In what is believed to be the largest study of long COVID-19 to date, researchers at Washington University School of Medicine in St. Louis showed that survivors of the disease, including those not sick enough to be hospitalized, have a 60% increased risk of death in the six months following diagnosis with the virus. The researchers also catalogued conditions associated with COVID-19.

The study, which involved more than 87,000 COVID-19 patients and nearly 5 million controls in a federal database, appeared in the journal Nature.

Research suggests that about 10% of COVI-19 patients become “long haulers” with long term effects of the disease.

“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, an assistant professor of medicine. “It is not an exaggeration to say that long COVID-19—the long-term health consequences of COVID-19—is America’s next big health crisis. More than 30 million Americans have been infected with this virus, and given that the burden of long COVID-19 is substantial….”

In this study, the researchers calculated the potential scale of the problems first identified from anecdotal accounts and smaller studies that pointed to wide-ranging side effects of surviving COVID-19, from breathing problems and irregular heart rhythms to mental health issues and hair loss.

“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,” said Al-Aly, also director of the Clinical Epidemiology Center and chief of the Research and Education Service at the Veterans Affairs St. Louis Health Care System.

At the six-month mark, excess deaths among all COVID-19 survivors were estimated at eight people 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.

“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.”

The researchers analyzed data from the national health-care databases of the U.S. Department of Veterans Affairs. The dataset included 73,435 VHA patients with confirmed COVID-19 but who were not hospitalized and, for comparison, almost 5 million VHA patients who did not have a COVID-19 diagnosis and were not hospitalized during this time frame. The veterans in the study were primarily men (almost 88%), but the large sample size meant that the study still included 8,880 women with confirmed cases.

The researchers confirmed that, despite being primarily a respiratory disease, long COVID-19 can affect nearly every organ system in the body. Evaluating 379 diagnoses of diseases possibly related to COVID-19, 380 classes of medications prescribed and 62 laboratory tests 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.

While no survivor suffered from all of these problems, many developed a cluster of several issues that have a significant impact on health and quality of life.

Among hospitalized patients, those who had COVID-19 fared considerably worse than those who had influenza, according to the analysis. 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. Survivors of COVID-19 also had a substantially higher risk of long-term medical problems.

In future analyses, Al-Aly and his colleagues plan to look at whether patients fared differently based on age, race and gender to gain a deeper understanding of the risk of death in people with long COVID-19.