Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post-COVID-19 Conditions

Abstract

Importance: Few risk factors for long-lasting (≥4 weeks) COVID-19 symptoms have been identified.

Objective: To determine whether high levels of psychological distress before SARS-CoV-2 infection, characterized by depression, anxiety, worry, perceived stress, and loneliness, are prospectively associated with increased risk of developing post-COVID-19 conditions (sometimes called long COVID).

Design, setting, and participants: This prospective cohort study used data from 3 large ongoing, predominantly female cohorts: Nurses' Health Study II, Nurses' Health Study 3, and the Growing Up Today Study. Between April 2020 and November 2021, participants were followed up with periodic surveys. Participants were included if they reported no current or prior SARS-CoV-2 infection at the April 2020 baseline survey when distress was assessed and returned 1 or more follow-up questionnaires.

Exposures: Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at study baseline early in the pandemic, before SARS-CoV-2 infection, using validated questionnaires.

Main outcomes and measures: SARS-CoV-2 infection was self-reported during each of 6 monthly and then quarterly follow-up questionnaires. COVID-19-related symptoms lasting 4 weeks or longer and daily life impairment due to these symptoms were self-reported on the final questionnaire, 1 year after baseline.

Results: Of 54 960 participants, 38.0% (n = 20 902) were active health care workers, and 96.6% (n = 53 107) were female; the mean (SD) age was 57.5 (13.8) years. Six percent (3193 participants) reported a positive SARS-CoV-2 test result during follow-up (1-47 weeks after baseline). Among these, probable depression (risk ratio [RR], 1.32; 95% CI = 1.12-1.55), probable anxiety (RR = 1.42; 95% CI, 1.23-1.65), worry about COVID-19 (RR, 1.37; 95% CI, 1.17-1.61), perceived stress (highest vs lowest quartile: RR, 1.46; 95% CI, 1.18-1.81), and loneliness (RR, 1.32; 95% CI, 1.08-1.61) were each associated with post-COVID-19 conditions (1403 cases) in generalized estimating equation models adjusted for sociodemographic factors, health behaviors, and comorbidities. Participants with 2 or more types of distress prior to infection were at nearly 50% increased risk for post-COVID-19 conditions (RR, 1.49; 95% CI, 1.23-1.80). All types of distress were associated with increased risk of daily life impairment (783 cases) among individuals with post-COVID-19 conditions (RR range, 1.15-1.51).

Conclusions and relevance: 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. Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection symptoms.

Figure 1.. Association Between Distress and Established COVID-19 Risk Factors With Subsequent Post–COVID-19 Conditions, April 2020 Through November 2021 (N = 3193)

All risk ratios are adjusted for covariates and established COVID-19 risk factors. Each type of distress is modeled separately as the independent variable, adjusted for age, sex, racial identity, health care worker status, partner’s education, body mass index (BMI), smoking status, and history of diabetes, hypertension, high cholesterol, asthma, and cancer. Estimates for established risk factors are from a single model with the following independent variables: age, sex, racial identity, health care worker status, partner’s education, BMI, smoking status, and history of diabetes, hypertension, high cholesterol, asthma, and cancer. Perceived stress and loneliness data were queried only in participants who were not active health care workers (n = 1628). Number of distress types is a count of probable depression, probable anxiety, somewhat or very worried about COVID, highest-quartile perceived stress, and lonely some of the time or often. BMI is calculated as weight in kilograms divided by height in meters squared. GAD-2 indicates 2-item Generalized Anxiety Disorder scale; PHQ-2, 2-item Patient Health Questionnaire; PSS-4, 4-item Perceived Stress Scale; Q, quartile.

Figure 2.. Prevalence of Long-term COVID-19–Related Symptoms by Types of Distress at Baseline (April-August 2020), Among 1403 Individuals With Post–COVID-19 Conditions

Rare symptoms of post–COVID-19 conditions that are not presented because of space constraints include intermittent fever; rash, blisters, or welts anywhere on the body; and mouth or tongue ulcers. Values do not add to 100% because midlevels of variables (ie, subclinical depressive and anxious symptoms, somewhat worried, and loneliness less than some of the time) are not shown because of space constraints. Perceived stress and loneliness were queried only in participants who were not active health care workers.

Figure 3.. Association of Distress With Risk of Daily Life Impairment From Post–COVID-19 Conditions Among 1403 Individuals With Post–COVID-19 Conditions

Each type of distress is modeled separately as the independent variable, adjusted for age, sex, racial identity, health care worker status, partner’s education, BMI, smoking status, and history of diabetes, hypertension, high cholesterol, asthma, and cancer. Perceived stress and loneliness were queried only in participants who were not active health care workers. Number of types of distress is a count of probable depression, probable anxiety, somewhat or very worried about COVID-19, highest-quartile perceived stress, and lonely some of the time or often. GAD-2 indicates 2-item Generalized Anxiety Disorder; PHQ-2, 2-item Patient Health Questionnaire; PSS-4, 4-item Perceived Stress Scale; Q, quartile.