key: cord-0790700-9h5mvgt2
authors: Fisher, Kiva A.; Olson, Samantha M.; Tenforde, Mark W.; Self, Wesley H.; Wu, Michael; Lindsell, Christopher J.; Shapiro, Nathan I.; Files, D. Clark; Gibbs, Kevin W.; Erickson, Heidi L.; Prekker, Matthew E.; Steingrub, Jay S.; Exline, Matthew C.; Henning, Daniel J.; Wilson, Jennifer G.; Brown, Samuel M.; Peltan, Ithan D.; Rice, Todd W.; Hager, David N.; Ginde, Adit A.; Talbot, H. Keipp; Casey, Jonathan D.; Grijalva, Carlos G.; Flannery, Brendan; Patel, Manish M.; Feldstein, Leora R.; Hart, Kimberly W.; McClellan, Robert; Tan, Hsi‐nien; Baughman, Adrienne; Hennesy, Nora A.; Grear, Brittany; Mlynarczyk, Kristin; Marzano, Luc; Plata, Zuwena; Caplan, Alexis; Ogokeh, Constance E.; Smith, Emily R.; Kim, Sara S.; Griggs, Eric P.; Richards, Bridget; Robinson, Sonya; Kim, Kaylee; Kassem, Ahmed M.; Sciarratta, Courtney N.; Marcet, Paula L.
title: Symptoms and recovery among adult outpatients with and without COVID‐19 at 11 healthcare facilities—July 2020, United States
date: 2021-01-06
journal: Influenza Other Respir Viruses
DOI: 10.1111/irv.12832
sha: 9deb71ff1db59df91d8d5faaa4cf0e6567eb76d5
doc_id: 790700
cord_uid: 9h5mvgt2

BACKGROUND: Symptoms of mild COVID‐19 illness are non‐specific and may persist for prolonged periods. Effects on quality of life of persistent poor physical or mental health associated with COVID‐19 are not well understood. METHODS: Adults aged ≥18 years with laboratory‐confirmed COVID‐19 and matched control patients who tested negative for SARS‐CoV‐2 infection at outpatient facilities associated with 11 medical centers in the United States were interviewed to assess symptoms, illness duration, and health‐related quality of life. Duration of symptoms, health‐related quality of life measures, and days of poor physical health by symptoms experienced during illness were compared between case patients and controls using Wilcoxon rank‐sum tests. Symptoms associated with COVID‐19 case status were evaluated by multivariable logistic regression. RESULTS: Among 320 participants included, 157 were COVID‐19 cases and 163 were SARS‐CoV‐2 negative controls. Loss of taste or smell was reported by 63% of cases and 6% of controls and was strongly associated with COVID‐19 in logistic regression models (adjusted odds ratio [aOR] = 32.4; 95% confidence interval [CI], 12.6‐83.1). COVID‐19 cases were more likely than controls to have experienced fever, body aches, weakness, or fatigue during illness, and to report ≥1 persistent symptom more than 14 days after symptom onset (50% vs 32%, P < .001). Cases reported significantly more days of poor physical health during the past 14 days than controls (P < .01). CONCLUSIONS: Differentiating COVID‐19 from other acute illnesses will require widespread diagnostic testing, especially during influenza seasons. Persistent COVID‐19‐related symptoms may negatively affect quality of life, even among those initially presenting with mild illness.

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide. COVID-19 disease severity ranges from asymptomatic illness to death. 1 Symptoms associated with SARS-CoV-2 infection are non-specific, making it difficult to distinguish COVID-19 from other diseases. Recent reports suggest that recovery from COVID-19 can be prolonged, even when initial symptoms are mild. 2, 3 Effects of prolonged recovery on health-related quality of life, including physical health, mental health, and return to usual activities, have received little attention for Descriptions of symptoms during the acute phase of COVID-19 have mainly relied on case series 5, 6 ; few studies have reported symptom profiles and return to baseline health using a comparison group without COVID-19. The objective of this investigation was to compare symptom prevalence and recovery among adults with and without COVID-19 who were tested at outpatient health facilities for SARS-CoV-2 infection during July 2020.

A matched case-control study was performed among a random sample of adults (≥18 years) tested for SARS-CoV-2 at outpatient facilities during July 1-29, 2020 . A COVID-19 case was laboratory-confirmed for SARS-CoV-2 by reverse transcriptase polymerase chain reaction (RT-PCR). Control participants ("controls") were defined as SARS-CoV-2 RT-PCR-negative results in patients who were symptomatic and tested at the same health facilities.

Potentially eligible patients were randomly selected in a ratio of 2 controls for each case patient from lists of adults who were tested at outpatient facilities associated with 11 academic medical centers in the Influenza Vaccine Effectiveness in the Critically Ill (IVY) Network. 7 

Participants were contacted by telephone beginning 14-26 days after patient's test date. Participant demographics and self-reported underlying chronic medical conditions were entered into REDCap® software. 8 Participants were asked how many days they felt unwell or had symptoms prior to getting tested. For each reported symptom or combination of symptoms (eg, nausea or vomiting or loss of appetite; body aches or weakness or fatigue; runny nose or congestion or sore throat; and loss of taste or smell), patients were asked if they experienced the symptom during illness, as well as if the symptom was still present at the time of the interview. Symptom question response options were binary (yes/no).

For all symptoms, participants were asked to recall the number of days they experienced the symptom. Questions about convalescence, or time to recovery, were asked at the time of the interview. 

Differences between case patients and controls were compared using chi-square tests and analysis of variance to assess demographic characteristics, underlying chronic condition and symptom prevalence. Symptom duration and health-related quality of life measures were compared between case patients and controls using Wilcoxon rank-sum tests. Because of a large number of unmatched pairs, due in part to the strict inclusion criteria (ie, symptomatic at the time of first test), unconditional logistic regression accounting for sitelevel clustering was used to assess symptom differences between case patients and controls, adjusting for race/ethnicity, sex, age, and presence of ≥1 underlying chronic medical condition. 10 Adjusted odds ratios (aOR) and 95% confidence intervals (CI) are reported.

Significance levels were set at P < .05. Analyses were performed using SAS version 9.4 software (SAS Institute).

After randomization and matching, a total of 1827 participants were identified for inclusion (615 case patients and 1212 controls).

Of those, 163 adults declined to participate. Of 802 adults successfully contacted who agreed to participate (295 cases and 507 controls), 470 were not eligible for the investigation (ie, reported no symptoms, had multiple tests, or both). Among 332 eligible participants, 12 interviews were excluded because participants did not answer symptom questions. The final sample included 320 participants, 157 COVID-19 case patients and 163 controls. Participants reported a median of 3 days (IQR, 2-4) of symptoms before SARS-CoV-2 test; interviews were conducted 15-52 days (median, 22 days) after illness onset. The participants were 53% female; the median age for both case patients and controls was 40 years (cases IQR, 28-53 years vs controls IQR, 30-53 years). Compared with controls, case patients were less likely to report being White, non-Hispanic, (60% vs 77%; P = .005), less likely to have completed college (51% vs 67%; P < .001), and less likely to report ≥1 underlying chronic medical condition (48% vs 61%; P = .02).

COVID-19 cases reported higher prevalence than controls for 9 of 11 categories of symptoms assessed (Table 1 ). In logistic regression models adjusted for age, sex, race/ethnicity and presence of ≥1 underlying chronic medical condition, the strongest association with COVID-19 was observed for reported loss of taste or smell (63% of cases vs 6% of controls, aOR = 32.4; 95% CI, 12.6-83.1), while fever (>100.4° Fahrenheit; 45% vs 20%, aOR = 3.3; 95% CI, 2.2-5.0) and body aches, weakness, or fatigue (78% vs 56%, aOR = 3.3; 95% CI, 2. 6-4.3) were also more likely to be reported among case patients than controls (Figure 1) .

Case patients had a longer recovery period from their illness compared with controls. Among participants who reported each TA B L E 1 Frequency and duration of reported symptoms experienced during acute illness among laboratory-confirmed COVID-19 cases compared with controls who tested negative for SARS-CoV-2 infection, July 2020 

Days of illness 121 (77%) 12 (8) (9) (10) (11) (12) (13) (14) (15) 138 (85%) 6 (4-9) <.01

Loss of taste or smell 98 (63%) 7 (4-14) 9 (6%) 5 (3) (4) (5) (6) (7) (8) (9) .30

Body aches/weakness/ fatigue 121 (78%) 10 (5-16) 91 (56%) 5 (3-10) <.01

Any cough 102 (65%) 7 (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) 72 (44%) 6 (2) (3) (4) (5) (6) (7) (8) .11

Diarrhea 69 (44%) 4 (2-7) 42 (26%) 3 (2) (3) (4) (5) .30

Nausea/vomiting/loss of appetite

Shortness of breath 57 (37%) 7 (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) 41 (25%) 4 (3) (4) (5) (6) (7) (8) .01

Felt feverish/chills 81 (53%) 3 (2-5) 61 (38%) 3 (2) (3) (4) (5) .84

Chest pain 37 (24%) 2 (1-5) 24 (15%) 2 (1) (2) (3) (4) .45

Abdominal pain 26 (17%) 3 (1) (2) (3) (4) (5) 29 (18%) 4 (2) (3) (4) (5) .43

Runny nose/congestion/ sore throat 98 (62%) 6 (3-10) 117 (72%) 5 (3) (4) (5) (6) (7) (8) .61

a Participants who reported experiencing symptom during illness were asked to recall symptom duration, in days. Responses were missing or unknown for reported loss of taste or smell (n = 3), body aches/weakness/fatigue (n = 3), fever (n = 5), diarrhea (n = 1), nausea/vomiting/loss of appetite (n = 2), shortness of breath (n = 1), chills (n = 4), abdominal pain (n = 1), and runny nose (n = 1). Symptom duration was missing or unknown for reported loss of taste or smell (n = 1), body aches/weakness/fatigue (n = 2), cough (n = 5), diarrhea (n = 2), nausea/vomiting/loss of appetite (n = 3), shortness of breath (n = 1), chills (n = 2), abdominal pain (n = 2), chest pain (n = 4), and runny nose (n = 5). b P-value from Wilcoxon rank-sum test for difference in number of days of symptoms reported among COVID-19 cases and controls. 

Our findings show that adults with laboratory-confirmed COVID-19 reported a broad range of symptoms and prolonged recovery compared with a matched comparison group of symptomatic adults who tested negative for SARS-CoV-2 infection. Compared with controls, case patients had over 30 times the odds of experiencing loss of taste or smell during acute illness. This finding is consistent with other reports that provide evidence for anosmia and dysgeusia associated with COVID-19 positivity. 11, 12 In the current study, body aches, weakness, and fatigue were reported more frequently among case patients compared with controls. Studies have reported fatigue as a prominent clinical manifestation of COVID-19. 13 These findings highlight challenges differentiating COVID-19 from common causes of acute illness among patients presenting to outpatient facilities. While report of loss of taste F I G U R E 1 Adjusted a odds ratios comparing odds of reported symptoms among COVID-19 cases b compared with controls c , July 2020. a Adjusted for race/ethnicity, sex, age, and presence of ≥1 underlying chronic medical condition (at least one of the following underlying chronic medical conditions: cardiac condition, hypertension, asthma, chronic obstructive pulmonary disease (COPD), immunodeficiency, psychiatric condition, diabetes, or obesity). b A COVID-19 case was laboratory-confirmed for SARS-CoV-2 by reverse transcriptase polymerase chain reaction (RT-PCR). c Control participants tested negative for SARS-CoV-2 infection by RT-PCR at the same health facilities. Potentially eligible patients were randomly selected in a ratio of 2 controls for each case patient from lists of adults who were tested at outpatient clinics associated with 11 academic medical centers participating in the Influenza Vaccine Effectiveness in the Critically Ill (IVY) Network or smell may be highly predictive of SARS-CoV-2 infection, widespread testing will be needed to identify COVID-19 patients with mild illness, especially during co-circulation with influenza and other respiratory viruses.

COVID-19 also has prolonged effects on both physical and mental health during recovery, even among patients with mild symptoms. Recognition of a post-viral syndrome characterized by persistent symptoms is growing. [14] [15] [16] Symptoms associated with this syndrome include fatigue, chills and sweats, body aches, difficulty concentrating (or "brain fog"), difficulty breathing or shortness of breath, and delayed return to pre-COVID-19 health. In addition, some patients have experienced anxiety and sleep disturbances. 14, 15 However, we did not observe a difference in these measures between cases and controls. Examination of health-related quality of life measures during recovery from acute illness was a novel aspect of this study. COVID-19 cases experienced significantly more days of poor physical health due to poor health than controls. In contrast, there were no differences in reported days of poor mental health in the past 14 days. The low prevalence of poor mental health was surprising given the documented effects of pandemic mitigation TA B L E 2 Number of days that COVID-19 cases and controls without COVID-19 reported impacts on physical or mental health, or limitations with usual activities Healthy days measure a

Not good physical health 156 5 (0-9) 162 0 (0-3) <.01

Not good mental health 155 0 (0-7) 160 1 (0-4) .91

Activity limitation 155 4 (0-7) 162 0 (0-3) <.01

Sad, depressed, blue 155 0 (0-4) 161 0 (0-2) .26

Anxious 154 1 (0-7) 160 1 (0-6) .87

Sleepless

.07

Full of energy 155 5 (1-12) 159 8 (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) .04 "Would you say that in general your health is excellent, very good, good, fair, or poor?" (data not shown); "Now thinking about your physical health, which includes physical illness and injury, for how many days during the past 14 days was your physical health not good?" (Not good physical health); "Now thinking about your mental health, which includes stress, depression, and problems with emotions, for how many days during the past 14 days was your mental health not good?" (Not good mental health); "During the past 14 days, for about how many days did poor physical or mental health keep you from doing your usual activities, such as self-care, work, or recreation?" (Activity limitation); "During the past 14 days, for about how many days did pain make it hard for you to do your usual activities, such as self-care, work, or recreation?" (Pain); "During the past 14 days, for about how many days have you felt sad, blue, or depressed?" (Sad, depressed, blue); "During the past 14 days, for about how many days have you felt worried, tense, or anxious?" (Anxious); "During the past 14 days, for about how many days have you felt you did not get enough rest or sleep?" (Sleepless); "During the past 30 days, for about how many days have you felt very healthy and full of energy?" (Full of energy 

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

A de-identified dataset for this study may be requested from CDC [www.cdc.gov/info].

Kiva A. Fisher https://orcid.org/0000-0002-5045-7944

Grijalva reports grants from Campbell Alliance, the National Institutes of Health, the Food and Drug Administration, the Agency for Health Care Research and Quality and Sanofi-Pasteur, and consultation fees from Pfizer

Lindsell reports grants from National Institutes of Health and the Department of Defense and other support from Marcus Foundation, Endpoint Health, Entegrion, bioMerieux, and Bioscape Digital, outside the submitted work. Nathan I. Shapiro reports grants from the National Institutes of Health

Janssen Pharmaceuticals, and Regeneron, outside the submitted work. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc, and Avisa, LLC, outside the submitted work. Adit A. Ginde reports grants from the National Institutes of Health and Department of Defense, outside the submitted work

Kiva Fisher: Conceptualization (equal); Formal analysis (lead)

Investigation (lead)

Visualization (equal)

Samantha M Olson: Formal analysis (equal)

Visualization (equal)

Writingoriginal draft (supporting)

Writing-review & editing (equal). Mark W Tenforde: Conceptualization (equal)

Writing-original draft (supporting)

Writingreview & editing (equal)

Funding acquisition (lead)

Resources (lead)

Supervision (equal)

Writing-original draft (supporting)

Michael Wu: Investigation (supporting)

Visualization (equal)

Writing-review & editing (supporting)

Software (equal)

Writing-review & editing (supporting). Nathan I Shapiro: Resources (lead)

Writing-review & editing (supporting). D. Clarke Files: Resources (lead)

Writing-review & editing (supporting)

Writing-review & editing (supporting)

Writing-review & editing (supporting). Matthew E Prekker: Resources (lead)

Writing-review & editing (supporting)

Matthew Exline: Resources (lead); Writing-review & editing (supporting)

Writingreview & editing (supporting)

Samuel Brown: Resources (lead); Writing-review & editing (supporting)

Writing-review & editing (supporting)

Writing-review & editing (supporting)

Writing-review & editing (supporting)

Writing-review & editing (supporting)

Writing-review & editing (support

Writing-review & editing (supporting). Carlos G Grijalva: Resources (lead)

Brendan Flannery: Conceptualization (equal)

Formal analysis (equal)

Supervision (lead)

Writing-original draft (supporting)

Writing-review & editing (equal)

Supervision (equal)

Writing-original draft (supporting)

Leora R Feldstein: Conceptualization (equal)

Supervision (equal)

Writing-original draft (supporting)

Writing-review & editing (equal)

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