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Symptoms and symptom clusters associated with SARS-CoV-2 infection in community-based populations: Results from a statewide epidemiological study

Background: Prior studies examining symptoms of COVID-19 are primarily descriptive and measured among hospitalized individuals. Understanding symptoms of SARS-CoV-2 infection in pre-clinical, community-based populations may improve clinical screening, particularly during flu season. We sought to identify key symptoms and symptom combinations in a community-based population using robust methods.

Methods: We pooled community-based cohorts of individuals aged 12 and older screened for SARS-CoV-2 infection in April and June 2020 for a statewide seroprevalence study. Main outcome was SARS-CoV-2 positivity. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for individual symptoms as well as symptom combinations. We further employed multivariable logistic regression and exploratory factor analysis (EFA) to examine symptoms and combinations associated with SARS-CoV-2 infection.

Results: Among 8214 individuals screened, 368 individuals (4.5%) were RT-PCR positive for SARS-CoV-2. Although two-thirds of symptoms were highly specific (>90.0%), most symptoms individually possessed a PPV <50.0%. The individual symptoms most greatly associated with SARS-CoV-2 positivity were fever (OR=5.34, p<0.001), anosmia (OR=4.08, p<0.001), ageusia (OR=2.38, p=0.006), and cough (OR=2.86, p<0.001). Results from EFA identified two primary symptom clusters most associated with SARS-CoV-2 infection: (1) ageusia, anosmia, and fever; and (2) shortness of breath, cough, and chest pain. Moreover, being non-white (13.6% vs. 2.3%, p<0.001), Hispanic (27.9% vs. 2.5%, p<0.001), or living in an Urban area (5.4% vs. 3.8%, p<0.001) was associated with infection.

Conclusions: Symptoms can help distinguish SARS-CoV-2 infection from other respiratory viruses, especially in community or urgent care settings where rapid testing may be limited. Symptoms should further be structured in clinical documentation to support identification of new cases and mitigation of disease spread by public health. These symptoms, derived from asymptomatic as well as mildly infected individuals, can also inform vaccine and therapeutic clinical trials.

Research in context: Evidence before this study: Using multiple journal articles queried from MEDLINE as well as a Cochrane systematic review, we examined all studies that described symptoms known to be associated with COVID-19. We further examined the guidelines from WHO and CDC on the symptoms those public health authorities consider to be associated with COVID-19. Most of the evidence comes from China, Italy, and the United States. Collectively prior research and guidance suggests there are a dozen symptoms reported by individuals who tested positive for COVID-19 in multiple countries. Symptoms include fever, cough, fatigue, anosmia, ageusia, shortness of breath, chills, myalgias, headache, sore throat, chest pain, and gastrointestinal issues. The evidence is generally of low quality as it is descriptive in nature, and it is biased towards hospitalized patients. Most studies report the proportion of patients hospitalized or testing positive for infection who report one or more symptoms within 3-14 days prior to hospitalization or infection. There has been little validation of symptoms among hospitalized or non-hospitalized patients. Furthermore, according to a Cochrane review, no studies to date assess combinations of different signs and symptoms.Added value of this study: This study employs multiple, rigorous methods to examine the ability of specific symptoms as well as symptom combinations/groups to predict laboratory-confirmed (RT-PCR) infection of SARS-CoV-2. Furthermore, the study is unique in its large sample drawn exclusively from community-based populations rather than hospitalized patients.Implication of all the available evidence: Combining the evidence from this study with prior research suggests that anosmia and ageusia are key symptoms that differentiate COVID-19 from influenza-like symptoms. Clinical screening protocols for COVID-19 should look for these symptoms, which are not commonly asked of patients who present to urgent care or hospital with flu-like symptoms.

Key points: Important symptoms specific to COVID-19 are fever, anosmia, ageusia, and cough. Two-thirds of symptoms were highly specific (>90.0%), yet most symptoms individually possessed a PPV <50.0%. This study confirms using robust methods the key symptoms associated with COVID-19 infection, and it also identifies combinations of symptoms strongly associated with positive infection.


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