Excess burden of respiratory and abdominal conditions following COVID-19 infections during the ancestral and Delta variant periods in the United States: An EHR-based cohort study from the RECOVER Program

Importance The frequency and characteristics of post-acute sequelae of SARS-CoV-2 infection (PASC) may vary by SARS-CoV-2 variant. Objective To characterize PASC-related conditions among individuals likely infected by the ancestral strain in 2020 and individuals likely infected by the Delta variant in 2021. Design Retrospective cohort study of electronic medical record data for approximately 27 million patients from March 1, 2020-November 30, 2021. Setting Healthcare facilities in New York and Florida. Participants Patients who were at least 20 years old and had diagnosis codes that included at least one SARS-CoV-2 viral test during the study period. Exposure Laboratory-confirmed COVID-19 infection, classified by the most common variant prevalent in those regions at the time. Main Outcome(s) and Measure(s) Relative risk (estimated by adjusted hazard ratio [aHR]) and absolute risk difference (estimated by adjusted excess burden) of new conditions, defined as new documentation of symptoms or diagnoses, in persons between 31-180 days after a positive COVID-19 test compared to persons with only negative tests during the 31-180 days after the last negative test. Results We analyzed data from 560,752 patients. The median age was 57 years; 60.3% were female, 20.0% non-Hispanic Black, and 19.6% Hispanic. During the study period, 57,616 patients had a positive SARS-CoV-2 test; 503,136 did not. For infections during the ancestral strain period, pulmonary fibrosis, edema (excess fluid), and inflammation had the largest aHR, comparing those with a positive test to those with a negative test, (aHR 2.32 [95% CI 2.09 2.57]), and dyspnea (shortness of breath) carried the largest excess burden (47.6 more cases per 1,000 persons). For infections during the Delta period, pulmonary embolism had the largest aHR comparing those with a positive test to a negative test (aHR 2.18 [95% CI 1.57, 3.01]), and abdominal pain carried the largest excess burden (85.3 more cases per 1,000 persons). Conclusions and Relevance We documented a substantial relative risk of pulmonary embolism and large absolute risk difference of abdomen-related symptoms after SARS-CoV-2 infection during the Delta variant period. As new SARS-CoV-2 variants emerge, researchers and clinicians should monitor patients for changing symptoms and conditions that develop after infection. STATEMENTS AND ACKNOWLEDGEMENTS 1. Authorship has been determined by ICJME recommendation 2. Disclosures to be obtained at time of submission 3. The content is solely the responsibility of the authors and does not necessarily represent the official views of the RECOVER Program, the NIH or other funders 4. We would like to thank the National Community Engagement Group (NCEG), all patient, caregiver and community Representatives, and all the participants enrolled in the RECOVER Initiative. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative, which seeks to understand, treat, and prevent the post-acute sequelae of SARS-CoV-2 infection (PASC). This research was funded by the National Institutes of Health (NIH) Agreement OTA OT2HL161847 as part of the Researching COVID to Enhance Recovery (RECOVER) research program. NIH played a role in evaluating and developing the overall structure of the RECOVER research program, but not in the design and analysis of this specific study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The use of the INSIGHT data was approved by the Institutional Review Board (IRB) of Weill Cornell Medicine following protocol 21-10-95-380 with the title “Adult PCORnet-PASC Response to the Proposed Revised Milestones for the PASC EHR/ORWD Teams (RECOVER).” The use of the OneFlorida+ data for this study was approved under the University of Florida IRB number IRB202001831. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable The data underlying the results presented in the study are available from the senior author.