The confounding range of COVID-19 symptoms

The range of experiences in people infected with SARS-CoV-2, the virus that causes COVID-19, spans from no symptoms to hospitalization to death, an observation NIAID director Anthony Fauci and other experts have repeatedly made recently.

• "In SARS-Cov-2 , there is an extreme divergence in host responses. We don’t yet know what is leading to that," says immunologist José Ordovas-Montañes of Boston Children's Hospital.

Details: Many people have mild symptoms of the disease — or none at all, meaning they can be unknowingly carrying and spreading the virus and complicating efforts to control its spread.

• 40%–45% of people infected with SARS-CoV-2 don't develop symptoms, according to one estimate based on several case studies.
• By comparison, 13% of health care workers infected with SARS-CoV-1, the virus behind the 2003 epidemic, were asymptomatic in one study in Singapore.
• But for many respiratory viruses, the rate of infection without symptoms is more than 70%.

On the other end of the spectrum are those were are hospitalized, including roughly 1 in 5 older people who test positive for the disease.

• Beyond pneumonia and acute respiratory distress syndrome, the long and varied list of common manifestations of COVID-19 in hospitalized patients includes cardiac, neurological, renal, hepatic, gastrointestinal, endocrine, thrombotic, and dermatological complications, according to a recent review by Aakriti Gupta of the Columbia University Irving Medical Center.
• "This virus is proving to be more than just a respiratory virus in terms of the manifestations, which we've seen with other respiratory viruses," says Amesh Adalja, a senior scholar at the John Hopkins Center for Health Security.
• Other viruses, like influenza, SARS-CoV-1 and Ebola, can affect the body in multiple ways.
• But with COVID-19, "the proportion of people in which this multiple organ injury is occurring is higher than anything we’ve seen before," says Gupta. For example, 40%–50% of hospitalized COVID-19 patients and up to 80% of patients admitted to the ICU have acute kidney injury, usually in addition to lung injury, compared to about 7% of patients with SARS.

The intrigue: It's possible other pandemic viruses — like the 1918 flu — had a wide range of different outcomes, but the molecular tools and diagnostics didn't exist to spot them. Or in the case of the coronaviruses that cause the common cold and don't kill people, we don't pay attention to those differences or bother to look for them.

• But COVID-19 does kill and, as data and science rapidly amass about the virus, the differences are more explicit — and more concerning.
• "Each virus has this particular balance of the types of cases you are going to get," says Ordovas-Montañes. "This virus has particularly captivated our attention because of how balanced it is across that spectrum."

What's happening: Researchers are trying to tease out the factors behind COVID-19's range.

There is the virus itself. "Coronaviruses are unusual in that they attack both the respiratory and gastrointestinal systems," says Rachel Roper, a virologist at East Carolina University.

• SARS-CoV-2 targets the ACE2 receptor on host cells to infect them. That receptor is expressed in many of the body’s tissues, and some studies find particles of the virus in heart, kidney and gut cells, suggesting it can get to other organs and possibly damage them directly.
• Or it could be that the virus is impairing the body’s innate immune responses, affecting pathways that regulate key processes in the body, or causing inflammation — any of which may allow the virus to reach into unexpected organ systems.

There is the person it infects, with their genetics, behaviors and environment. A host of pre-existing conditions — for example, previous lung and heart disease — increases the risk of serious COVID-19 complications.

And there is the society that person lives in. Geographic and racial disparities in this pandemic suggest other factors, like the distribution of health services, may need to be considered, says C. Brandon Ogbunu, an assistant professor at Yale University who studies disease evolution and ecology.

• "Even more so than other outbreaks, the variation from person to person, the multisystem nature, the way it hits demographics different, the way the disease manifests differently in national contexts — it defies a simple medical or biomedical narrative," he says.
• COVID-19 may be more akin to noninfectious diseases — like diabetes and schizophrenia — that have complex interactions with sociological, historical and behavioral factors," says Ogbunu.

The bottom line: "The story of understanding COVID-19 has been the story of understanding these diversities," says Ogbunu. "This is a test of our modern understanding of what a disease is."

Editor's note: This story has been updated to clarify that the roughly 1 in 5 hospitalization rate for people who test positive for the disease pertains to older people.