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.

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External comparators, also referred to as historical or synthetic controls, present transformational opportunities for broad context and insights alongside clinical research results. The recent confluence of access to quality real-world data (RWD), advanced epidemiologic methods, and legislative directives to regulators for expanded use of RWD is increasing interest in real-world external comparators, opening the door to achieve broader generalizability and learn more, faster. In this less standardized area of research, tailored scientific methodology must be applied for external comparators to accomplish clinical development objectives. Here, we describe methodological considerations for design and illustrate how RWD comparators have been used for regulatory and reimbursement decisions.