key: cord-0925570-btk7hjbq
authors: Klein, Hadar; Asseo, Kim; Karni, Noam; Benjamini, Yuval; Nir-Paz, Ran; Muszkat, Mordechai; Israel, Sarah; Niv, Masha Y.
title: Onset, duration and unresolved symptoms, including smell and taste changes, in mild COVID-19 infections. A cohort study in Israeli patients
date: 2021-02-16
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.02.008
sha: 537c133cec565cfefbcdc581058f8dc9a81dba92
doc_id: 925570
cord_uid: btk7hjbq

OBJECTIVES: This study aims to characterize longitudinal symptoms of mild COVID-19 patients for a period of six months, and potentially aid in disease management. METHODS: Phone interviews were conducted with 103 mild COVID-19 patients in Israel, over a six-month period (April 2020 to October 2020). Patients were recruited via social media and word to mouth and were interviewed up to 4 times, depending on their unresolved symptoms reports. Inclusion criteria required participants to be Israeli residents aged ≥18 years, with positive COVID-19 RT-PCR results and non-severe symptoms. Symptoms' onset, duration, severity, and resolution were analyzed. RESULTS: 44% (45/103), 41% (42/103), 39% (40/103) or 38% (39/103) of the patients experienced headache, fever, muscle ache, or dry cough as the first symptom respectively. Smell and taste changes were experienced 3.9 ± 5.4 and 4.6 ± 5.7 days (mean ± SD) after disease onset, respectively. Among prevalent symptoms, fever had the shortest duration (5.8 ± 8.6 days), and taste and smell changes were the longest-lasting symptoms (17.2 ± 17.6 and 18.9 ± 19.7 days, durations censored at 60 days). Longer recovery of the sense of smell correlated with the extent of smell change. At the six-month follow-up, 46% (47/103) of the patients had at least one unresolved symptom, most commonly fatigue (22%, 23/103), smell and taste changes (15%, 15/103 and 8%, 8/103 respectively), and breathing difficulties (8%, 8/103). CONCLUSIONS: Long-lasting effects of mild COVID-19 manifested in almost half of the participants reporting at least one unresolved symptom after six months.

Israel, over a six-month period (April 2020 to October 2020). Patients were recruited 35 via social media and word to mouth and were interviewed up to 4 times, depending 36 on their unresolved symptoms reports. Inclusion criteria required participants to be 37 Israeli residents aged ≥18 years, with positive COVID-19 RT-PCR results and non-38 severe symptoms. Symptoms' onset, duration, severity, and resolution were 39 analyzed. respectively. Smell and taste changes were experienced 3.9 ± 5.4 and 4.6 ± 5.7 days 43 (mean ± SD) after disease onset, respectively. Among prevalent symptoms, fever had 44 the shortest duration (5.8 ± 8.6 days), and taste and smell changes were the longest- 45 lasting symptoms (17.2 ± 17.6 and 18.9 ± 19.7 days, durations censored at 60 days). 46 Longer recovery of the sense of smell correlated with the extent of smell change. At 47 INTRODUCTION 56 The coronavirus disease has become a worldwide pandemic, with more 57 than 80 million cases and over a million deaths (World Health Organization, 58 December 30 th , 2020). COVID-19 symptoms, severity and duration vary widely [1] [2] [3] [4] . 59 COVID-19 initially targets the human respiratory system, with the most common 60 symptoms being fever, cough, shortness of breath, fatigue, muscle aches, headache, 61 loss of smell or taste, sore throat, congestion, nausea/vomiting and diarrhea [5] . 62 Other commonly reported symptoms include sputum production, hemoptysis, and 63 lack of appetite [6, 7] . 64 "Long COVID" is emerging as a phenomenon where patients have long-term corresponding to "no sense of smell/taste" and 10 to "excellent sense of 103 smell/taste"). The Likert scale is common in chemosensory research, providing a 104 quantitative and easy-to-use intuitive scale, and was used to evaluate COVID-19 105 related smell and taste impairments [15, 17, 18] . 106 The analysis included only the symptoms listed by the Centers for Disease Control 107 and Prevention (CDC) as of December 2020 (taste change, smell change, fever, dry 108 cough, productive cough, muscle aches, headache, runny nose, sore throat, diarrhea, 109 breathing difficulty, vomit/nausea, and fatigue) [5] , or symptoms that were prevalent 110 (>50%) in our sample. 111 Disease onset was defined as the first appearance of any of the COVID-19 symptoms 112 listed above. "Number of days after disease onset" was calculated by subtracting the 113 date of the first symptom to occur from the date of the symptom's appearance. 114 Mean (± standard deviation (SD)) was calculated for each symptom. 115 Unresolved symptoms refer to those that were unresolved at the six-month follow-116 up interviews. 117 Order of appearance was calculated from the onset dates reported by the 118 participants for each symptom. 119 Duration was calculated from the onset and resolution dates of each symptom. If 120 patients reported unresolved symptoms (no resolution date), or could not report a Maximal severity of smell and taste change was calculated as the difference between 128 the rating of the respective sense level before the illness and its rating during the 129 illness, rated on a 1-10 scale. smell change, fever, dry cough, productive cough, muscle aches, headache, runny 177 nose, sore throat, diarrhea, breathing difficulty and vomiting/nausea) [5] , and an 178 additional symptom was prevalent in more than 50% (53/103) of patients (lack of 179 appetite). Fatigue is a current CDC symptom that did not explicitly appear in the changes at all. 222 The durations of changes in smell and taste reported at the six-week follow-up, were 223 highly correlated (0.71, p<0.001) (web-only Supplementary Figure S2A) . 224 A weak yet significant correlation was found between change severity and its 225 duration for smell ( Figure S2B , correlation 0.37, p=0.0016), but not for taste (web-226 only Supplementary Figure S3 ). Our study reveals that headache, fever, dry cough, and muscle aches were often the 236 first symptoms to appear, while smell and taste changes were not. Fatigue was 237 usually the first symptom among patients who reported it in 1 st interview. Notably, 238 the low prevalence of fatigue in our study compared to other reports [20] , is due to 239 self-reporting under the "any other symptom" question, rather than an explicit 240 question in the questionnaire. recovery time, although for a group of patients the time to recover smell was 245 unrelated to smell change severity. Almost half of the patients did not recover from 246 all their symptoms six months after their first questionnaire, most of them reporting 247 fatigue, smell and taste changes, and breathing difficulties. These unresolved 248 symptoms occurred together or separately, and some were not reported during the 249 previous follow-ups. 250 We found slightly lower prevalence of taste and smell changes as first symptoms 251 compared to Spinato et al. [21] , possibly due to recall bias caused by retrospective 252 data collection in our study. Our long (up to six months) follow-up and quantitative 253 (rather than binary) monitoring of smell and taste changes probably accounts for the 254 longer duration of smell and taste changes we found, compared to other 255 studies [22] [23] [24] . Subpopulations of patients for whom smell change severity was or 256 was not related to resolution time was also reported by Gerkin et al. [25] , but Patients were contacted for the second and third interviews only if they did not 280 report recovery. In principle, it is possible that some of the recovered patients could 281 have recurrences of symptoms as well [30] . Therefore, for the six-month follow-up 282 we contacted all the participants in the study for reports of unresolved symptoms. 283 Long period studies of larger groups of COVID-19 patients, with more follow-ups are 284 required to further monitor and characterize the manifestations of "long 285 COVID" [8, 9] . 

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COVID-19)

Symptom Duration and Risk Factors 340

Multistate Health Care Systems Network -United States

The lasting misery of coronavirus long-haulers

The epidemiology and pathogenesis of coronavirus 349 disease (COVID-19) outbreak

Clinical Characteristics of COVID-19 Patients With 352

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Long COVID: let patients help define long-lasting COVID symptoms

Facing up to long COVID

Neurological Manifestation in a Critically ill COVID-19 Patient

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Long-term consequences of COVID-19: 366 research needs

Prevalence, Severity, Timing, and Associated Characteristics

Gemelli Against COVID-19 Post-Acute Care Study 373

Persistent Symptoms in Patients After Acute COVID-19

Self-rated smell ability enables highly specific 376 predictors of COVID-19 status: a case control study in Israel. OFID. doi: 377 of print

Trend of Olfactory and Gustatory Dysfunction 383 in COVID-19 Patients in a Quarantine Facility

Frequency and outcome of olfactory 386 impairment and sinonasal involvement in hospitalized patients with

Controlling the False Discovery Rate: A Practical and 389

Powerful Approach to Multiple Testing

COVID-19 patients' clinical characteristics

discharge rate, and fatality rate of meta-analysis

Alterations in Smell or Taste in Mildly 395

Symptomatic Outpatients With SARS-CoV-2 Infection

Prevalence and Duration of Acute Loss of Smell or 398

Taste in COVID-19 Patients

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Recent smell loss is the best predictor 408 of print

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COVID-19 infection

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Islands -a longitudinal study among non-hospitalized patients

online ahead of print

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12 States

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 314 We thank the Global Consortium for Chemosensory Research (GCCR) team for 315 fruitful collaborations and discussions. We thank Yehuda Tarnovsky for help with