Largest study to date on long COVID identifies broad list of diagnoses


As of May 25, 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has infected more than 526 million people and caused more than 6.28 million deaths worldwide.

Scientific and clinical evidence has shown the presence of potential post-acute and long-term effects of SARS-CoV-2 infection in multiple organ systems. Past research has mainly focused on small samples of patients or specific populations.

Study: Understanding post-acute sequelae of SARS-CoV-2 infection through data-driven analysis with longitudinal electronic health records: findings from the RECOVER initiative. Image Credit: sasirin pamai / Shutterstock.com

A new study available on the medRxiv* The preprint server characterizes the post-acute sequelae of SARS-CoV-2 infection (PASC) using data from two large national patient-centered clinical research networks (PCORnet), which include 11 million of patients in New York (NYC) and 16.8 million patients in Florida.

Disadvantages of existing studies

Recently, many retrospective cohort analyzes have described PASC using real-world patient data; however, there are two main limitations to these existing studies.

First, the disease etiology and pathophysiology of PASC are complicated, implying that conventional study design based on assumptions may lead to biased results. Additionally, these studies have typically been conducted on small sample sizes or specific patient populations, raising questions about the generalizability of these findings.

About the study

The current study overcomes the aforementioned challenges by developing a high-throughput causal inference pipeline to identify potential symptoms of PASC. This study is part of the US National Institutes of Health (NIH) COVID Research to Enhance Recovery (RECOVER) initiative.

Here, the researchers used electronic health records (EHRs) from two major national PCORnets: INSIGHT and OneFlorida+. While INSIGHT covers patients in the New York (NYC) metro area, OneFlorida+ covers patients in Florida, Georgia, and Alabama. A total of 137 potential PASC diagnoses and 459 potential PASC drugs were considered.

The researchers constructed an outcome-specific cohort with patients who were diagnosis- or medication-free at baseline for each diagnosis and medication. Then, a reverse propensity treatment reweighting (IPTW) was applied to adjust for confounders and an adjusted hazard ratio and excess burden in the post-acute phase of infection were calculated. Only new incidences in the post-acute period were considered, as this provided the most efficient way to define PASC phenotypes.

Study results

A range of diagnostics and drugs have been shown to be consistent with higher adjusted hazard ratios and excess burdens in SARS-CoV-2 infected patients compared to uninfected people. PASC turned out to be a multi-organ disease, as diagnostics and medications covered a wide range of organ systems.

Identified potential incident PASC conditions of the INSIGHT cohort, March 2020 to November 2021. a.  Risk reports adjusted for incident diagnostics.  b.  Adjusted hazard ratios of incident drug use.  Sequelae results were determined from day 30 after SARS-CoV-2 infection and the adjusted hazard ratio was calculated at 180 days after SARS-CoV-2 infection.  The colors represent different organ systems.

Identified potential incident PASC conditions of the INSIGHT cohort, March 2020 to November 2021. a. Risk reports adjusted for incident diagnostics. b. Adjusted hazard ratios of incident drug use. Sequelae results were determined from day 30 after SARS-CoV-2 infection and the adjusted hazard ratio was calculated at 180 days after SARS-CoV-2 infection. The colors represent different organ systems.

Diagnoses included respiratory, dermatological, cardiovascular, nervous and other problems. Additionally, an increased risk of mis-prescribing in a diverse set of medications was observed by scientists, some of which included medications for asthma, cough, blood thinners, and constipation.

The adjusted excess burden of different potential PASC diagnoses was analyzed in a diverse set of groups. To that end, hospitalized patients reported more excess cases of potential PASC diagnoses and medications in the INSIGHT and OneFlorida+ cohorts.

Female, older, non-white patients had a higher excess of PASC cases. Comorbidity status also played an important role, although dyspnea always showed the highest excess burden. More potential PASC conditions have been identified in patients with heart problems, type II diabetes, and chronic kidney disease (CKD).

Overall, the adjusted hazard ratios (aHR) identified in the INSIGHT cohort were higher than in the OneFlorida+ cohort. Specifically, the rates of thromboembolism and pulmonary fibrosis were 50% higher in the INSIGHT cohort.

Nine diagnoses and nine drugs were identified in the OneFlorida+ cohort, compared to 25 diagnoses and 51 drugs in the INSIGHT cohort. The heterogeneity of the results could be caused by different periods of infection and patient characteristics.

Adjusted excess cumulative incidence of post-acute sequelae of SARS-CoV-2 infection (PASC) in the INSIGHT cohort, March 2020 to November 2021, stratified by acute severity status, age groups, gender, racial groups and pre-existing conditions.  P-value < 3,6 × 10−4 a été utilisée pour sélectionner les diagnostics significatifs.  Différents panneaux de couleur représentent différents systèmes d'organes, y compris (de haut en bas) : système nerveux, peau, système respiratoire, système circulatoire, organes hématopoïétiques, endocrinien et métabolique, système digestif, système génito-urinaire et signes généraux.  CAD, maladie coronarienne ;  CKD, maladie rénale chronique ;  DPC, maladie pulmonaire chronique ;  DT2, diabète de type 2 ;  En bonne santé : aucune condition préexistante documentée et aucun symptôme de type PASC au départ.  Deux codes de diagnostic de la CIM-10 B948 (séquelles d'autres maladies infectieuses et parasitaires spécifiées) et U099 (état post-COVID-19, non spécifié) ont également été utilisés pour comparer les séquelles post-aiguës générales de l'infection par le SRAS-CoV-2 dans différents groupes.

Adjusted excess cumulative incidence of post-acute sequelae of SARS-CoV-2 infection (PASC) in the INSIGHT cohort, March 2020 to November 2021, stratified by acute severity status, age groups, gender, racial groups and pre-existing conditions. P-value −4were used to select significant diagnoses. Different colored panels represent different organ systems, including (from top to bottom): nervous system, skin, respiratory system, circulatory system, blood-forming, endocrine and metabolic organs, digestive system, genitourinary system and general signs. CAD, coronary artery disease; CKD, chronic kidney disease; CPD, chronic lung disease; T2D, type 2 diabetes; Healthy: No documented pre-existing conditions and no PASC-like symptoms at baseline. Two ICD-10 diagnostic codes B948 (sequelae of other specified infectious and parasitic diseases) and U099 (post-COVID-19 condition, unspecified) were also used to compare general post-acute sequelae of infection by SARS-CoV-2 in different groups.

Strengths and limitations

Key strengths of this study include the data-driven approach and the large general adult patient population. Additionally, researchers used data from two large-scale clinical research networks spanning diverse patient groups, which revealed heterogeneity in PASC manifestations, improving generalizability. Additionally, since the United States has experienced multiple waves of COVID-19 during the enrollment period, the results highlight the different epidemiological and clinical characteristics.

Comparison of post-acute sequelae of SARS-CoV-2 risks in the INSIGHT cohort versus the OneFlorida+ cohort, March 2020 to November 2021. Adjusted hazard ratios were reported.  Colored panels represent different organ systems including (from top to bottom): nervous system, skin, respiratory system, circulatory system, blood-forming, endocrine and metabolic organs, digestive system and others general signs.

Comparison of post-acute sequelae of SARS-CoV-2 risks in the INSIGHT cohort versus the OneFlorida+ cohort, March 2020 to November 2021. Adjusted hazard ratios were reported. Colored panels represent different organ systems including (from top to bottom): nervous system, skin, respiratory system, circulatory system, blood-forming, endocrine and metabolic organs, digestive system and others general signs.

The current study also has some limitations. First, the exposure group was not randomized, although the researchers balanced out hypothetical confounders and found consistent results.

An additional limitation was that participants resided in New York and Florida, which may not be representative of other populations. Third, the study considered only incident events, while leaving worsening and relapse conditions for future research.

A final limitation was that the study period did not allow inclusion of patients infected during the phase dominated by the Omicron variant and did not include information on vaccination status.

conclusion

The researchers observed that adults surviving beyond 30 days after their diagnosis of COVID-19 had high incident risks and burdens. Additionally, PASC has been shown to be a complex condition that involves multiple organ systems. Significant heterogeneity was observed between geographic regions and patient subgroups.

Taken together, the study results deepen our understanding of PASC and underscore the need for further research to inform the diagnosis and prevention of PASC.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

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