key: cord-1023270-h8selyrb
authors: Bershteyn, Anna; Dahl, Angela M; Dong, Tracy Q; Deming, Meagan E; Celum, Connie L; Chu, Helen Y; Kottkamp, Angelica C; Greninger, Alexander L; Hoffman, Risa M; Jerome, Keith R; Johnston, Christine M; Kissinger, Patricia J; Landovitz, Raphael J; Laufer, Miriam K; Luk, Alfred; Neuzil, Kathleen M; Paasche-Orlow, Michael K; Pitts, Robert A; Schwartz, Mark D; Stankiewicz Karita, Helen C; Thorpe, Lorna E; Wald, Anna; Zheng, Crystal Y; Wener, Mark H; Barnabas, Ruanne V; Brown, Elizabeth R
title: Self-Assessed Severity as a Determinant of COVID-19 Symptom Specificity: A Longitudinal Cohort Study
date: 2022-02-13
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac129
sha: 81994ff221699ede53b4da25de6bcf88e8554d20
doc_id: 1023270
cord_uid: h8selyrb

COVID-19 symptom definitions rarely include symptom severity. We collected daily nasal swabs and symptom diaries from contacts of SARS-CoV-2 cases. Requiring ≥1 moderate or severe symptom reduced sensitivity to predict SARS-CoV-2 shedding from 60.0% (CI: 52.9−66.7%) to 31.5% (CI: 25.7−38.0%), but increased specificity from 77.5% (CI:75.3−79.5%) to 93.8% (CI: 92.7−94.8%).

M a n u s c r i p t Background COVID-19 symptom assessments are widely used to screen attendees of congregate venues such as schools, [1] workplaces, [2] and entertainment facilities. [3] However, COVID-19 symptoms are non-specific and overlap with other conditions. [4] Common symptom definitions, such as those of the United States (US) Centers for Disease Control (CDC) [5] and World Health Organization (WHO) [6] , do not include metrics of severity, giving equal weight to mild, moderate, and severe symptoms. We examined symptom severity among adults receiving daily SARS-CoV-2 testing.

Between March and August 2020, 780 asymptomatic outpatients in the US enrolled in a hydroxychloroquine post-exposure prophylaxis trial after close contact with a confirmed COVID-19 case. [7] For 16.2% (N=126) of participants, exposure to SARS-CoV-2 occurred through caring for a patient with SARS-CoV-2 in a clinical setting without appropriate personal protective equipment. For the remaining 83.8% (N=654) of participants, exposure occurred through shared residence or prolonged close contact in a confined space.

Participants completed symptom surveys and nasal swabs daily for 14 days. Swabs were tested for SARS-CoV-2 RNA as described previously. [8] Symptoms were self-assessed as "mild" (symptoms did not interfere with daily activities); "moderate" (symptoms interfered with daily activities); "severe" (symptoms prevented daily activities, required an emergency room visit, or required hospitalization).

We studied the association between symptom severity and SARS-CoV-2 detection. In our primary analysis, viral detection was defined as cycle threshold (Ct) ≤40, symptom severity was defined as the most severe symptom reported, and COVID-19 symptoms were defined by CDC criteria. [5] CDC criteria were cough, shortness of breath, loss of taste, or A c c e p t e d M a n u s c r i p t loss of smell; or least two of the following: fever, chills, myalgia, headache, sore throat, nausea or vomiting, diarrhea, fatigue, congestion, or runny nose. We further performed alternative analyses in which viral detection was defined as Ct≤30, symptom severity was defined as a minimum threshold below which symptoms were excluded from contributing toward criteria, and COVID-19 symptoms were defined by WHO criteria. [6] WHO criteria were fever and dry cough; or loss of taste or smell; or at least three of the following: fever, dry cough, fatigue, headache, muscle aches, sore throat, coryza (nasal congestion, runny nose, or sneezing), shortness of breath, nausea or vomiting, or diarrhea. Two-sided 95% confidence intervals (CIs) were produced using generalized estimating equations with clustering by participant. [9] The study was approved by the Western Institutional Review Board, with reliance agreements with the collaborating institutions. The study was registered with ClinicalTrials.gov (NCT04328961). All study participants provided written informed consent.

Median age of participants was 39 (IQR: 26-51), and 59.6% (N=465) were assigned female sex at birth. SARS-CoV-2 RNA was detected in 23.2% (N=181) of participants during follow-up, with 10.6% testing positive on the first day of follow-up (prevalent infection), and 12.6% testing negative on the first day and positive on a subsequent day (incident infection). Age and sex were similar for participants with prevalent, incident, or no SARS-CoV-2 detected (median age 37, 37, and 39 respectively; proportion female 55.4%, 57.1%, and 60.0% respectively).

On a given day, the mean number of COVID-19 symptoms reported by any participant was 1.15, of which 83.3% were mild, 14.9% were moderate, and 1.8% were A c c e p t e d M a n u s c r i p t severe. For participants shedding SARS-CoV-2 on a given day, the mean number of symptoms reported was 3.11, of which 75.7% were mild, 20.5% were moderate, and 3.8% were severe. For participants not shedding SARS-CoV-2 on a given day, the mean number of symptoms reported was 0.95, of which 85.8% were mild, 13.1% were moderate, and 1.1% were severe.

Mild symptoms that met CDC criteria were reported on 28.5% of days when participants shed SARS-CoV-2 and 16.3% of days when participants did not shed SARS-CoV-2 ( Figure 1A and B). At least one moderate or severe symptom, combined with symptoms of any severity meeting CDC criteria, were reported on 31.5% of days when participants shed SARS-CoV-2 and 6.2% of days when participants did not shed SARS-CoV-2. Moderate or severe symptoms were mostly reported in the first week of shedding ( Figure   1C ) and rarely reported prior to shedding onset or among participants who never shed SARS-CoV-2 ( Figure 1D ). Symptom severity changed frequently over the course of follow-up ( Figure 1C , lines between bars). CDC symptom criteria were met at least once by 80.7% of participants who ever shed SARS-CoV-2 and 58.3% of participants who never shed SARS-CoV-2. CDC criteria plus ≥1 moderate or severe symptom occurred in 52.5% of participants who ever shed SARS-CoV-2 and 26.6% of participants who never shed SARS-CoV-2.

Adding ≥1 moderate or severe symptom to CDC criteria would decrease the sensitivity (i.e., true positive rate) of symptoms for concurrent SARS-CoV-2 shedding from 60.0% (CI: 52.9−66.7%) to 31.5% (CI: 25.7−38.0%), but would increase the specificity (i.e., true negative rate) from 77.5% (CI: 75.3−79.5%) to 93.8% (CI: 92.7−94.8%). Similar tradeoffs were observed for shedding the following day or on any future day of follow-up (Supplementary Table S1 ). Adding ≥1 moderate or severe symptom increased the positive A c c e p t e d M a n u s c r i p t In the alternative analyses, moderate or severe symptoms were more common with Ct≤30. True positive rate was higher (41.5%, CI: 32.5−51.1%), but true negative rate was lower (92.7%, CI: 91.5−93.8%) with Ct≤30. When only moderate or severe symptoms were considered or when WHO criteria were used, the true positive rate was lower and the true negative rate was higher (Supplementary Table S1 ). Individual symptoms most predictive of SARS-CoV-2 infection were loss of smell, fever, and loss of taste (Supplementary Table S2 ).

When restricting to moderate or severe symptoms, individual symptoms most predictive of SARS-CoV-2 infection were loss of smell, chills, and loss of taste.

Participants who reported moderate or severe symptoms at least once during followup tended to be younger (median age 36.5, IQR 25-48) than those who remained asymptomatic or reported only mild symptoms (median age 40, IQR 27-51), however, participants who reported moderate or severe symptoms and also tested positive at least once during follow-up tended to be older (median age 39, IQR 25-50) than those who remained asymptomatic or had only mild symptoms despite testing positive at least once during followup (median age 36.5, IQR 23-53). A similar proportion were female among those who reported moderate or severe symptoms (61%) and those who remained asymptomatic or reported only mild symptoms (59%).

In this cohort of US adults recently exposed to a confirmed SARS-CoV-2 case, COVID-19 symptom criteria were highly non-specific. A majority of participants never shedding SARS-CoV-2 over a two-week period met CDC symptom criteria on at least one A c c e p t e d M a n u s c r i p t day. On a given day, more than one in five participants not shedding SARS-CoV-2 met symptom criteria, predominantly due to mild symptoms.

Augmenting COVID-19 symptom definitions to include ≥1 moderate or severe symptom increased specificity of symptom criteria, but decreased sensitivity. Such a trade-off may be appropriate when specificity is desirable, such as when individuals not meeting symptom criteria will undergo further screening for SARS-CoV-2. For example, many work, education, travel, and entertainment venues require symptomatic individuals to remain at home, but additionally require SARS-CoV-2 testing for attendees.

Our study has several limitations. Study participants were US adults recently exposed to a confirmed COVID-19 case and may not be generalizable to other populations. Symptom self-assessment occurred in the context of a clinical trial rather than screening for event attendance, which may have resulted in different reporting patterns, including a possible Hawthorne effect. [10] Symptom and shedding profiles do not account for SARS-CoV-2 variants that emerged since mid-2020. Finally, study participants were unvaccinated; symptoms likely differ for vaccinated individuals.

Adding symptom severity can improve the specificity of COVID-19 symptom definitions. However, positive predictive values were low even when including symptom severity, highlighting the limitations of COVID-19 symptom self-assessment. 

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A Framework for Evaluating Approaches to Symptom Screening in the Workplace During the COVID-19 Pandemic

Screening for SARS-CoV-2 Antigen Before a Live Indoor Music Concert: An Observational Study

Clinical Suspicion of COVID-19 in Nursing Home Residents: Symptoms and Mortality Risk Factors

Coronavirus Disease 2019 (COVID-19) | CDC. Available at

World Health Organization Headquarters (HQ). WHO COVID-19 Case definition

World Health Organization

Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Trajectory of Viral RNA Load Among Persons With Incident SARS-CoV-2 G614 Infection (Wuhan Strain) in Association With COVID-19 Symptom Onset and Severity

Statistical Analysis of Correlated Data Using Generalized Estimating Equations: An Orientation

Understanding the Hawthorne effect

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t Number of person-days during which participants did not meet CDC symptom criteria (gray) or met CDC symptom criteria with only mild (blue), at least one moderate (purple), or at least one severe symptom (red). Person-days are sub-divided by whether a participant is (A) concurrently shedding (B) not concurrently shedding, and (C) by day since shedding onset or (D) never shedding during follow-up. Lines between bars in Panel C depict changes in symptom status of individual participants on sequential days.A c c e p t e d M a n u s c r i p t