Risk of New Hospitalization Post-COVID-19 Infection for Non-COVID-19 Conditions

Definition of Cohort

The cohort for this study consisted of all adult patients aged 18 years and older who were tested for COVID-19 between January 1, 2020, and July 5, 2020, within the UF Health system, in any encounter type (ambulatory, emergency department [ED], inpatient, etc). The databank contained EHR data for all patients in the current cohort through December 30, 2020. COVID-19 diagnosis was validated by PCR. Baseline dates for COVID-19-positive patients were established at the date of their earliest recorded PCR-confirmed positive COVID-19 test, and baseline for COVID-19-negative patients was assessed at the earliest recorded negative COVID-19 test. Each patient was only included once in the analysis. For patients with multiple COVID-19 tests, if at least 1 test gave a positive result, the patient was classified as COVID-19 positive, and the date of their earliest positive COVID-19 test result was used as their baseline date. For patients with multiple COVID-19 tests that were all negative, the patient was classified as COVID-19 negative, and the date of their earliest negative COVID-19 test results was used as their baseline date. Patients were tested in the context of seeking care for COVID-19; the tests were not part of general screening and surveillance.

Only patients with at least 180 days of follow-up time after their baseline date were retained in the cohort. Patients with more than 180 days of follow-up were censored at 180 days. Mortality data were available in the databank, and patients who died within their 180-day window were included in the analysis and censored at the date of their recorded death. Mortality data were obtained from both patient electronic health records and the Social Security Death Index.

COVID-19-positive patients were also categorized as having had either a severe or mild/moderate COVID-19. Patients seen only in an outpatient setting were classified as having mild/moderate COVID-19, while those hospitalized for any reason during their first 30 days of follow-up were classified as severe. The cohort was also censored for 30 days after baseline in the COVID-19 negative patients or until 30 days post-hospital discharge for the severe COVID-19 patients to ensure that health care utilization was post-acute and not part of the initial COVID-19 episode of care (eg, readmission).

Outcome Variables

Based on previous literature regarding organ systems affected by COVID-19 and likely complications, outcomes were determined as the occurrence of hospital admission for a cardiovascular, respiratory, or clotting disorder-related diagnosis.^8⇓–10 The targeted hospitalizations investigated as cardiovascular outcomes were myocardial infarction, heart failure, and stroke. The respiratory hospitalizations were pneumonia, hypoxemia, and acute respiratory distress syndrome. The clotting disorder hospitalizations were deep vein thrombosis, venous thromboembolism, and pulmonary embolism.

The International Classification of Diseases, Tenth Version (ICD-10) codes used to define these outcomes are given in Table 1. Outcomes were assessed as hospitalization for any of these causes and by category. In the combined analysis, the earliest occurrence of admission for a cardiovascular, respiratory, or clotting disorder complication was used for patients who experienced multiple hospitalizations during the follow-up time frame.

Because COVID-19 may lead to hospitalizations for other causes than just the ones we have identified that have a plausible mechanism, we also examined hospitalizations for any cause. In the all hospitalizations analysis, a patient could have had any diagnosis associated with their hospitalization, including those not listed in Table 1.

Comorbidities

Comorbidities and demographic variables which could potentially confound the associations between mild/moderate COVID-19, severe COVID-19, and no COVID-19 and the risk of hospitalization for post-acute COVID-19 complications were collected at baseline for each member of the cohort. Demographic variables included patient age, race, ethnicity, sex, and insurance status. Comorbidities included hypertension, chronic obstructive pulmonary disease (COPD)/asthma, diabetes mellitus, and overweight/obesity. Hypertension, COPD/asthma, and diabetes mellitus were determined using ICD-9/10 codes (Table 1), and a patient's status as overweight/obese was determined using weight and height measurements available in the EHR. Body mass index (BMI) in kg/m² was recorded at baseline or the closest available measurement in time.

Analysis

Hazard ratios for the risk of hospitalization for post-acute COVID-19 complications by COVID-19 status were determined using Cox proportional hazard models. We obtained hazard ratios for hospital admissions based on COVID-19 diagnosis category, using COVID-19 negative status as the reference. These analyses were then modified to control for age, sex, race, insurance status, and comorbidities. The proportional hazards assumption was confirmed by inspecting the Schoenfeld residual plots for each variable included in the models and testing the time-dependent β coefficients. Analyses were conducted using the survival package in R v4.0.3.