








key: cord-335007-27a3h2lo
authors: Dreyer, Nancy A.; Reynolds, Matthew; DeFilippo Mack, Christina; Brinkley, Emma; Petruski-Ivleva, Natalia; Hawaldar, Kalyani; Toovey, Stephen; Morris, Jonathan
title: Self-reported symptoms from exposure to Covid-19 provide support to clinical diagnosis, triage and prognosis: An exploratory analysis
date: 2020-11-03
journal: Travel Med Infect Dis
DOI: 10.1016/j.tmaid.2020.101909
sha: 
doc_id: 335007
cord_uid: 27a3h2lo

BACKGROUND: Symptomatic COVID-19 is prevalent in the community. We identify factors indicating COVID-19 positivity in non-hospitalized patients and prognosticators of moderate-to-severe disease. METHODS: Appeals conducted in April-June 2020 in social media, collaborating medical societies and patient advocacy groups recruited 20,476 participants ≥18 years who believed they had COVID-19 exposure. Volunteers consented on-line and reported height, weight, concomitant illnesses, medication and supplement use, residential, occupational or community COVID-19 exposure, symptoms and symptom severity on a 4-point scale. Of the 12,117 curated analytic population 2,279 reported a COVID-19 viral test result: 865 positive (COVID+) and 1,414 negative (COVID-). RESULTS: The triad of anosmia, ageusia and fever best distinguished COVID+ from COVID-participants (OR 6.07, 95% CI: 4.39 to 8.47). COVID+ subjects with BMI≥30, concomitant respiratory disorders or an organ transplant had increased risk of moderate-to- severe dyspnoea. Race and anti-autoimmunity medication did not affect moderate-to-severe dyspnea risk. CONCLUSIONS: The triad of anosmia, ageusia and fever differentiates COVID-19. Elevated risks of severe symptoms outside the hospital were most evident among the obese and those with pulmonary comorbidity. Race and use of medication for autoimmune disease did not predict severe disease. These findings should facilitate rapid COVID-19 diagnosis and triage in settings without testing. TRIAL REGISTRATION: Clinicaltrials.gov NCT04368065, EU PAS register EUPAS36240.

Limited information is available concerning the symptomatology of human coronavirus disease 2019 (COVID-19) outside of the hospital [1, 2] . Here we follow a research model developed in collaboration with the European Medicines Agency that validated person-generated healthdata as a reliable method for pharmacovigilance [3] , and use established best practices for patient registries that have been particularly useful in pandemic threats [4, 5, 6] . We build on these models using community-driven research to characterize symptoms indicative of a positive COVID-19 viral test result and identify risk factors for development of serious symptoms of COVID-19 infection outside the hospital setting.

Respondent-driven sampling in the US from April 2 nd to July 14 th 2020 inclusive, yielded 20,476 adults who completed registration, demographics and symptoms forms at www.helpstopCOVID19.com. Participants were recruited using social media, with additional awareness raising activities undertaken by medical societies and patient advocacy groups.

Every state in the US is represented, with most participants coming from populous states with high infection rates: California (9%), New York (9%), Florida (7%) and Texas (6%). Participants provided information about testing and test results; noting that only viral testing was available during this sampling timeframe and most participants reported not having been tested (70%).

Reported were: COVID-19-like symptoms using a checklist [7] and ranked the reported symptoms on a 4-point severity scale from very mild to severe; comorbidities; presence of fever, use of prescription and non-prescription medication, vitamins and supplements; occupation as well as age, gender and ethnicity. Survey respondents were invited to participate in longitudinal follow-up twice a week for four weeks and every two weeks for the following two months. Participants were not required to answer every question. No remuneration was provided.

A curated analytic data set (n=12,117) was created for adults who completed baseline screening of symptoms and demographics, and which excluded likely fabricated entries based on a combination of clinical flags (e.g., body mass index (BMI) <15 or >60, height < 4ft) and likely duplicates, determined by nearly identical respondent entries within 10 minutes of each other. No missing data were imputed. Participants who tested positive (COVID+) were compared to those who tested negative (COVID-). Odds ratios (OR) and 95% confidence interval (CI) were used to estimate the likelihood that a symptom or characteristic (or constellation thereof) would be present given a positive test result. A multivariable logistic regression was used to estimate the OR (95%CI) of developing moderate or severe 5dyspnea among COVID+ participants. Two models were applied -a reduced model that included demographic characteristics and a full model that added comorbidities and medication use.

A total of 12,117 participants were included in the curated dataset (71% female; median age 43 years and 24% non-Caucasian), out of which n=2,279 (19%) reported a COVID-19 test result.

Baseline data are shown for 2,279 participants, including COVID+ (n=863) and COVID-(n=1,414). Participants reporting a COVID-19 test result had a mean age of 41 years, with 13% over 60 years of age, and nearly twice as many females as males; 20% of participants reported education level of "high school or less" (Table 1) .

Fever, cough, fatigue and aches and pains were the most commonly reported symptoms, with more symptoms reported on average by COVID+ than COVID-participants (5.5 vs 3.4) ( triad. COVID+ participants who reported anosmia or ageusia also had a mean of nine symptoms, in contrast to a mean of just two for those without either symptom.

Moderate or severe 6dyspnea was more frequently reported by COVID+ (24%) than COVID-(15%) participants. Among COVID+ participants the risk of moderate or severe 6dyspnea did not differ by age, gender, race, or ethnicity. Particularly, risk was elevated among the obese (BMI>30) (OR 2.30 95%CI 1.40, 3.78) and those taking medications for respiratory disorders (OR 3.68 95%CI 2.04, 6.62). There was no strong evidence of elevated risk for 6dyspnea among participants with cardiovascular disease or those taking medications for diabetes, hypertension and autoimmune conditions (Table 3) .

This research program is unusual in its evaluation of symptomatology for COVID-19 in the community setting [8] and may be particularly helpful in a number of travel medicine related settings, e.g. on board cruise ships and in other maritime settings, including naval vessels; during military deployments and in remote or resource poor settings [9, 10, 11, 12, 13] . Anosmia and ageusia were the most likely symptoms indicative of a positive test results, and participants reporting either of these had more symptoms and of greater severity [8] . This is in line with previous findings and experimental evidence supporting involvement of the olfactory apparatus [14, 15] . The triad of anosmia, ageusia and fever provided a particularly powerful symptom constellation differentiating COVID+ from COVID-in the community. This triad may offer an expeditious way to identify probable COVID-19 infections in the community, especially in the absence of reliable, widespread testing [9, 16, 17] The triad could be taken as pathognomonic during the pandemic and trigger anti-COVID interventions in the absence of reliable nearpatient diagnostics. This may be particularly helpful in many travel medicine or community based settings including resource-poor, logistically challenged or remote settings, as well as in closed community settings e.g. the military, prisons, care homes, seagoing vessels. Further support for a clinical diagnosis of COVID-19 might also be a history of vomiting. Although nonspecific, vomiting is in general not a feature of respiratory tract infections in the community [18, 19] .

Severe 7dyspnea is indicative of severe disease that may require hospitalization and may presage possible pulmonary fibrosis or other sequelae [20, 21, 22, 23] . While our findings are congruent with obesity being a known risk factor for severe disease, the association of significant 7dyspnea with obesity in a community setting raises concerns about referral thresholds. It may well be prudent to have a very low threshold for referral and admission of symptomatic obese patients. The same consideration could also apply to patients with underlying respiratory disorders. However, there was no evidence for a marked increase in risk among people who reported underlying cancer or cardiovascular disease, or those taking medications for autoimmune disease, diabetes, or hypertension. The absence of increased risk of severe disease in users of medication for auto-immune disorders is similar to previous findings indicating that use of disease modifying agents does not increase the risk of complications from seasonal influenza [24] . The findings of increased risk of severe disease in the presence of obesity were in line with existing evidence on COVID-19 [25] and are somewhat in contrast with previous findings in seasonal influenza, which pointed to decreasing risk of influenza complications with increasing BMI [26] , supporting the distinct pathology and immunopathology of COVID-19.

Our findings would be strengthened by complementary analyses of other clinical and treatment information for obese participants and those on medication for auto-immune disorders, including if and how they are being treated for these underlying conditions; a possible explanation may be that individuals with more severe conditions were underrepresented in our study, but this remains speculative. Further validation may be derived from additional data collection and analysis from subsequent waves of infection, a process that has already been initiated.

It is important to keep in mind that these data are voluntarily reported, are not a representative sample of the US population, and thus will not support inferences about distribution of symptoms in the US. Recognizing that self-reported information has limitations, comparisons between respondents may nevertheless indicate true causal relationships and can serve to stimulate further research as the medical and scientific community seek to learn more J o u r n a l P r e -p r o o f about this infection. This methodology appears to be useful in capturing relevant real world data, particularly symptom severity, without requiring physical presentation for clinical assessment, and offers valuable perspective on the true burden of illness as well as signaling those at particularly high risk of severe symptoms and, in parallel, those unlikely to be at such increased risk. The findings may help guide diagnosis and triage in settings where there is not ready access to rapid and reliable diagnostic testing. Approximately 10-12% of participants did not respond to one or more of these questions b N=852 (7%) of all participants, n=80 (9.2%) of COVID+ and n=97 (6.9%) of COVID-participants did not provide an answer in this section Notes: shortness of breath and severity assessed at baseline. Participants who reported shortness of breath, but did not report severity of the symptom were excluded from this analysis (n=11). a Referent category includes participants who reported not having the condition of interest or not taking the medication of interest

Pathophysiology, transmission, diagnosis and treatment of coronarvirus disease 2019 (COVID-19). A review

Prevalence of asymptomatic SARS-CoV-2 infection. A narrative review

Direct-to-patient research: piloting a new approach to understanding drug safety during pregnancy

Recognizing true H5N1 infections in humans during confirmed outbreaks

Registries for Evaluating Patient Outcomes: A User's Guide. Conducted under Contract No

Agency for Healthcare Research and Quality

Investigating outbreaks of novel infectious disease: an international case study

Real-time tracking of self-reported symptoms to predict potential COVID-19

COVID-19: Travel health and the implications for sub -Saharan Africa

More than 30 coronavirus cases on Pacific aircraft carrier, new ones discovered on another carrier in Japan: officials

Coronavirus : plusieurs cas suspects à bord du porte-avions français Charles-de-Gaulle

French aircraft carrier heads home early due to possible COVID-19 cases

Dolfijn breekt reis af vanwege corona -Nieuwsbericht -Defensie.nl". defensie.nl

Olfactory and gustative disorders for the diagnosis of COVID-19

SARS-CoV-2 infects and damages the mature and immature olfactory sensory neurons of hamsters

Van den Bruel A. Antibody tests for identification of current and past infection with SARS-CoV-2. Cochrane Database of Systematic Reviews

Oseltamivir effectiveness in seasonal influenza patients taking symptomatic therapy: retrospective analysis of RCT data

Clinical features of COVID-19 and influenza: a comparative study on Nord Franche-Comte cluster. Microbes and infection

Long term respiratory complications of covid-19

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. The Lancet

COVID-19 patients with pulmonary fibrotic tissue: clinical pharmacological rational of antifibrotic therapy

Pulmonary fibrosis secondary to COVID-19: a call to arms?

Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study

Single cell sequencing unraveling genetic basis of shared immunologic switch between Severe COVID19 and Obesity

Epub ahead of print

Body mass index and the incidence of influenza-associated pneumonia in a UK primary care cohort. Influenza and other respiratory viruses

We would like to acknowledge Dr. Sally McNagny for her clinical insights and Alison Bourke for her contributions to the data curation.Funding Sources: No funding was received for this work.

