key: cord-0904014-gy2ivymv authors: Desgranges, F.; Tadini, E.; Munting, A.; Regina, J.; Paraskevas, F.; Karachalias, E.; Viala, B.; Suttels, V.; Haefliger, D.; Kampouri, E.; Van Singer, M.; Tschopp, J.; Rochat Stettler, L.; Schaad, S.; Brahier, T.; Hugli, O.; Mueller Chabloz, Y.; Gouveia, A.; Opota, O.; Carron, P.-N.; Guery, B.; Papadimitriou-Olivgeris, M.; Boillat-Blanco, N. title: Post-COVID-19 syndrome in outpatients: a cohort study date: 2021-04-20 journal: nan DOI: 10.1101/2021.04.19.21255742 sha: 3c5d54b4693c27ae9addff2c4a6faa3a5e7a66de doc_id: 904014 cord_uid: gy2ivymv Background Some patients experience long-term symptoms after COVID-19, but data on outpatients with mild-to-moderate COVID-19 are scarce. Objective To describe persisting symptoms more than 3 months after infection in PCR-confirmed COVID-19 in comparison to negative SARS-CoV-2 PCR outpatients and to identify predictors of long-term symptoms in COVID-19. Setting Outpatient clinics of a Swiss university center. Patients 418 symptomatic outpatients with PCR-confirmed COVID-19 (COVID-positive) and 89 negative SARS-CoV-2 PCR (COVID-negative). Design Prospective cohort study. Measurements Predefined long-term symptoms were evaluated though a phone interview >3 to 10 months after diagnosis. Associations between long-term symptoms and PCR test result, as well predictors of persisting symptoms in COVID-positive were evaluated by multivariate logistic regression including potential confounders (age, sex, smoking, comorbidities, time of the phone survey). Results The study population consisted mostly of young (median of 41 versus 36 years in COVID-positive and COVID-negative, respectively; p=0.020) health care workers (67% versus 82%; p=0.006).. Persisting symptoms were reported by 223 (53%) COVID-positive and 33 (37%) COVID-negative (p=0.006). Overall, 21% COVID-positive and 15% COVID-negative (p=0.182) consulted a doctor for these symptoms. Four surveyed symptoms were independently associated with COVID-19: fatigue (adjusted odds ratio [aOR] 2.14, 95%CI 1.04-4.41), smell/taste disorder (26.5, 3.46-202), dyspnea (2.81, 1.10-7.16) and memory impairment (5.71, 1.53-21.3). Among COVID-positive, female gender (aOR 1.67, 95% CI 1.09-2.56) and overweight/obesity (1.67, 1.10-2.56) were predictors of persisting symptoms. Limitations Undiagnosed SARS-CoV-2 infection in COVID-negative cannot be completely excluded. Conclusion More than half of COVID-positive outpatients report persisting symptoms up to 10 months after infection and 21% seek medical care for this reason. These data suggest that post-COVID syndrome places a significant burden on society and especially healthcare systems. p=0.006).. Persisting symptoms were reported by 223 (53%) COVID-positive and 33 (37%) COVID-negative (p=0.006). Overall, 21% COVID-positive and 15% COVID-negative (p=0.182) consulted a doctor for these symptoms. Four surveyed symptoms were independently associated with COVID-19: fatigue (adjusted odds ratio [aOR] 2.14, 95%CI 1.04-4.41), smell/taste disorder (26.5, 3.46-202) , dyspnea (2.81, 1.10-7.16) and memory impairment (5.71, 1.53-21.3). Among COVID-positive, female gender (aOR 1.67, 95% CI 1.09-2.56) and overweight/obesity (1.67, 1.10-2.56) were predictors of persisting symptoms. Undiagnosed SARS-CoV-2 infection in COVID-negative cannot be completely excluded. More than half of COVID-positive outpatients report persisting symptoms up to 10 months after infection and 21% seek medical care for this reason. These data suggest that post-COVID syndrome places a significant burden on society and especially healthcare systems. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2021 1 More than one year after the first cases of Coronavirus disease 2019 (COVID-19) (1), the 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic remains a constant 3 threat challenging the capacity of healthcare systems and affecting well-being of many 4 individuals. The clinical presentation and outcome of acute COVID-19 is well described, most 5 patients presenting with mild disease and only a minority needing hospital admission (2) . 6 While most affected people experience complete resolution of their symptoms after two to 7 six weeks (3, 4) , symptoms lasting more than 3 months have been reported in social media (5-8 7) and in observational studies (8) (9) (10) (11) (12) (13) . Three studies reported that a large number of patients 9 have persisting symptoms for more than 6 months after COVID-19: one study including adults 10 discharged from hospital (14) and two studies including outpatients with mild-to-moderate 11 disease (15, 16) . Recent guidelines defined post-COVID-19 syndrome as the persistence of 12 signs and symptoms for more than 3 months after infection in the absence of an alternative 13 diagnosis (17). 14 Although they represent the vast majority of cases, data on long-term consequences in 15 outpatients with mild-to-moderate COVID-19 are still scarce. To the best of our knowledge, 16 no study compared the prevalence of persisting symptoms among patients screened for 17 similar symptoms, between those tested positive for SARS-CoV-2 and those tested negative. 18 Therefore, the association between PCR-confirmed COVID-19 and long-term symptoms is not 19 well established. Furthermore, no study explored the factors associated with persisting 20 symptoms in outpatients. These data are crucial as they may modify patients' follow-up after 21 their infection and influence public health vaccination strategies by identifying additional 22 population groups that should be prioritized. 23 We aimed to compare the prevalence of symptoms persisting for more than 3 months 24 between SARS-CoV-2 PCR-confirmed (COVID-positive) and PCR-negative (COVID-negative) 25 patients in outpatient clinics, and to identify predictors of persisting symptoms in COVID-26 positive. 27 This cohort study recruited consecutive PCR-confirmed COVID-19 patients (COVID-positive 31 group) during their initial visit in the emergency department (ED) or in the SARS-CoV-2 32 screening center of the University hospital of Lausanne, as well as in the two outpatient clinics 33 of the University of Lausanne, Switzerland, between February 26 th and April 27 th 2020. During 34 the study period, SARS-CoV-2 screening was restricted to symptomatic patients (i.e. 35 symptoms of acute respiratory tract infection, anamnestic fever or sudden loss of smell or 36 taste) with at least one risk factor for severe COVID-19 (i.e. ≥ 65 years old or presence of a 37 comorbidity such as hypertension, diabetes, cancer, chronic cardiac or respiratory disease, 38 immunosuppression) and to symptomatic health workers (18) . Validated nucleic acid 39 amplification tests were used and a dedicated trained medical team performed the 40 nasopharyngeal swabs (19) . 41 We included a control group of outpatients attending the same health facilities during the 42 same period with symptoms suggestive of COVID-19 (cough and/or dyspnea) at presentation, 43 but a negative PCR SARS-CoV-2 result in nasopharyngeal swab (COVID-negative group). This 44 group was part of a prospective cohort of patients with acute respiratory infections previously 45 described (20, 21) . 46 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In both groups, there was a majority of women and health care workers. Approximately a third 115 of patients suffered from a comorbidity, mainly obesity, arterial hypertension, and asthma 116 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Table 1 ). Most patients were tested within the first week of symptom onset and had normal 117 vital signs at initial consultation. Compared to COVID-negative, COVID-positive were slightly 118 older and less often health care workers, active smokers, and asthmatic. COVID-positive 119 reported less often a history of fever, dyspnea, or sore throat at the time of evaluation. 120 The study team assessed long-term symptoms via the phone survey at a median of 105 days 121 (interquartile range [IQR], 121-204 days) and 242 days (IQR 236-248 days) after the initial 122 consultation in the COVID-positive and COVID-negative groups, respectively (p<0.001). The 123 study team called 190 (45%) COVID-positive during the first period (>3 to 5 months after the 124 initial visit), 102 (24%) during the second period (>5 to 7 months) and 126 (30%) during the 125 third period (>7 to 10 months). Patients surveyed in the first period were significantly older, 126 less often health-care workers and had more comorbidities than those in the two other 127 periods (Appendix Table 1 ). The study team called all COVID-negative during the third period. 128 At the time of the phone survey, 223/418 (53%) COVID-positive and 33/89 (37%) COVID-130 negative patients (p=0.006) reported the presence of any long-term symptom ( Figure 1A , 131 Table 2 ). 132 In COVID-positive, the main reported symptoms were fatigue (n=132, 32%), smell or taste 133 disorder (n=93, 22%), dyspnea (n=66, 16%), headache (n=50, 12%), memory impairment 134 (n=48, 11%), hair loss (n=43, 10%), and sleep disorder (n=41, 10%). The prevalence of long-135 term symptoms was similar during the 3 periods surveyed ( Figure 2B ). In COVID-negative, the 136 main reported symptoms were fatigue (n=15, 17%), headache (n=10, 11%), sleep disorder 137 (n=10, 11%), and dyspnea (n=7, 8%). 138 COVID-positive reported more often smell or taste disorder (p=0.001), fatigue (p=0.006) and 139 memory impairment (p=0.003) than COVID-negative. The prevalence of other symptoms was 140 similar between COVID-positive and COVID-negative. The proportions of patients with ≥ 2 and 141 ≥ 3 symptoms were greater in COVID-positive than COVID-negative (38% vs 19%; p=0.001 and 142 23% vs 9.0 %; p=0.002, respectively). The proportion of patients requiring a medical 143 consultation for persisting symptoms was similar between COVID-positive and COVID-144 negative (21% versus 15%, p=0.182). 145 After adjusting for potential confounders, COVID-positive status was a predictor for reporting 147 any symptom (adjusted odds ratio [aOR] 2.04, 95% CI 1.14-3.67; p=0.02), fatigue (aOR 2.14, 148 (Table 2 ). Of note, dyspnea associated with 151 limited physical activity (NYHA ≥2), as well as other long-term symptoms were not associated 152 with COVID status. 153 While 57% of women presented long-term symptoms, only 47% of men did (p=0.049). While 155 59% of overweight/obese patients presented long-term symptoms, only 49% of patients with 156 healthy weight did (p=0.041). After adjusting for potential confounders, independent 157 predictors of reporting any long-term symptoms were still female gender (aOR 1.67, 95% CI 158 1.09-2.56; p=0.019) and overweight/obesity (aOR 1.67, 95% CI 1.10-2.56; p=0.017; Table 3 ). 159 The same predictors were associated with long-term fatigue. Predictor of dyspnea was 160 overweight/obesity. Predictor of smell or taste disorder was female gender. Predictor of 161 memory impairment was active smoking (Figure 3 ). Predictors of other long-term symptoms, 162 which were not associated with COVID status, are presented in Appendix table 2. 163 164 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In a large cohort of PCR-confirmed COVID-19 outpatients, we evaluated the prevalence of 166 persisting symptoms 3 to 10 months after diagnosis and compared it with a cohort of negative 167 SARS-CoV-2 PCR patients included during the same period with a similar clinical presentation. 168 In these study populations consisting mostly of young and healthy participants, most working 169 as health care workers, we showed that 53% of patients with PCR-confirmed COVID-19 report 170 persisting symptoms, while 37% with negative SARS-CoV-2 PCR do. Interestingly, only 4 out of 171 the 14 surveyed persisting symptoms were independently associated with COVID status, i.e. 172 fatigue, smell or taste disorder, dyspnea and memory impairment. 173 The type and prevalence of long-lasting symptoms in COVID-positive are consistent with 174 existing literature. In a systematic review and meta-analysis of studies evaluating the 175 prevalence of persisting symptoms up to 110 days after COVID-19 of various severities, the 176 five more common symptoms were fatigue (58%), headache (44%), attention disorder (27%), 177 hair loss (25%) and dyspnea (24%), while agueusia, anosmia and memory loss were reported 178 by 23%, 21% and 16% of the studies populations (24) . Two studies evaluating hundreds of 179 laboratory-confirmed COVID-19 outpatients have reported the prevalence of symptoms 180 lasting more than 6 months after diagnosis: 33-39% participants with at least one symptom, 181 14-55% with fatigue, 22% with dyspnea, and 14% with loss of sense of smell or taste (15, 16) . 182 The differences between studies may be explained by various patients' selection criteria, data 183 collection methods, and definitions of symptoms. 184 Strikingly, the proportion of COVID-positive patients with long-term symptoms was similar 185 between the three surveyed periods. Our findings are supported by a few longitudinal studies, 186 which analyzed the evolution of residual symptoms and showed a stable proportion after the 187 acute phase and up to 7 months (7, 25) . 188 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In our study 23% of COVID-positive required at least one additional medical visit for COVID-189 19-related symptoms, which is close to the proportion of 36% found in another study (16) . 190 These data show the burden on ambulatory health-care facilities related to post-COVID- 19 191 syndrome. However, we did not find a statistical difference in the proportion of patients 192 requiring an additional medical consultation between COVID-positive and COVID-negative, 193 which might be due to a lack of statistical power. 194 Our results shed more light on the association between SARS-CoV-2 infection and long-term 195 symptoms. While some symptoms were more frequent in PCR-confirmed COVID- 19 196 outpatients, the prevalence of others was not different to SARS-CoV-2 PCR negative patients. 197 In particular, the prevalence of headache and sleep disorder, two predominant persisting 198 symptoms in COVID-negative patients, was similar between COVID-negative and COVID-199 positive. Both symptoms may originate from mixed etiologies including psychosocial factors 200 and/or non-specific post-infectious consequences. The COVID-19 pandemic has greatly 201 impacted our psychosocial behaviors due to confinement, social distancing, mask wearing and 202 changing work conditions. Some symptoms may be a consequence of these unprecedented 203 changes (26) . Furthermore, long-term sequelae after an acute respiratory infection may not 204 be limited to coronaviruses, as shown with severe H7N9 infection leading to lung disability 205 and psychological impairment at 2 years of follow-up (27) . 206 Another study evaluating 6-month sequelae in outpatients with COVID-19 included a small 207 control group of healthy volunteers and showed that 33% of COVID-positive outpatients and 208 5% of volunteers presented symptoms (15) . However, the limited sample size (21 healthy 209 volunteers) and their normal health status prevents comparison with our results. Another 210 report also showed that 26% of seropositive health care workers present long-term symptoms 211 8 months after mild COVID, while only 9% of seronegative do (28) . Inclusion of patients 212 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Overweight/obesity was an independent predictor of the presence of any long-term 215 symptom, fatigue and dyspnea. Overweight and obesity are increasingly associated with poor 216 outcomes in COVID-19. In a systematic review and meta-analysis of 22 studies and in a large 217 CDC analysis in the United States population, overweight and/or obesity in COVID-19 were 218 associated with an increased risk of hospital admission, invasive ventilation, and death, 219 especially among patients younger than 60 years-old (29, 30) . Another study reported an 220 association between body mass index and persisting symptoms after more than 28 days (31) . 221 The mechanisms responsible for post-COVID-19 syndrome are not understood yet and may 222 be multiple (32, 33) . Long-term symptoms may be due to higher initial organ damages related 223 to dysregulated inflammatory response. This may be true in people with overweight and 224 obesity (34) (35) (36) , since the adipose tissue has a high expression of angiotensin-converting 225 enzyme 2 receptors and secretes pro-inflammatory cytokines. 226 While previous studies showed that male gender is a risk factor for severe outcome in COVID-227 19 (37), we identified female gender as a predictor for post-COVID-19 syndrome and 228 specifically for persisting fatigue and smell or taste disorder. Although not always consistent, 229 some studies have described an association between female gender and long-COVID (31), 230 persisting fatigue (12) (13) (14) , post-exertional polypnea (13) , decreased rates of recovery (16), 231 and anxiety or depression (14, 16) . Gender differences in immunity, as illustrated by the higher 232 representation of women in autoimmune diseases (38) , may explain divergent findings with 233 Our study has some limitations. First, most surveyed symptoms are subjective and prone to 235 observer bias. Symptoms may also come from an intercurrent condition at the time of COVID-236 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CoV-2 infection. Furthermore, this reflects the clinical reality that physicians face in a post-239 COVID consultation. Since the prevalence of most symptoms was lower than 10%, the absence 240 of difference may be due to a lack of statistical power to detect an association with COVID- 19. 241 Our study suffers from a selection bias due to SARS-CoV-2 test criteria (health care workers or 242 presence of a risk factor of adverse outcome) at the time of the study, which may prevent 243 generalization of our findings to the broad population. In addition, we included a SARS-CoV-2 244 PCR negative control group, who had a slightly different clinical presentation (only patients 245 with acute respiratory symptoms) compared to COVID-positive (any symptom suggestive of 246 . Furthermore, we cannot formally exclude that some COVID-negative had an 247 undiagnosed SARS-CoV-2 infection due to a false negative PCR result. However, we used a 248 validated SARS-CoV-2 RT-PCR test on a nasopharyngeal swab performed by a dedicated 249 trained medical team to minimize technical and sample collection bias (19, 39) . 250 In conclusion, our study shows that more than half of outpatients with mild-to-moderate 251 COVID-19 report long-term symptoms 3 to 10 months after diagnosis and that 21% seek 252 medical care for this reason. These data suggest that post-COVID syndrome places a significant 253 burden on society and especially healthcare systems. There is an urgent need to inform 254 physicians and political authorities about the natural long-term course of COVID-19 in order 255 to plan an appropriate and dedicated management of those with disabling persisting 256 symptoms. 257 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2021. ; https://doi.org/10.1101/2021.04.19.21255742 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We thank all the patients who accepted to participate and make this study possible. We thank all healthcare workers of the triage center and of the emergency department of the University Hospital of Lausanne, who supported the study and managed COVID-19 suspected patients. We thank Nadia Cattaneo and Martin Delaloye who participated to patients' follow-up. We thank Tanguy BG: study design, data interpretation and critical review of the manuscript. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Tables 17 OH, YMC, AG, PNC, BG: data interpretation and critical review of the manuscript. EK: data analysis, interpretation, and critical review of the manuscript. TB, SS: patients' inclusion, and critical review of the manuscript. OO: microbiological data interpretation and critical review of the manuscript MPO had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This work was supported by an academic award of the Leenaards Foundation (to NBB), the Infectious Disease Service and the emergency department of Lausanne University Hospital. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2021. ; https://doi.org/10.1101/2021.04.19.21255742 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Missing data: 1 BMI, 98 days from symptoms onset, 39 temperature, 84 heart rate, 310 respiratory rate, 41 SpO2 on ambient air, 7 SARS-CoV-2 cycle threshold value. Two-sided chi-squared or Fisher tests were performed when comparing proportions, and Mann-Whitney U tests were performed for continuous variables. BMI: body mass index; SpO2: oxygen saturation; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; RT-PCR: real time reverse transcriptase polymerase chain reaction. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Data are number (%) of patients or median (interquartile range). *symptoms associated with the presence of any long-term symptom. ° analysis adjusted for age, sex, smoking, overweight/obesity, diabetes, asthma, hypertension, cancer, cardiovascular disease, chronic inflammatory disease, period of the phone survey. Missing data: 1 BMI Odds ratio for age indicates the risk of the presence of any symptom per 5-year age increase. OR: odds ratio; aOR: adjusted odds ratio; CI: confidence interval. Selected symptoms are those associated with COVID status. Multivariable analysis adjusted for age, sex, smoking, overweight/obesity, diabetes, asthma, hypertension, cancer, cardiovascular disease, chronic inflammatory disease, period of the phone survey. 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