By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A cohort study from the U.S. Department of Veterans Affairs found many survivors of COVID-19 had significant loss of health six months after their acute illness, with greater risk associated with severity of the acute infection.

SOURCE: Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature 2021; Apr 22. doi: 10.1038/s41586-021-03553-9. [Online ahead of print].

Most individuals with COVID-19 experience a full recovery. However, a significant minority do not and instead experience long-lasting symptoms, for which the etiology remains poorly understood. Therefore, Al-Aly and colleagues sought to comprehensively analyze the post-acute sequelae of COVID-19 using a high-dimensional approach.

The study included a cohort of 73,435 patients from the Veterans Health Administration (VHA) with COVID-19 who survived at least the first 30 days after a COVID-19 diagnosis and who were not hospitalized. These patients were compared to a control group of 4,990,835 VHA patients who did not have COVID-19 and were not hospitalized. More than 99.99% of standardized differences between the two groups were < 0.1 after adjustment, indicating that their baseline characteristics were similar. The investigators also evaluated the risk of death associated with 379 diagnoses (based on ICD-10 codes), 380 medication classes, and 62 laboratory tests beyond the first 30 days from COVID-19 diagnosis.

After the first 30 days of illness, COVID-19 survivors had a higher risk of dying (hazard ratio [HR], 1.59; range 1.46-1.73). The most commonly affected organ system for COVID-19 sequelae was the respiratory tract (28.51 per 1,000 COVID-19 patients at six months). There was an increased incidence of bronchodilator use (22.23 per 1,000 COVID-19 patients at six months), antitussive and expectorant use (12.83), anti-asthmatic use (8.87), and steroid use (7.65). An excess burden of nervous system disorders was found, including nervous system signs and symptoms (14.32 per 1,000 COVID-19 patients at six months) and headaches (4.10). Mental health problems were more frequent as well, including sleep-wake disorders (14.53 per 1,000 COVID-19 patients at six months), anxiety and fear-related disorders (5.42), and trauma and stress-related disorders (8.93). The led to an excess burden of incident use of antidepressants (7.83) and benzodiazepines, sedatives, and anxiolytics (22.23).

Many COVID-19 survivors had cardiovascular sequelae as a result of their infection, including cardiac dysrhythmias (8.41 per 1,000 COVID-19 patients at six months), circulatory signs and symptoms (6.65), chest pain (10.08), coronary atherosclerosis (4.38), and heart failure (3.94). Gastrointestinal issues included esophageal disorders (6.90), abdominal pain (5.73), and an increased use of laxatives (9.22) and antidiarrheal agents (2.87). An excess burden in incident acute pulmonary embolism (2.63 per 1,000 COVID-19 patients at six months) and use of anticoagulants (16.43) was found. Finally, there was an excess burden of poor general well-being in the COVID-19 survivors. They had increased malaise and fatigue (12.64 per 1,000 COVID-19 patients at six months), muscle disorders (5.73), and musculoskeletal pain (13.89). Abnormal laboratory values included decreased hemoglobin (31.03 per 1,000
COVID-19 patients at six months), decreased hematocrit levels (30.73), decreased serum albumin (6.44), and increased alanine aminotransferase (7.62).

Next, the investigators compared COVID-19 survivors who were hospitalized (n = 13,654) to subjects with influenza who survived at least 30 days after hospitalization (n = 13,997). Similar to the preceding findings, the COVID-19 survivors had a higher burden of pulmonary and extrapulmonary sequelae, including neurologic disorders (19.78 per 1,000 hospitalized COVID-19 patients at six months), mental health disorders (7.75 [4.72, 10.10]), metabolic disorders (43.53), cardiovascular disorders (17.92), gastrointestinal disorders (19.28), coagulation disorders(14.31), pulmonary embolism (18.31), and malaise and fatigue (36.49). 

Finally, the investigators used the receipt of influenza vaccination in odd and even months as a negative control. They tested the association between receipt of influenza vaccination in even months (n = 762,039) compared to odd months (n = 599,981) with all 821 of the analyzed high-dimensional clinical outcomes in the study. None of the associations reached the threshold of statistical significance.


Post-acute COVID-19 syndrome, also known as long COVID, is now recognized as a multi-organ disease with a multitude of symptoms. The study by Al-Aly and colleagues is important because it quantifies the risk survivors of COVID-19 have for negative effects on their health six months after their acute illness. Although the idea is not proven, many experts believe that an overactive immune response to the acute COVID-19 infection, rather than ongoing viral replication, is the underlying biological mechanism.

Sometimes other viral illnesses can produce post-infectious sequelae, but COVID-19 appears to be unique in this regard in terms of the number of symptoms and their duration. The Centers for Disease Control and Prevention (CDC) is conducting multi-year studies to investigate post-COVID conditions further.1

There are a few limitations to the study. First, the investigators used a database from the VHA, so males were overrepresented in the patient population. Second, the impact of SARS-CoV-2 variant strains and widespread vaccination on long-term symptoms remains to be elucidated. Finally, with high-dimensional data sets, the number of features can exceed the number of observations, thus increasing the risk for confounding.

As more people survive COVID-19, many will need additional follow-up and care. Since this will burden an already stretched healthcare system further, additional studies are needed urgently to help inform future health system planning. 


  1. Centers for Disease Control and Prevention. Post-COVID conditions. Updated April 8, 2021.