key: cord-0773750-ock4izyl
authors: Nitecki, Maya; Taran, Boris; Ketko, Itay; Geva, Gil; Yosef, Roey; Toledo, Itay; Twig, Gilad; Avramovitch, Eva; Gordon, Barak; Derazne, Estela; Fink, Noam; Furer, Ariel
title: Self-reported symptoms in healthy young adults to predict potential COVID-19 disease
date: 2021-01-06
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.12.028
sha: f2e438fabb3029cf82a6bbaa910a2bc21cc09247
doc_id: 773750
cord_uid: ock4izyl

OBJECTIVE: To assess the utility of self-reported symptoms in identifying positive COVID-19 cases among predominantly healthy young adults, in a military setting. METHODS: A questionnaire regarding COVID-19 symptoms and exposure history was administered to all individuals contacting the Israeli Defense Forces “Corona call-center”, prior to polymerase chain reaction (PCR) testing. Surveyed symptoms included cough, fever, sore throat, rhinorrhea, loss of taste or smell, chest pain and gastrointestinal symptoms. Factors were compared between positive and negative cases based on confirmatory test results, and positive likelihood ratios (LR) were calculated. Results were stratified by sex, BMI, previous medical history and dates of questioning and a multivariable analysis for association with positive test was conducted. RESULTS: Of 24,362 respondents, 59.1% were men with a median age of 20.5 years (IQR 19.6-22.4). Significant positive LRs were associated with loss of taste or smell (LR 3.38, 95%CI 3.01-3.79), suspected exposure (LR 1.33, 95%CI 1.28-1.39) and fever (LR 1.26, 95%CI 1.17-1.36). Those factors were also associated with positive PCR result in a multivariable analysis (OR 3.51 (3.04-4.06), OR 1.86 (1.65-2.09) and OR 1.34 (1.19-1.51), respectively). Reports of loss of taste or smell increased gradually over time and were significantly more frequent at the late period of the study (63/5,231 (1.21%), 156/7,941 (1.96%), and 1,505/11,190 (13.45%), p<0.001). CONCLUSION: Loss of taste or smell, report of a suspicious exposure and fever (>37.5(º)C) were consistently associated with positive LRs for a positive SARS-CoV-2 PCR test result, in a population of predominantly young and healthy adults.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first reported 50 in China in December 2019 [1] and by March 11 th 2020 declared as a pandemic [2] . To 51 date, the reported disease burden exceeds 71 million people, with a death toll of 52 approximately 1,600,000 worldwide [3] . 53 Insufficient viral RNA testing capacity [4] [5] [6] , which results in propagation of the virus 54 by undiagnosed infected individuals [7, 8] cripples the ability of health authorities to 55 control viral spread [9, 10] . Thus, prioritizing testing and efficiently isolating positive 56 cases is a vital aim. To this end, several studies examined the utility of self-reported 57 symptoms in predicting COVID-19 and found a correlation between constitutional and 58 respiratory symptoms with a positive test [11] [12] [13] . However, low response rates in 59 young healthy adults [12, 13] and their exclusion from studies [11] , results in a dearth of 60 data guiding testing in this population. As the proportion of young infected adults 61 increases [14] [15] [16] , and their potential in propagating disease spread grows [8, 17, 18] , 62 there is an impending need to better characterize the symptom distribution suggestive 63 of infection in this group. 64 The Israel Defense Forces (IDF) is comprised mostly of young healthy individuals who 65 have undergone extensive medical screening [19] . Therefore, in this study we used a 66 retrospective cohort design to evaluate the association between symptoms in young 67 adults and a positive test result.

Study population 71 The special IDF COVID-19 center (ICC) handled documentation of all individuals with 72 suspicious symptoms, those quarantined, and all confirmed COVID-19 cases. This 73 included collection of data obtained via contact tracing and an inquiries 'hotline'. ICC 74 referred soldiers for swab tests based on report of symptoms and exposure history. We 75 included all individuals who were deemed eligible for COVID-19 testing by the ICC, 76 including those voluntarily calling to report symptoms or a suspected exposure, or 77 those actively addressed following an epidemiological investigation. Eligibility for 78 confirmatory testing was directed by the surgeon general and approved by public 79 health officers on a case-by-case basis. Testing was approved for those with: 1) 80 presence of at least two acute respiratory symptoms (cough, shortness of breath, sore 81 throat, fever > 38 • C); or 2) one symptom combined with a suspicious exposure; or 3) 82 loss of taste or smell as a sole symptom. Table S1 151 for comparison with the included cohort). Ultimately, 24,362 respondents were 152 included in the analysis. Over half (59.1%) were men, with a median age of 20.5 (IQR, 153 19.6-22.4) years of whom 65% (n=15,534) had unimpaired health at baseline. Of all PCR 154 tests, 5.5% (n=1,338) were positive, 5.7% in men and 5.2% in women. During the first, 155 second and third periods of the study, a total of 5,231, 7,941, and 11,190 tests were 156 conducted with a 2.25% (n=118), 2.29% (n=182) and 9.27% (n=1,038) positivity rate, 157 respectively. Characteristics of the study population are shown in table 1.

Cough was the most commonly reported symptom (13,675/24,362, 56.1%), followed by 160 report of suspected exposure (12,211/24,362, 50.1%) and fever (6,896/24,362, 28.3%). The 161 item with highest sensitivity (65.5% (63-68.1%)) was suspected exposure, followed by 162 cough (55.5% (52.9-58.2%)) and fever (35.1% (32.6-37.7%)). Highest specificity was seen 163 with GI symptoms (98.6% (98.5-98.8%)), followed by chest pain (98.2% (98.1-98.4%)) 164 and loss of taste or smell (93.7% (93.4-94.1%) ). Loss of taste or smell was also found to 165 have the highest PPV (16.4% (14.8-17.9%)). Suspected exposure was found to have the 166 highest NPV (96.2% (95.9-96.5%)) followed by loss of taste or smell (95.3% (95.2-95.5%)) 167 and fever (95% (94.8-95.2%)). The overall distribution of reports on surveyed factors, 168 sensitivity, specificity, PPV and NPV, are summarized in Table 2 . 169 Comparing the distribution of reports over time (Fig. 2a , Tables S2-S3) demonstrated 170 that suspected exposure decreased between first and second periods (2,303/5,231 171 (44.0%), 2,411/7,941 (30.4%) respectively, p<0.001), and was significantly higher at the 172 third period (7,498/11,190 (67.0%), p<0.001). The same trend was seen with reports of 173 cough (2,747/5,321 (52.5%), 3,591/7,941 (45.2%), 7,337/11,190 (65.6%), p<0.001) and fever loss of taste or smell, a significant gradual increase in reporting during the three study 176 periods occurred (63/5,321 (1.2%), 156/7,941 (1.96%), 1,505/11,190 (13.5%), all p <0.001).

For context, disease burden in Israel during this timeline decreased between the first 178 and second periods and increased drastically in the third period (Fig. 2b ).

Of symptoms surveyed, loss of taste or smell had highest positive LR (LR 3.38, 95%CI 181 3.01-3.79). Suspected exposure (LR 1.33, 95%CI 1.28-1.39) and fever (LR 1.26, 95%CI 182 1.17-1.36) were also found to have significant positive LR (Fig. 3) . Stratification by sex, 183 baseline health status, particular comorbidities and BMI did not principally affect the 184 results (Table S4 -S9, Fig. S1 ).

Loss of taste or smell (LR 11.25, (Table 3) . Fever was also found to have significant (Table S2) .

In a multivariable logistic regression loss of taste or smell (OR 3.51, 95%CI 3.04-4.06), 194 fever (OR 1.34, 95%CI 1.19-1.51) and history of exposure (OR 1.86. 95%CI 1.65-2.09) 195 were the only factors independently associated with a positive test (Table S10) .

In order to make better use of limited COVID-19 confirmatory tests and identify those 198 at highest risk for infection, in Israel, like in many other countries, certain criteria were 199 used to determine testing eligibility [24] [25] [26] . In this study, suspicious exposure, loss of 200 taste or smell and fever were associated with a COVID-19 molecular diagnosis in over 201 24,000 young adults suggesting that self-reported symptoms are an effective way to 202 triage testing in this population. 203 Previous reports have been inconsistent with respect to the association between fever 204 and a positive test [11] [12] [13] . These conflicting data may stem from the inclusion of 205 populations with a variety of age groups, a factor shown to affect clinical manifestation 206 and disease severity [27, 28] . Varying definitions of fever between studies, and different 207 survey components (where in some body-temperature was not a mandatory question) 208 also contribute to unequivocal findings. In the current study fever >37.5 • C was 209 significantly associated with COVID-19 diagnosis. Yet, when three consequent periods 210 were compared, fever had significant positive LR only in the late period. This could 211 represent lack of power in earlier periods due to smaller participants number, or true 212 increase in fever as a manifestation of disease. Nonetheless, given the high likelihood 213 observed we suggest prioritizing febrile or sub-febrile individuals for testing especially 214 if they are young and healthy at baseline. This recommendation should be taken with 215 caution as the specificity of fever was 72% in our study and we hypothesize that with 216 upsurge in seasonal cold and flu during wintertime this will decrease.

Our results suggest exposure was associated with disease only in earlier periods and 218 not in the latest one. When considering the countrywide disease burden, it is evident 219 that by the third period infection was widespread and much more prevalent. Thus, 220 naturally, exposures were more probable and overall reports increased. However, 221 compliance with measures taken to decrease transmission, such as mandated mask use 222 in public places, and stricter enforcement perhaps resulted in many of these contacts 223 being less endangering in the latest period. Based on our findings and the relatively low specificity of 51%, it is reasonable to refine the definition of an exposure to 225 achieve better specificity in these circumstances.

In general, we found symptom reporting to be time dependent and mostly parallel to attributed to an increase in prevalence of a different illness manifesting with these 239 symptoms, but it is highly unlikely that this could explain a nine-fold increase within a 240 month. Nonetheless, loss of taste or smell remain significantly and consistently 241 associated with a positive likelihood for COVID-19 disease, and fair PPV, despite the 242 possible reporting bias. As this is a specific complaint [30] reaching as high as 94% in 243 our cohort, unlike other flu-like symptoms, we suggest that young individuals 244 presenting with loss of taste or smell should be prioritized for testing. In contrast to 245 previous reports [11,13] we did not find respiratory symptoms to be associated with a 246 positive test.

Our study includes a unique cohort comprised mainly of young healthy adults, a 248 subgroup that has been overlooked in previous reports [11] [12] [13] but is the most common Table S3 for elaborated results of statistical analysis). Table 3 : 428 consequent periods (see Fig. 2b legend for details). 

Transmission, Diagnosis, and Treatment of Coronavirus 373

COVID-19): A Review

Terrorism and weapons of mass destruction: managing 376

Self-reported loss of smell without nasal obstruction to identify COVID-19

multicenter Coranosmia cohort study

a recent (<14 day) international travel;IDF-Israel Defense Forces. GI-gastrointestinal symptoms i.e. 426 abdominal pain, vomiting