TY - JOUR
T1 - Immunofibrotic drivers of impaired lung function in postacute sequelae of SARSCoV-2 infection
AU - Chun, Hyung J.
AU - Coutavas, Elias
AU - Pine, Alexander B.
AU - Lee, Alfred I.
AU - Yu, Vanessa L.
AU - Shallow, Marcus K.
AU - Giovacchini, Coral X.
AU - Mathews, Anne M.
AU - Stephenson, Brian
AU - Que, Loretta G.
AU - Lee, Patty J.
AU - Kraft, Bryan D.
N1 - Funding Information:
The authors thank Amanda Brucker and Shein-Chung Chow for their statistical expertise and assistance with analytical interpretation and manuscript preparation, and Antoinette Santoro for assistance with patient enrollment. The study was funded in part by the National Heart, Lung, and Blood Institute (K08HL130557 to BDK and R01HL142818 to HJC), the American Heart Association (Transformational Project Award to HJC), the DeLuca Foundation Award (to ABP), a donation from Jack Levin to the Benign Hematology Program at Yale, and divisional/departmental funds from Duke University.
Funding Information:
FUNDING. National Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.
Publisher Copyright:
Copyright: © 2021, Chun et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/7/22
Y1 - 2021/7/22
N2 - BACKGROUND. Individuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity. METHODS. We performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors. RESULTS. Sixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53). CONCLUSION. Subjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets. FUNDING. National Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.
AB - BACKGROUND. Individuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity. METHODS. We performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors. RESULTS. Sixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53). CONCLUSION. Subjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets. FUNDING. National Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.
UR - http://www.scopus.com/inward/record.url?scp=85111048366&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.148476
DO - 10.1172/jci.insight.148476
M3 - Article
C2 - 34111030
AN - SCOPUS:85111048366
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 14
M1 - e148476
ER -