A new report published in the journal Science Translational Medicine estimates that potentially 16.8 million Americans were infected but not officially diagnosed with severe acute respiratory syndrome 2 (SARS-CoV-2) by July 2020. In addition, the results suggest there were nearly five undetected coronavirus cases for every diagnosed coronavirus infection in the first six months of the pandemic.
Younger people had the most undiagnosed coronavirus infections, likely because coronavirus disease 2019 (COVID-19) is less severe compared to older adults. Based on the results, researchers from the National Institute of Health (NIH) suggest coronavirus infections were more widespread than previously indicated by diagnostic testing eluding to more infection-induced immunity than what was previously thought.
The team writes:
These data are of great importance as we consider the impact vaccination may have on the future course of the pandemic and plan for current and future available vaccines to be administered. In addition, these data can also help us to better assess the public health measures taken during the pandemic and how to take the best approaches forward during any future public health emergencies.”
Blood sample collection
To determine the total number of people infected in the population, the researchers collected blood samples from people across the United States, advertised online through the NIH. Recruitment occurred from April 1, 2020, to August 4, 2020.
About 8,058 adults who had been undiagnosed with COVID-19 donated their blood and filled out a clinical questionnaire for the study. Researchers then analyzed the number of antibodies specific for SARS-CoV-2 in the blood serum.
While participant sampling was representative of the U.S. population, the team did acknowledge that their sample population skewed toward people who were more highly educated, had higher employment rates, and had better healthcare access than the general U.S. population.
Seropositivity in undiagnosed American adults
About 304 study participants were seropositive, making up 4.6% of undiagnosed adults with SARS-CoV-2 in the U.S. population. They estimated that for every diagnosed COVID-19 infection, there were 4.8 more cases left undiagnosed.
Among seropositive participants, 36.51% were IgG+, IgM+, IgA+ , 28.29% were IgG+ IgM− IgA+, 17.11% were IgG+, IgM−, IgA−, 13.16% were IgG+ IgM+ IgA−, 4.28% were IgG− IgM+ IgA− , and 0.66% were IgG−, IgM+ IgA+,” wrote the team.
The regional area appeared to influence seropositivity rates. Participants from the Northeast and Mid-Atlantic regions showed the highest rates of seropositivity. In contrast, the Midwest had the lowest seropositivity rate.
Urban areas had higher seropositivity at 5.3% than rural areas with a 1.1% seropositivity rate.
People who were 18 to 44 years had the highest seropositivity at 5.9%, with females being higher than males.
Seropositivity in undiagnosed adults was the highest among African Americans at 14.2%. Asian adults had the lowest seropositivity rate.
Other factors associated with low seropositivity rate included those who worked from home, had a previous vaccination for influenza or pneumonia, and health conditions that can worsen COVID-19 infection, such as heart disease, diabetes, and skin cancer.
On the other hand, participants who reported that they were previously exposed to someone with SARS-CoV-2 tended to have higher seropositivity.
As of July 2020, an estimated 4.79 COVID-19 infections were left undiagnosed for every identified COVID-19 case.
With the rapid SARS-CoV-2 transmission in mind, the researchers suggest this leads to about 16.8 million undiagnosed adults by July 2020. The official count in July 2020 was 3.5 million COVID-19 cases in the United States.
The research team concludes that the U.S. may have had more people with temporary immunity after recovering from natural infection than previously predicted. However, more long-term studies on immunity in the U.S. population are needed to fully understand how long immunity from natural infection lasts compared to the vaccine, how infection-induced immunity affects the vaccine response, and whether herd immunity is feasible in controlling SARS-CoV-2.
Study limitations
Selection bias is a concern as participants volunteered rather than being randomly selected for the study. This calls into question whether the study cohort was representative of the general U.S. population.
In this study, participants were more likely to be well-educated and have access to healthcare. Future studies with larger samples sizes would help in making more detailed and potentially more accurate estimates.
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