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New Case Western Reserve University, National Institute on Drug Abuse study finds people with substance-use disorders may be at higher risk for SARS-CoV-2 breakthrough infections

An analysis of electronic health records of nearly 580,000 fully vaccinated people in the United States found that while the risk of SARS-CoV-2 breakthrough infection among those with substance-use disorders was low overall, it was higher for people who misuse substances such as alcohol, tobacco, marijuana and opioids.

The study, led by researchers at Case Western Reserve University and the National Institute on Drug Abuse (NIDA)—part of the National Institutes of Health—was published in World Psychiatry.

The study also determined that co-occurring health conditions and adverse socioeconomic factors of health—more common in people with substance-use disorders—appear to be largely responsible for the increased risk of SARS-CoV-2 breakthrough infections. People with substance-use disorders also had elevated rates of severe outcomes, including hospitalization and death, following breakthrough infections.

Photo of Rong Xu
Rong Xu

“With the dominance of the Delta variant, waning vaccine immunity and high comorbidity burden in the U.S. population—six in 10 adults have a chronic disease—it is important to continuously evaluate the effectiveness of COVID-19 vaccines and the long-term effects of COVID-19,” said Rong Xu, a professor of biomedical informatics and director of the Center for Artificial Intelligence in Drug Discovery at the Case Western Reserve School of Medicine and a senior author on the study.

Previous analyses conducted in the early stages of the pandemic found that people with substance-use disorders were at increased risk of SARS-CoV-2 infection. They also were more likely to have severe disease requiring hospitalization or resulting in death. This was particularly true for Black people with a substance-use disorder, the researchers concluded.

Since that September 2020 study, vaccines became widely available for people ages 12 and older that greatly reduce the risk of COVID-19 and severe disease. However, clinical trials evaluating the effectiveness of these vaccines did not specifically include people with substance-use disorders. Because many people with substance-use disorders are immunocompromised from drug use and co-occurring diseases, researchers hypothesized that this population might be at increased risk of breakthrough infections after getting vaccinated.

To investigate these questions, the researchers analyzed the nearly 580,000 electronic health records from people with and without substance-use disorders who were fully vaccinated against COVID-19 between Dec. 1, 2020, and Aug. 14, 2021, and who had not been infected with SARS-CoV-2 before the vaccination. The status of infection was based on the ICD-10 diagnosis code of COVID-19 or lab-test confirmed presence of SARS-CoV-2 and related RNA.

They identified the proportion of people in each group who contracted COVID-19 at least two weeks after their final vaccination. This analysis was repeated after matching patients with and without substance-use disorders for demographic characteristics; socioeconomic factors that influence health, such as housing or employment instability; and lifetime physical illnesses, such as high blood-pressure, heart disease, obesity, or diabetes. The team also examined if fully vaccinated people with breakthrough infections had a different risk for hospitalization and death, compared with matched people without breakthrough infections.

The researchers found that the risk of breakthrough infections was significantly higher in people with substance-use disorders than in those without:

  • 7% of vaccinated people with substance-use disorders had a breakthrough infection during the study, compared with 3.6% of people without substance-use disorders.
  • The risk varied slightly among people with different substance-use disorders, ranging from 6.8% for people with tobacco-use disorder to 7.8% for those with marijuana-use disorder.

“These results emphasize that the same risk factors that affected COVID-19 severity before vaccine was available are still risk factors in breakthrough infections,” said Pamela Davis, dean emerita and the Arline and Curtis Garvin Research Professor at Case Western Reserve School of Medicine and a lead author on the study. “This means that care for ongoing conditions aside from COVID-19 remains very important for both patients and physicians to reduce overall disease morbidity.” 

The study suggests that the increased risk of breakthrough infections in people with substance-use disorders was mainly due to co-occurring diseases and adverse socioeconomic characteristics. When these factors were controlled for, people with most substance-use disorders no longer had elevated rates of breakthrough infections. The only exception were people with marijuana-use disorder, who still were 55% likely to experience breakthrough infections as people without substance-use disorders, even though they tended to be younger and had fewer co-occurring health conditions.

The authors hypothesized that factors such as adverse effects of marijuana on lung and immune function may have contributed to the higher risk for breakthrough infection in this group.

In addition, breakthrough infections were found to greatly increase the risk of severe outcomes, including hospitalization and death, regardless of the presence of substance-use disorders. Among the people with substance-use disorders, 22.5% of those with a breakthrough infection required hospitalization, and 1.7% died during the study period, compared with 1.6% and 0.5%, respectively, among people with substance-use disorders but no breakthrough infection. Additionally, the risk of severe outcomes after breakthrough infection was higher in patients with substance-use disorders.

For more information contact Bill Lubinger at