Defining the Subtypes of Long COVID and Risk Factors for Prolonged Disease: Population-Based Case-Crossover Study
Authors: Resendez Skyler , Brown Steven H , Ruiz Ayala Hugo Sebastian , Rangan Prahalad , Nebeker Jonathan , Montella Diane , Elkin Peter L 
Published: February 2024

Background
There have been over 772 million confirmed cases of COVID-19 worldwide. A significant portion of these infections will lead to long COVID (post–COVID-19 condition) and its attendant morbidities and costs. Numerous life-altering complications have already been associated with the development of long COVID, including chronic fatigue, brain fog, and dangerous heart rhythms.

Objective
We aim to derive an actionable long COVID case definition consisting of significantly increased signs, symptoms, and diagnoses to support pandemic-related clinical, public health, research, and policy initiatives.

Methods
This research employs a case-crossover population-based study using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) data generated at Veterans Affairs medical centers nationwide between January 1, 2020, and August 18, 2022. In total, 367,148 individuals with ICD-10-CM data both before and after a positive COVID-19 test were selected for analysis. We compared ICD-10-CM codes assigned 1 to 7 months following each patient’s positive test with those assigned up to 6 months prior. Further, 350,315 patients had novel codes assigned during this window of time. We defined signs, symptoms, and diagnoses as being associated with long COVID if they had a novel case frequency of ≥1:1000, and they significantly increased in our entire cohort after a positive test. We present odds ratios with CIs for long COVID signs, symptoms, and diagnoses, organized by ICD-10-CM functional groups and medical specialty. We used our definition to assess long COVID risk based on a patient’s demographics, Elixhauser score, vaccination status, and COVID-19 disease severity.

Results
We developed a long COVID definition consisting of 323 ICD-10-CM diagnosis codes grouped into 143 ICD-10-CM functional groups that were significantly increased in our 367,148 patient post–COVID-19 population. We defined 17 medical-specialty long COVID subtypes such as cardiology long COVID. Patients who were COVID-19–positive developed signs, symptoms, or diagnoses included in our long COVID definition at a proportion of at least 59.7% (268,320/449,450, based on a denominator of all patients who were COVID-19–positive). The long COVID cohort was 8 years older with more comorbidities (2-year Elixhauser score 7.97 in the patients with long COVID vs 4.21 in the patients with non–long COVID). Patients who had a more severe bout of COVID-19, as judged by their minimum oxygen saturation level, were also more likely to develop long COVID.

Conclusions
An actionable, data-driven definition of long COVID can help clinicians screen for and diagnose long COVID, allowing identified patients to be admitted into appropriate monitoring and treatment programs. This long COVID definition can also support public health, research, and policy initiatives. Patients with COVID-19 who are older or have low oxygen saturation levels during their bout of COVID-19, or those who have multiple comorbidities should be preferentially watched for the development of long COVID.