key: cord-0780916-izlg8zu6
authors: Shojaee, A.; Dela Cruz, C.; Siner, J.; Zinchuk, A.; Kaminski, N.; Aryan, Y.
title: Viral Pneumonia is Associated with Increased Risk and Earlier Development of Post-Inflammatory Pulmonary Fibrosis
date: 2021-03-13
journal: nan
DOI: 10.1101/2021.03.08.21252412
sha: 1ec8bd9dbed88578607a80324ca83a12dc5f9610
doc_id: 780916
cord_uid: izlg8zu6

Severe inflammatory response, acute respiratory distress syndrome, and death are established serious consequences of the acute phase of severe viral pneumonia. However, the long-term respiratory outcomes of severe viral pneumonia, including its association with pulmonary fibrosis, are less known. Objective: To determine whether viral pneumonia is associated with an increased incidence of post-inflammatory pulmonary fibrosis. Design: We performed two retrospective observational cohort studies using longitudinal hospitalization records from the States of California (2005-2011) and Florida (2009-2015) for the discovery and validation studies, respectively. Patients who were 85-years-old and younger with at least two hospital encounters but without a prior diagnosis of pulmonary fibrosis were included. International Classification of Diseases-9 (ICD9) codes of primary and secondary diagnoses and procedures were used to identify the exposure: diagnosis of viral pneumonia; the outcome: incidence of post-inflammatory pulmonary fibrosis [PIPF, ICD9: 515]; and the confounders. Methods: Chronological age was used as the study time scale. Non-parametric Kaplan-Meier (KM) estimator and semiparametric Cox Proportional Hazard modelling were used to assessing the risk of PIPF. P-values < 10-3 were considered significant. Results: Among 9,802,565 patients from California and 8,741,345 patients in Florida cohorts, the prevalence of PIPF was 0.61% and 0.62% over 7 and 6.75 years, respectively. Patients with incident PIPF were older than those without [68(SD: 11) vs. 40(22) years]; among patients with PIPF, those with viral pneumonia diagnosis were younger than those without [63(12) versus 68(11) years]. Incidence of PIPF was higher for those with viral pneumonia diagnosis versus those without [1.6 (CI:1.51-1.69) vs. 0.91 (CI:0.86-0.96)] cases per 1000 person-years in California and in Florida [1.11 (CI:1.06 -1.16) vs, 0.93 (CI:0.89-0.98)]. Viral pneumonia was associated with increased risk of incident PIPF in both California aHR = 1.49 (1.38, 1.61), and Florida aHR of 1.26 (1.20, 1.33) cohorts (Table). Among patients who developed PIPF, the median time to diagnosis was 7.41 (6.16 -8.66) and 4.80 (4.34 - 5.26) years earlier for patients with viral pneumonia versus without in California and Florida cohorts. The association of viral pneumonia was not found for idiopathic pulmonary fibrosis [ICD9: 516.3]. Our findings suggest that patients hospitalized with viral pneumonia may have long term respiratory sequela that is often overlooked and suggest a need for additional studies focusing on phenotyping susceptible patients. This finding is especially important in light of the current COVID-19 pandemic because viral pneumonia is the most common manifestations of the disease, which could lead to subsequent fibrosis.

cohorts (Table) . Among patients who developed PIPF, the median time to diagnosis was 7.41 (6.16 -8.66 ) and 4.80 (4.34 -5.26 ) years earlier for patients with viral pneumonia versus without in California and Florida cohorts. The association of viral pneumonia was not found for idiopathic pulmonary fibrosis [ICD9: 516.3]. Our findings suggest that patients hospitalized with viral pneumonia may have long term respiratory sequela that is often overlooked and suggest a need for additional studies focusing on phenotyping susceptible patients. This finding is especially important in light of the current COVID-19 pandemic because viral pneumonia is the most common manifestations of the disease, which could lead to subsequent fibrosis.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 13, 2021. ; https://doi.org/10.1101/2021.03.08.21252412 doi: medRxiv preprint

Severe inflammatory response, acute respiratory distress syndrome (ARDS), and death are established serious consequences of the acute phase of severe viral pneumonia. However, the long-term respiratory outcomes of severe viral pneumonia, including its association with pulmonary fibrosis, are less known.

Objective: To determine whether viral pneumonia is associated with an increased incidence of post-inflammatory pulmonary fibrosis. Participants: Patients who were 85-years-old and younger with at least two hospital encounters but without a prior diagnosis of pulmonary fibrosis were included. International Classification of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Univariate hazard ratio (HR) and HR adjusted for all confounders (aHR) with 95% confidence intervals (CI) are reported. P-values < 10 -3 were considered significant. Statistical analyses were performed using R software, version 3.5.3 (R Project for Statistical Computing; R Foundation). (Table) . Among patients who developed PIPF, the median time to diagnosis was 7.41 (6.16 -8.66) and 4.80 (4.34 -5.26) years earlier for patients with viral pneumonia versus without in California and Florida cohorts (Figure) . The association of viral pneumonia was not found for idiopathic pulmonary fibrosis [ICD9: 516.3] (7).

Our results suggest that viral pneumonia is an independent risk factor for PIPF.

The risk was increased by 46% and 26% in the discovery and validation cohorts, respectively.

Moreover, among individuals eventually diagnosed with PIPF, those with viral pneumonia were younger and developed PIPF earlier. Limitations of the study include lack of information on disease severity and reliance on hospitalization ICD9 codes, which is likely to significantly underestimate viral pneumonia and PIPF diagnoses and identify PIPF patients at a later stage.

Nevertheless, this is the first study demonstrating increased risk for post-inflammatory pulmonary fibrosis in patients with viral pneumonia in two large independent cohorts. Our findings suggest that patients hospitalized with viral pneumonia may have long term respiratory sequela that is often overlooked and suggest a need for additional studies focusing on phenotyping susceptible patients. This finding is especially important in light of the current COVID-19 pandemic because viral pneumonia is the most common manifestations of the disease (8), which could lead to subsequent fibrosis (9).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 13, 2021. ; 

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