LOUIS—More than a year into the COVID-19 pandemic, the extended burden on the VA healthcare system is just becoming clear.
The reason? Many veterans, including those who had what appeared to be mild cases, are grappling with a range of health problems months after SARS-CoV-2 infection should have resolved.
Research led by the VA Saint Louis Health Care System and Washington University Medical School is considered the largest comprehensive study of long COVID-19 to this point. The report, published in the journal Nature, revealed that COVID-19 survivors at the VA—including those never sick enough to be hospitalized—have an increased risk of death in the six months following diagnosis of the virus.1
The significance goes far beyond the VA, however, suggesting the extensive burden everywhere of long-term complications from COVID-19.
“Our study demonstrates that, up to six months after diagnosis, the risk of death following even a mild case of COVID-19 is not trivial and increases with disease severity,” said senior author Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center and chief of the Research and Education Service at the Veterans Affairs St. Louis Health Care System. “It is not an exaggeration to say that long COVID-19the long-term health consequences of COVID-19—is America’s next big health crisis. Given that more than 30 million Americans have been infected with this virus and given that the burden of long COVID-19 is substantial, the lingering effects of this disease will reverberate for many years and even decades. Physicians must be vigilant in evaluating people who have had COVID-19. These patients will need integrated, multidisciplinary care.”
The study cohort included 73,435 users of the Veteran Health Administration with COVID-19 who survived at least the first 30 days after COVID-19 diagnosis and were not hospitalized, and 4,990,835 VHA users who did not have COVID-19 and were not hospitalized.
“The acute clinical manifestations of COVID-19 are well characterized; however, its post-acute sequalae have not been comprehensively described,” the researchers explained. “Here, we use the national healthcare databases of the U.S. Department of Veterans Affairs to systematically and comprehensively identify 6-month incident sequalae including diagnoses, medication use, and laboratory abnormalities in 30-day survivors of COVID-19.”
In addition to the higher risk of death, recovered COVID-19 patients in the first 30 days of illness also have higher health resource utilization because of problems with the respiratory system and a range of other ailments involving the nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain and anemia.
“We show increased incident use of several therapeutics including pain medications (opioids and non-opioids), antidepressants, anxiolytics, antihypertensives, and oral hypoglycemics and evidence of laboratory abnormalities in multiple organ systems,” the study added.
Even beyond the acute period, patients—whether they recovered at home or were hospitalized or admitted to intensive care—have a risk of longer term health issues, often involving the pulmonary system but also beyond that, according to the analysis. “The results provide a roadmap to inform health system planning and development of multidisciplinary care strategies to reduce chronic health loss among COVID-19 survivors.”
While many smaller studies have looked at specific issues, this effort was much broader in scale. “This study differs from others that have looked at long COVID-19 because, rather than focusing on just the neurologic or cardiovascular complications, for example, we took a broad view and used the vast databases of the Veterans Health Administration (VHA) to comprehensively catalog all diseases that may be attributable to COVID-19,” pointed out.
After getting through the initial infection and the first 30 days of illness, COVID-19 survivors had a nearly 60% increased risk of death over the following six months compared with the general population, the authors reported. In fact, at six months, excess deaths among all COVID-19 survivors were estimated at 8 per 1,000 patients. Among patients who were ill enough to be hospitalized with COVID-19 and who survived beyond the first 30 days of illness, there were 29 excess deaths per 1,000 patients over the following six months.
‘Tip of the Iceberg’
“These later deaths due to long-term complications of the infection are not necessarily recorded as deaths due to COVID-19,” Al-Aly said. “As far as total pandemic death toll, these numbers suggest that the deaths we’re counting due to the immediate viral infection are only the tip of the iceberg.”
While veterans in the study were primarily men, about 88%, researchers used a large-enough sample to include 8,880 women veterans with confirmed cases.
A separate analysis using VHA data dealt with 13,654 patients hospitalized with COVID-19 compared with 13,997 patients hospitalized with seasonal flu. All patients survived at least 30 days after hospital admission, and the analysis included six months of follow-up data.
One of the most important takeaways is that, while it begins as a respiratory virus, SARS-CoV-2 potentially can affect nearly every organ system in the body. Evaluating 379 diagnoses of diseases possibly related to COVID-19, 380 classes of medications that were prescribed and 62 laboratory tests that were administered, the researchers identified newly diagnosed major health issues that persisted in COVID-19 patients over at least six months and that affected nearly every organ and regulatory system in the body.
The broad range included:
- Respiratory system: persistent cough, shortness of breath and low oxygen levels in the blood.
- Nervous system: stroke, headaches, memory problems and problems with senses of taste and smell.
- Mental health: anxiety, depression, sleep problems and substance abuse.
- Metabolism: new onset of diabetes, obesity and high cholesterol.
- Cardiovascular system: acute coronary disease, heart failure, heart palpitations and irregular heart rhythms.
- Gastrointestinal system: constipation, diarrhea and acid reflux.
- Kidney: acute kidney injury and chronic kidney disease that can, in severe cases, require dialysis.
- Coagulation regulation: blood clots in the legs and lungs.
- Skin: rash and hair loss.
- Musculoskeletal system: joint pain and muscle weakness.
- General health: malaise, fatigue and anemia.
Combinations varied by survivor, but many developed a cluster of more than one system. “The mechanism(s) which underly the post-acute and chronic manifestations of COVID-19 are not entirely clear,” researchers wrote. “Some of the manifestations may be driven by a direct effect of the viral infection and may be putatively explained by several hypotheses including persistent virus in immune-privileged sites, aberrant immune response, hyperactivation of the immune system, or autoimmunity. Indirect effects including changes in social (e.g. reduced social contact and loneliness), economic (e.g. loss of employment), and behavioral conditions (e.g. changes in diet and exercise) that may be differentially experienced by people with COVID-19 may also shape health outcomes in COVID-19 survivors and may be responsible drivers of some of the clinical manifestations reported here. A better delineation of the direct and indirect effects and a deeper understanding of the underlying biologic mechanisms and epidemiologic drivers of the multifaceted long-term consequences of COVID-19 is needed.”
At the same time, the authors determined that veterans with COVID-19 fared far worse than those who had influenza: COVID-19 survivors had a 50% increased risk of death compared with flu survivors, with about 29 excess deaths per 1,000 patients at six months. In addition, survivors of COVID-19 also were determined to have a substantially higher risk of long-term medical problems.
“Compared with flu, COVID-19 showed remarkably higher burden of disease, both in the magnitude of risk and the breadth of organ system involvement,” Al-Aly said. “Long COVID-19 is more than a typical postviral syndrome. The size of the risk of disease and death and the extent of organ system involvement is far higher than what we see with other respiratory viruses, such as influenza.”
Another important determination was that the health risks in COVID-19 survivors increased with the severity of disease, with hospitalized patients who required intensive care being at highest risk of long-term complications and death.
“Some of these problems may improve with time—for example, shortness of breath and cough may get better—and some problems may get worse,” Al-Aly added. “We will continue following these patients to help us understand the ongoing impacts of the virus beyond the first six months after infection. We’re only a little over a year into this pandemic, so there may be consequences of long COVID-19 that are not yet visible.”
- Ziyad Al-Aly, Yan Xie, Benjamin Bowe. High-dimensional characterization of post-acute sequalae of COVID-19. Nature, 2021; DOI: 10.1038/s41586-021-03553-9