Might clinical laboratories soon be called on to conduct mass testing to find people who show little or no symptoms even though they are infected with the coronavirus?    

Clinical laboratory managers understand that as demand for COVID-19 testing exceeds supplies, what testing is done is generally performed on symptomatic patients. And yet, it is the asymptomatic individuals—those who are shown to be infected with the SARS-CoV-2 coronavirus, but who experience no symptoms of the illness—who may hold the key to creating effective treatments and vaccinations.

So, as the COVID-19 pandemic persists, scientists are asking why some people who are infected remain asymptomatic, while others die. Why do some patients get severely ill and others do not? Researchers at the University of California San Francisco (UCSF) and Stanford University School of Medicine (Stanford Medicine) are attempting to answer these questions as they investigate viral transmission, masking, immunity, and more.

And pressure is increasing on researchers to find the answer. According to Monica Gandhi, MD, MPH, an infectious disease specialist and Professor of Medicine at UCSF, millions of people may be asymptomatic and unknowingly spreading the virus. Gandhi is also Associate Division Chief (Clinical Operations/Education) of the Division of HIV, Infectious Diseases, and Global Medicine at UCSF’s Zuckerberg San Francisco General Hospital and Trauma Center.

“If we did a mass testing campaign on 300 million Americans right now, I think the rate of asymptomatic infection would be somewhere between 50% and 80% of cases,” she told UCSF Magazine.

On a smaller scale, her statement was borne out. In a study conducted in San Francisco’s Mission District during the first six weeks of the city’s shelter-in-place order, UCSF researchers conducted SARS-CoV-2 reverse transcription-PCR and antibody (Abbott ARCHITECT IgG) testing on 3,000 people. Approximately 53% tested positive for COVID-19 but had no symptoms such as fever, cough, and muscle aches, according to data reported by Carina Marquez, MD, UCSF Assistant Professor of Medicine and co-author of the study, in The Mercury News.

While their study undergoes peer-review, the researchers published their findings on the preprint server medRxiv, titled, “SARS-CoV-2 Community Transmission During Shelter-in-Place in San Francisco.”

Pandemic Control’s Biggest Challenge: Asymptomatic People

In an editorial in the New England Journal of Medicine (NEJM), Gandhi wrote that transmission of the virus by asymptomatic people is the “Achilles heel of COVID-19 pandemic control.”

In her article, Gandhi compared SARS-CoV-2, the coronavirus that causes COVID-19, to SARS-CoV-1, the coronavirus that caused the 2003 SARS epidemic. One difference lies in how the virus sheds. In the case of SARS-CoV-2, that takes place in the upper respiratory tract, but with SARS-CoV-1, it takes place in the lower tract. In the latter, symptoms are more likely to be detected, Gandhi explained. Thus, asymptomatic carriers of the coronavirus may go undetected.

Viral loads with SARS-CoV-1, which are associated with symptom onset, peak a median of five days later than viral loads with SARS-CoV-2, which makes symptom-based detection of infection more effective in the case of SARS-CoV-1,” Gandhi wrote. “With influenza, persons with asymptomatic disease generally have lower quantitative viral loads in secretions from the upper respiratory tract than from the lower respiratory tract and a shorter duration of viral shedding than persons with symptoms, which decreases the risk of transmission from paucisymptomatic persons.”

Rick Wright (above), an insurance broker in Redwood City, Calif., was infected with the COVID-19 coronavirus while aboard a Diamond Princess Cruise. He underwent 40 days of isolation, and though he consistently tested positive for the coronavirus, he experienced no symptoms of the illness. “I never felt sick. Not a cough, wheezing, headache. Absolutely nothing,” he told Mercury News. (Photo copyright: The Mercury News.)

Stanford Studies Immune Responses in COVID-19 Patients

Meanwhile, scientists at the Stanford University School of Medicine were on their own quest to find out why COVID-19 causes severe disease in some people and mild symptoms in others.

“One of the great mysteries of COVID-19 infections has been that some people develop severe disease, while others seem to recover quickly. Now, we have some insight into why that happens,” Bali Pulendran, PhD, Stanford Professor of Pathology, Microbiology, and Immunology and Senior Author of the study in a Stanford Medicine news release.

The study, published in Science, titled, “Systems Biological Assessment of Immunity to Mild Versus Severe COVID-19 Infection in Humans,” was based on analysis of 76 patients with COVID-19 and 69 healthy people from Hong Kong and Atlanta. The researchers pointed to flailing immune systems and “three molecular suspects” in the blood of COVID-19 patients they studied.

The Stanford research suggested that three molecules—EN-RAGE, TNFSF14, and oncostatin-M—“correlated with disease and increased bacterial products in human plasma” of COVID-19 patients. 

“Our multiplex analysis of plasma cytokines revealed enhanced levels of several proinflammatory cytokines and a strong association of the inflammatory mediators EN-RAGE, TNFSF14, and OSM with clinical severity of the disease,” the scientists wrote in Science.

Pulendran hypothesized that the molecules originated in patients’ lungs, which was the infection site. 

“These findings reveal how the immune system goes awry during coronavirus infections, leading to severe disease and point to potential therapeutic targets,” Pulendran said in the news release, adding, “These three molecules and their receptors could represent attractive therapeutic targets in combating COVID-19.”

Clinical Laboratories May Do More Testing of Asymptomatic People

The research continues. In a televised news conference, President Trump said COVID-19 testing plays an important role in “preventing transmission of the virus.” Clearly this is true and learning why some people who are infected experience little or no symptoms may be key to defeating COVID-19.

Thus, as the nation reopens, clinical laboratories may want to find ways to offer COVID-19 testing beyond hospitalized symptomatic patients and people who show up at independent labs with doctors’ orders. As supplies permit, laboratory managers may want to partner with providers in their communities to identify people who are asymptomatic and appear to be well, but who may be transmitting the coronavirus. 

—Donna Marie Pocius

Related Information:

We Thought It Was Just a Respiratory Virus—We Were Wrong

Coronavirus: Why Don’t People Get Sick Despite Being Infected?

Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control COVID-19

Study Reveals Immune System-Deviations in Severe COVID-19 Cases, a Stanford Study Shows

Why Do Some Get Sick and Others Don’t? Study May Unravel Mystery

Systems Biological Assessment of Immunity to Mild Versus Severe COVID-19 Infection in Humans