Existing studies provide evidence that after the acute phase of SARS-CoV-2 infection, many symptoms and signs may continue, or even worsen or update, involving multiple organ systems, including cardiovascular, metabolic, renal, etc.

Category：science

2025-10-13

This article is original to the Translational Medicine Network, please indicate the source for reprinting

Author: Lily

Introduction : The COVID-19 global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the lives of hundreds of millions of people. Existing research provides evidence that after the acute phase of SARS-CoV-2 infection, many symptoms and signs may persist, or even worsen or update (called post-acute sequelae of SARS-CoV-2 infection, PASC), involving multiple organ systems, including cardiovascular, metabolism, kidneys, etc. Various studies have attempted to explore the underlying biological mechanisms of PASC, although most have generally been conducted in small patient cohorts.

Recently, a study published in "Nature Medicine" (Nature Medicine) analyzed the electronic health records of nearly 35,000 patients stored in two large clinical research networks in the United States. It performed machine learning analysis on more than 137 symptoms and conditions and identified four PASC subphenotypes. These subphenotypes are associated with different patient demographics, underlying diseases prior to SARS-CoV-2 infection, and severity of the acute infection phase. This study provides insights into the heterogeneity of PASC and may inform stratified decisions in the management of PASC conditions.

https://www.nature.com/articles/s41591-022-02116-3

Subphenotype 1 - Heart and Kidney

subphenotype 1 consists of 7,047 patients (33.75%) and is dominated by cardiac, renal and circulatory diseases - such as cardiac and circulatory disease, renal failure, anemia and fluid and electrolyte disorders. Compared with other subtypes, patients in this subtype are older (median age 65.0 years, IQR (52.0-75.0)) and have the highest proportion of males among the four subtypes: 48.53%. Patients also have higher COVID-19 acute severity (hospitalization rate 61.15%), use of mechanical ventilation (4.81%) and intensive care services (9.95%).

During the first wave of the pandemic (March to June 2020), this subphenotype had the highest proportion of patients infected with SARS-CoV-2 (37.38%). Patients with this subphenotype had a higher proportion of pre-existing conditions than other subphenotypes. conditions, especially hematologic, circulatory, and endocrine comorbidities; and, a higher probability of taking prescription medications for circulatory, endocrine disorders, or anemia.

Subphenotype 2 - Respiratory, Sleep and Anxiety

Subphenotype 2 includes 6,838 (32.75%) patients, Respiratory diseases, sleep disturbances, anxiety, and symptoms such as headaches and chest pains are the predominant symptoms. The median age of patients with this subphenotype during the acute SARS-CoV-2 infection stage was 51.0 years (IQR (35.0-64.0)), 62.8% were female, and the hospitalization rate was 31.28%. Between November 2020 and November 2021, compared with the other three subphenotypes, this subphenotype had the largest proportion of patients testing positive for SARS-CoV-2 (64.47%).

Patients with this subphenotype have a higher baseline comorbidity burden for respiratory diseases such as upper respiratory sequelae and chronic obstructive pulmonary disease . These patients are associated with a higher incidence of antiasthmatic, antiallergic, and anti-inflammatory medications, including inhaled steroids, levalbuterol, and montelukast.

Subphenotype 3 – Musculoskeletal and Neurological

subphenotype 3 consists of 4,879 patients (23.37%) and mainly involves musculoskeletal and neurological sequelae - such as musculoskeletal pain, headache and sleep-wake disorders. The median age of patients with this subphenotype is 57.0 years (IQR 42.0–69.0), with women accounting for 60.71%. Compared with other subphenotypes, this phenotype had the highest proportion of patients (78.4%) with more than 5 outpatient visits before infection with SARS-CoV-2.

Patients with this phenotype have a higher baseline comorbidity burden of autoimmune and allergic diseases (such as rheumatoid arthritis and asthma) as well as other musculoskeletal and neurological disorders, including soft tissue, bone, and sleep disorders. The subphenotype is associated with greater prescription of painkillers (e.g., , ibuprofen, , and ketorolac).

Subphenotype 4 - Digestive and Respiratory

Subphenotype 4 included 2,117 (10.14%) patients with primarily digestive and respiratory diseases. The median age of patients with this subphenotype was 54.0 years (IQR 39.0–67.0), and 61.64% were female. During the acute phase of SARS-CoV-2 infection, the zero baseline emergency department visit rate was the highest (57.06%), but the mechanical ventilation rate (0.8%) and intensive care admission rate were the lowest (2.79%) . Compared with other subphenotypes, subphenotype 4 has a lower overall burden of underlying disease but a slightly higher prevalence of digestive system diseases, such as vomiting blood, gastric and duodenal diseases, and digestive system tumors; and a higher frequency of ingestion of prescription digestive system medications.

Research significance
05
"These results will inform ongoing research on the underlying mechanisms of long-term COVID and its potential treatments." said Fei Wang, associate professor of population health sciences who led the study.
Dr. Rainu Kaushal, lead researcher on the study and senior associate dean for clinical research at Weill Cornell Medical College, said: "Understanding the epidemiology of long-term COVID enables clinicians to help patients understand their symptoms and prognosis and facilitates multi-specialty care for patients. Electronic health records provide a window into this situation, allowing us to better characterize long-term COVID-19 symptoms to inform other types of research, including basic discovery and clinical trials. ”
Reference:
https://www.news-medical.net/news/20221221/Study-Long-COVID-has-four-major-subtypes-defined-by-diffe rent-clusters-of-symptoms.aspx
https://www.nature.com/articles/s41591-022-02116-3
Note: This article is intended to introduce the progress of medical research and cannot be used as a reference for treatment plans. If you need health guidance, please go to a regular hospital.
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