Loss of Lung Function Led to Loss of Life during the COVID-19 Pandemic

Over 7 million persons across the world died during the COVID-19 pandemic, with most dying of severe pneumonia and respiratory failure (1). According to the Centers for Disease Control and Prevention, the strongest known risk factors for severe COVID-19 and mortality were advanced age; obesity; and comorbidities, including chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, interstitial lung disease, pulmonary embolism, and pulmonary hypertension (2). However, this conclusion is based largely on data from methodologically “weak” studies that contained small sample sizes or used suboptimal study designs (e.g., cross-sectional and case-control studies, convenience sampling, retrospective cohorts), making results susceptible to distortions and biases. This may also explain the marked inconsistencies in findings across studies. For example, in COPD, a systematic review of 59 studies found that, on average, patients had a two- to fourfold increase in the risk of severe COVID-19, including mortality, compared with individuals without COPD (3); however, individually, there was tremendous variation in the results across studies, with some reporting no such association or even a protective relationship (3, 4). Similar inconsistencies have been noted with cigarette smoking, with some studies showing that it is a strong and independent risk factor for severe COVID-19 and others showing the opposite (protective) effect (5). Impaired lung function and presence of emphysema have also been noted to be significant risk factors in some but not all studies (6), creating confusion.

The study by Balte and colleagues in this issue of the Journal (pp. 1196–1210) provides crucial data that close the gap in knowledge and resolve the conundrum of the role that chronic lung diseases played in the pathogenesis and outcomes of persons infected with SARS-CoV-2 (7). The authors should be congratulated for creating the largest supercohort of its kind to date by pooling high-quality data from 11 large, independent cohorts (N = 29,323; mean age, 67 yr) that included spirometry, detailed clinical and phenotyping information, and careful follow-up of participants during the COVID-19 pandemic (7). In a subset of these cohorts, there were also data from thoracic or cardiac computed tomography (CT), enabling assessment of features such as emphysema and interstitial lung abnormalities (ILAs) as risk factors for severe COVID-19. What were their topline results?

First, severe COPD, as determined on the basis of spirometry (FEV₁ <50% of predicted), but not mild or moderate airflow obstruction increased the risk of severe COVID-19 (defined as either hospitalization or death caused by COVID-19) by approximately twofold, independent of other risk factors such as advanced age or obesity (7). Consistent with these findings, the presence of emphysema on a CT scan elevated the risk of severe COVID-19, with the highest quartile conferring a 64% higher risk than the lowest quartile of emphysema burden. Interestingly, neither the presence of any ILAs nor fibrotic ILAs (defined as lung distortion, honeycombing, or traction bronchiectasis in at least 5% of a lung zone) were significantly associated with the incidence of severe COVID-19, dispelling the notion that preexisting small fibrotic lesions “exploded” during acute SARS-CoV-2 infection and caused severe disease (8).

Second, Balte and colleagues found that “restrictive” physiology on spirometry was a significant risk factor for severe COVID-19, although the exact causes of this relationship remain a mystery (7). Although high-attenuation areas on CT scans were associated with restrictive spirometry, ILAs including fibrotic ILAs were not, suggesting that these individuals did not have forme fruste or early interstitial lung disease. On the other hand, restrictive spirometry was significantly associated with obesity and comorbidities, particularly cardiometabolic conditions such as diabetes and hypertension (7). A previous study of persons with restrictive physiology on spirometry (with normal TLC) found that the vast majority had airway disease (either asthma or COPD) or obesity as the principal cause of the spirometric abnormality (9). On the basis of this and other findings (9, 10), we posit that the large majority had (subclinical) airway disease or chest wall restriction from adiposity as the basis for their restrictive pattern on spirometry in the study by Balte and colleagues (7).

What are the molecular mechanisms underlying impaired lung function that predispose individuals to severe COVID-19? Many patients with underlying chronic lung diseases such as COPD have dysregulated immune responses in the airways, typically characterized by impaired IFN release with viral infections (11), defective adaptive immunity (12), and, ironically, immune hyperactivation with severe viral infections, especially involving pathways related to inflammasome activation and cGAS-STING signaling (caused by viral nucleic acid stimulation) (13). These responses in aggregate may elicit cytokine storms, which are frequently observed during severe COVID-19 and are responsible for multiple end-organ damage. The COPD airways also demonstrate endothelial dysfunction, which may enhance viral cytotoxicity and lead to vascular thrombotic events (14) and overexpress the SARS-CoV-2 viral host entry receptor, angiotensin-converting enzyme 2 in the epithelium (15, 16), which may explain the increased risk of COVID-19 in general.

Regardless of the mechanisms, impaired lung function, as evinced by reduced FEV₁ and/or FVC, was the only significant risk factor for both nonsevere and severe COVID-19 that survived statistical adjustments in the study by Balte and colleagues. Dynamically, FVC decline was the only lung function parameter that, over time, was significantly associated with the incidence of severe COVID-19 (7).

Thus, this study highlights the importance of impaired lung function (regardless of the cause), and in particular FVC, in the pathogenesis of severe COVID-19 (7). This may not be surprising, given its name “vital” (in FVC), emphasizing its essential role in supporting life. One important lesson learned from the COVID-19 pandemic is the primal importance of preserving lung function and enhancing lung health in the prevention of tragedies in another respiratory pandemic; to this end, early diagnosis of airway disease and aggressive treatment are essential because “when you can’t breathe, nothing else matters.”