Among a cohort who never had COVID-19 but tested positive within 1 year after baseline, depression, anxiety, stress, loneliness, and concerns about infection were linked to a 33% to 50% increased risk of self-reported postinfection symptoms lasting at least 4 weeks, as well as functional impairment, finds a study published today in JAMA Psychiatry.
"We were surprised by how strongly psychological distress before a COVID-19 infection was associated with an increased risk of long COVID," said first author Siwen Wang, MD, a researcher in the Department of Nutrition at Harvard T.H. Chan School of Public Health, in a Harvard news release. "Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension."
A team led by Clarkson University researchers analyzed data from three large ongoing, predominantly female Nurses' Health Study II, Nurses' Health Study 3, and the Growing Up Today Study. Participants completed at least one follow-up survey about their symptoms, COVID-19 test results, and any related hospitalizations from April 2020 to November 2021 (6 monthly, then quarterly for 336 days). Median time from baseline to infection was 30 weeks.
More distress, more risk
Among 54,960 participants, average age was 57.5 years, 96.5% were White, 38.0% were active healthcare workers, 96.6% were female, and 6% tested positive for COVID-19 during follow-up.
Among the 3,193 participants with a positive test result, all types of distress were significantly tied to an increased risk of long-COVID conditions in a dose-dependent manner after adjustment for demographic factors. The risk ratio [RR] for probable depression was 1.39, while it was 1.47 for anxiety, 1.43 for being very worried about COVID-19, 1.50 for being in the highest quartile of perceived stress, and 1.35 for being lonely sometimes or often.
Participants who had at least two types of distress before testing positive for COVID-19 were at nearly double the risk for long COVID (RR, 1.49), and all conditions were tied to an increased risk of impairment in the ability to complete daily activities (783 cases) in participants with long COVID (RR, 1.15 to 1.51).
At baseline, those who had probable depression or anxiety were younger and more likely to work in healthcare and had a higher prevalence of asthma. Relative to the reference group, participants who were very worried about COVID-19 were more likely to be female and of minority race and to have asthma. Compared with participants with the least perceived stress, those with the most stress were younger and more likely to have asthma.
Participants who had depression and anxiety and those who were very worried about COVID-19, lonely, or had the most stress were more likely than others to have a body mass index of at least 35 kilograms per meter squared and to be single.
Among participants with a positive COVID-19 test result during follow-up, 43.9% reported long-COVID conditions. Of these, 86.9% reported symptoms persisting 2 months or longer, and 55.8% said they had at least occasional daily life impairment related to long COVID. The most common symptoms were fatigue (56.0%), abnormal smell or taste (44.6%), shortness of breath (25.5%), "brain fog" (24.5%), and impaired memory (21.8%).
All COVID-19 symptoms but persistent cough and impaired smell or taste were more prevalent in participants with versus without each type of distress. Individuals with distress at baseline reported more long-COVID symptoms (eg, average depression symptoms, 3.4; vs 2.5 for no depression). Symptoms of depression or anxiety, worry, and stress at baseline were linked to a 25% to 51% higher risk of symptoms that interfered with activities occasionally to always.
Symptoms not psychosomatic
The authors noted that long-COVID symptoms associated with prolonged psychological distress can interfere with the ability to return to work and can decrease quality of life. "The findings of this study suggest that preinfection psychological distress may be a risk factor for post–COVID-19 conditions in individuals with SARS-CoV-2 infection," they wrote.
But they cautioned against misinterpreting the results as supporting the idea that long-COVID symptoms are psychosomatic. "First, among respondents who developed post–COVID-19 conditions, more than 40% had no distress at baseline," they wrote. "Second, symptoms of post–COVID-19 conditions differ substantially from symptoms of mental illness."
In addition, they said, while physical activity is protective against relapse of mental illness, more than half of participants with long-COVID symptoms reported lapses triggered by physical activity. Results were also similar after excluding participants who reported only psychiatric, cognitive, or neurologic symptoms.
Rather, inflammation and immune dysregulation associated with prolonged psychological distress may help explain the increased risk of long COVID in this group.
"Further research should investigate whether interventions that reduce distress help prevent or treat post–COVID-19 conditions," the researchers concluded. "Identification and treatment of biological pathways linking distress with long-term COVID-19 symptoms may benefit individuals with post–COVID-19 conditions or other chronic postinfection syndromes."
Senior author Andrea Roberts, PhD, said in the news release, "To the best of our knowledge, this is the first prospective study to show that a wide range of social and psychological factors are risk factors for long COVID and daily life impairment due to long COVID.
"We need to consider psychological health in addition to physical health as risk factors of long COVID-19. These results also reinforce the need to increase public awareness of the importance of mental health and to get mental health care for people who need it."
