Characteristics and determinants of pulmonary long COVID

Abstract

BACKGROUNDPersistent cough and dyspnea are prominent features of postacute sequelae of SARS-CoV-2 (also termed "long COVID"); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Using longitudinal pulmonary function testing (PFT) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary long COVID.METHODSThis single-center retrospective study included 1,097 patients with clinically defined long COVID characterized by persistent pulmonary symptoms (dyspnea, cough, and chest discomfort) lasting for 1 or more months after resolution of primary COVID infection.RESULTSAfter exclusion, a total of 929 patients with post-COVID pulmonary symptoms and PFTs were stratified as diffusion impairment and pulmonary restriction, as measured by percentage predicted diffusion capacity for carbon monoxide (DLCO) and total lung capacity (TLC). Longitudinal evaluation revealed diffusion impairment (DLCO ≤ 80%) and pulmonary restriction (TLC ≤ 80%) in 51% of the cohort overall (n = 479). In multivariable modeling regression analysis, invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary long COVID with diffusion impairment and restriction (adjusted odds ratio [aOR] = 9.89, 95% CI 3.62-26.9]). Finally, a subanalysis of CT imaging identified radiographic evidence of fibrosis in this patient population.CONCLUSIONLongitudinal PFTs revealed persistent diffusion-impaired restriction as a key feature of pulmonary long COVID. These results emphasize the importance of incorporating PFTs into routine clinical practice for evaluation of long COVID patients with prolonged pulmonary symptoms. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary long COVID patients.FUNDINGNational Institute of Allergy and Infectious Diseases (AI156898, K08AI129705), National Heart, Lung, and Blood Institute (HL153113, OTA21-015E, HL149944), and the COVID-19 Urgent Research Response Fund at the University of Alabama at Birmingham.

Keywords: Bioinformatics; Diagnostic imaging; Diagnostics; Infectious disease; Pulmonology.

Figure 1. Accrual of long COVID patients with persistent pulmonary symptoms in the UAB Health System.

Study flow chart.

Figure 2. Diffusion-impaired restriction is a key feature of persistent pulmonary long COVID.

(A and B) Results of percentage predicted total lung capacity (TLC) (A) and diffusing capacity for carbon monoxide (DLCO) (B) are shown for 3 clinic visits with stratification by restriction severity (color) measured during the first visit PFT and presence or absence of diffusion impairment (hashed lines). Box-and-whisker plots represent the median (black center line) and 25th and 75th percentiles (box boundaries) for each PFT measured, with number of patients (n) reported below each group. Normal TLC and DLCO are denoted by the gray color on the plot at 80%. (C) Alluvial diagram displays patient PFT trajectories over 3 consecutive visits (n = 100 total) with relative improvement or decline as measured by TLC (color) and DLCO (hashed lines). Labeling of alluvial diagram axes groups with fewer than 5 patients was omitted for visual clarity.

Figure 3. CT image findings in pulmonary long COVID with diffusion-impaired restriction.

(A–D) Representative CT images of pulmonary long COVID patients with diffusion impairment (DLCO ≤ 80%) with severe (TLC ≤ 50%), moderate (TLC 51%–70%), mild (TLC 71%–80%), and no restriction (TLC > 80%) assessed at the first long COVID clinic visit. Corresponding bar charts of CT pathology (%, n = patients) are displayed for each group. (Note: architectural distortion, traction bronchiectasis, and honeycombing are termed “Other Fibrosis”).