excess of lower respiratory tract infections (4). We have also previously found that viable fungal and bacterial microorganisms can be isolated from gastric juice in people with lung disease, and in people without lung disease, when pH exceeds 4. Stomach acid may be considered an important element of gastric homeostasis and overall microbiological defense.

With regard to viral infection, PPIs are a putative risk for influenza, rotavirus, and Middle East respiratory syndrome coronavirus infection. In stringent mRNA and protein expression studies, one of the highest expression sites for angiotensin-converting enzyme 2 protein, a key protein involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host cell entry, leading to COVID-19, is the upper gastrointestinal tract. An increased, dose-dependent risk of COVID-19 has recently been shown, among PPI users, in a substantial North American study of 53,130 people in which 3,386 reported a positive COVID-19 test (5). Regression analysis showed that individuals using PPIs up to once a day (odds ratio, 2.15; 95% CI, 1.90–2.44) or twice daily (odds ratio, 3.67; 95% CI, 2.93–4.60) had significant, PPI dose response–associated, increased odds for reporting a positive COVID-19 test (5). A Korean nationwide cohort study with propensity score matching studied a potential role for PPIs as a risk in severe COVID-19, including 132,316 people tested for SARS-CoV-2. In confirmed COVID-19, the current use of PPIs conferred a 79% greater risk of severe clinical outcomes (6).

We suggest that PPI treatment may have been taken by many of the people with IPF in the study from Drake and colleagues, with the potential that the control group systematically had less exposure. We wonder if the authors were able to consider this in their analyses or have data that might inform this. We would be very interested in the authors’ expert opinion on the potential role of “aerodigestive” pathophysiology in their findings.