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Veterans who came down with COVID-19 who didn't require hospitalization still experienced a higher risk of death six months later, as well as increased use of certain medications, compared with veterans without the illness, researchers found.

In a cohort of more than 74,000 veterans, COVID-19 survivors who were not hospitalized and survived at least the first 30 days of illness had an increased risk of death versus those without COVID-19 (HR 1.59, 95% CI 1.46-1.73), with an excess death rate of 8.39 per 1,000 COVID-19 patients at six months, reported Ziyad Al-Aly, MD, of VA Saint Louis Health Care System in Missouri, and colleagues.

They also observed an excess burden of using medications, such as anti-anxiety drugs, opioid and non-opioid analgesics, and antihypertensive drugs among the COVID-19 patients at six months, the authors wrote in .

"The constellation of evidence suggests that 30-day survivors of COVID-19 exhibited increased risk of death and health resource utilization, and substantial burden of health loss (spanning pulmonary and several extrapulmonary organ systems) and highlights the need for a holistic and integrated multidisciplinary long-term care of COVID-19 survivors," Al-Aly and colleagues wrote.

Prior studies on long COVID from other countries, as well as smaller U.S. studies, examined pulmonary and extrapulmonary manifestations, but as the group noted, "the post-acute sequelae of COVID-19 are not yet clear."

They analyzed data from 74,435 users of the Veterans Health Administration (VHA) who had COVID-19, but were not hospitalized, and survived at least 30 days after diagnosis. They were compared with almost five million VHA users who neither had COVID-19 nor were hospitalized.

COVID survivors were a mean age of 61, 88% were men, and 70% were white. VHA users were older (mean age of 69), but were also mostly men and mostly white.

Not only did COVID-19 patients have an increased risk of death, but they had higher chances of outpatient care encounters (HR 1.20, 95% CI 1.19-1.21) at a greater frequency.

The team not only examined clinical manifestations, but associated medication use. They found a high burden of incident use of benzodiazepine sedatives and anxiolytics (22.23 per 1,000), as well as bronchodilators (22.23 per 1,000). There was also high incident use of non-opioid analgesics (19.97 per 1,000) and opioid analgesics (9.39 per 1,000), in addition to antilipemic agents (11.56 per 1,000) and beta blockers (9.74 per 1,000).

Similar to prior research, the group also found a higher incident burden of pulmonary and extrapulmonary manifestations, such as nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, and gastrointestinal disorders, as well as more general symptoms, such as malaise, fatigue, musculoskeletal pain, and anemia.

"The risk and associated burden of post-acute [sequelae] is evident even among those whose acute disease was not severe enough to necessitate hospitalization -- the segment that represents the majority of people with COVID-19," the authors wrote.

They offered hypotheses for these conditions, such as "persistent virus in immune-privileged sites, aberrant immune response, hyperactivation of the immune system, or autoimmunity," and even some explanations relating to the pandemic itself, such as social isolation, loneliness, or changes in diet or exercise routines.

This cohort consisted of predominantly men, so findings may not be generalizable to women. The authors also could not definitively prove that the post-acute sequelae in COVID survivors were caused by the infection itself, which was another study limitation.

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