In an analysis of almost 55,000 adult participants in three ongoing studies, having depression, anxiety, worry, perceived stress, or loneliness early in the pandemic, before SARS-CoV-2 infection, was associated with a 50% increased risk for developing long COVID. These types of psychological distress were also associated with a 15% to 51% greater risk for impairment in daily life among individuals with long COVID.
Psychological distress was even more strongly associated with developing long COVID than were physical health risk factors, and the increased risk was not explained by health behaviors such as smoking or physical comorbidities, researchers note.
“Our findings suggest the need to consider psychological health in addition to physical health as risk factors of long COVID-19,” lead author Siwen Wang, MD, postdoctoral fellow, department of nutrition, Harvard T. H. Chan School of Public Health, Boston, said in an interview.
“We need to increase public awareness of the importance of mental health and focus on getting mental health care for people who need it, increasing the supply of mental health clinicians and improving access to care,” she said.
The findings were published online in JAMA Psychiatry.
Postacute sequelae of SARS-CoV-2 (“long COVID”), which are “signs and symptoms consistent with COVID-19 that extend beyond 4 weeks from onset of infection” constitute “an emerging health issue,” the investigators write.
Dr. Wang noted that it has been estimated that 8-23 million Americans have developed long COVID. However, “despite the high prevalence and daily life impairment associated with long COVID, it is still poorly understood, and few risk factors have been established,” she said.
Although psychological distress may be implicated in long COVID, only three previous studies investigated psychological factors as potential contributors, the researchers note. Also, no study has investigated the potential role of other common manifestations of distress that have increased during the pandemic, such as loneliness and perceived stress, they add.
To investigate these issues, the researchers turned to three large ongoing longitudinal studies: the Nurses’ Health Study II (NSHII), the Nurses’ Health study 3 (NHS3), and the Growing Up Today Study (GUTS).
They analyzed data on 54,960 total participants (96.6% women; mean age, 57.5 years). Of the full group, 38% were active health care workers.
Participants completed an online COVID-19 questionnaire from April 2020 to Sept. 1, 2020 (baseline), and monthly surveys thereafter. Beginning in August 2020, surveys were administered quarterly. The end of follow-up was in November 2021.
The COVID questionnaires included questions about positive SARS-CoV-2 test results, COVID symptoms and hospitalization since March 1, 2020, and the presence of long-term COVID symptoms, such as fatigue, respiratory problems, persistent cough, muscle/joint/chest pain, smell/taste problems, confusion/disorientation/brain fog, depression/anxiety/changes in mood, headache, and memory problems.
Participants who reported these post-COVID conditions were asked about the frequency of symptoms and the degree of impairment in daily life.
Inflammation, immune dysregulation implicated?
The Patient Health Questionnaire–4 (PHQ-4) was used to assess for anxiety and depressive symptoms in the past 2 weeks. It consists of a two-item depression measure (PHQ-2) and a two-item Generalized Anxiety Disorder Scale (GAD-2).
Non–health care providers completed two additional assessments of psychological distress: the four-item Perceived Stress Scale and the three-item UCLA Loneliness Scale.
The researchers included demographic factors, weight, smoking status, marital status, and medical conditions, including diabetes, hypertension, hypercholesterolemia, asthma, and cancer, and socioeconomic factors as covariates.
For each participant, the investigators calculated the number of types of distress experienced at a high level, including probable depression, probable anxiety, worry about COVID-19, being in the top quartile of perceived stress, and loneliness.
During the 19 months of follow-up (1-47 weeks after baseline), 6% of respondents reported a positive result on a SARS-CoV-2 antibody, antigen, or polymerase chain reaction test.
Of these, 43.9% reported long-COVID conditions, with most reporting that symptoms lasted 2 months or longer; 55.8% reported at least occasional daily life impairment.
The most common post-COVID conditions were fatigue (reported by 56%), loss of smell or taste problems (44.6%), shortness of breath (25.5%), confusion/disorientation/ brain fog (24.5%), and memory issues (21.8%).
Among patients who had been infected, there was a considerably higher rate of preinfection psychological distress after adjusting for sociodemographic factors, health behaviors, and comorbidities. Each type of distress was associated with post-COVID conditions.
In addition, participants who had experienced at least two types of distress prior to infection were at nearly 50% increased risk for post–COVID conditions (risk ratio, 1.49; 95% confidence interval, 1.23-1.80).
Among those with post-COVID conditions, all types of distress were associated with increased risk for daily life impairment (RR range, 1.15-1.51).
Senior author Andrea Roberts, PhD, senior research scientist at the Harvard T. H. Chan School of Public Health, Boston, noted that the investigators did not examine biological mechanisms potentially underlying the association they found.
However, “based on prior research, it may be that inflammation and immune dysregulation related to psychological distress play a role in the association of distress with long COVID, but we can’t be sure,” Dr. Roberts said.
Contributes to the field
Commenting for this article, Yapeng Su, PhD, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center in Seattle, called the study “great work contributing to the long-COVID research field and revealing important connections” with psychological stress prior to infection.
Dr. Su, who was not involved with the study, was previously at the Institute for Systems Biology, also in Seattle, and has written about long COVID.
He noted that the “biological mechanism of such intriguing linkage is definitely the important next step, which will likely require deep phenotyping of biological specimens from these patients longitudinally.”
Dr. Wang pointed to past research suggesting that some patients with mental illness “sometimes develop autoantibodies that have also been associated with increased risk of long COVID.” In addition, depression “affects the brain in ways that may explain certain cognitive symptoms in long COVID,” she added.
More studies are now needed to understand how psychological distress increases the risk for long COVID, said Dr. Wang.
The research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Dean’s Fund for Scientific Advancement Acceleration Award from the Harvard T. H. Chan School of Public Health, the Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award, and the Veterans Affairs Health Services Research and Development Service funds. Dr. Wang and Dr. Roberts have reported no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Su reports no relevant financial relationships.
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