Cruise ship passengers who embarked from the coast of Argentina in mid-March were unaware that they were living in a COVID-19 hotspot for more than a week after the ship departed.
The reason why these passengers were oblivious? Because a majority of the cruise ship's cases were asymptomatic.
Researchers are now pointing to this cruise ship outbreak, in which all passengers were provided surgical masks, as evidence that universal masking may result in a higher proportion of asymptomatic COVID-19 cases. Other outbreaks of mostly asymptomatic cases where widespread masking was implemented, in places like jails and meatpacking plants, provide epidemiological data that masks could reduce viral inoculum -- and as a result, decrease the severity of illness.
Writing in the , Monica Gandhi, MD, and George Rutherford, MD, of the University of California in San Francisco, hypothesized that widespread population masking may act as a sort of "variolation," exposing individuals to a smaller amount of viral particles and producing an immune response.
Gandhi told 鶹ý that the viral inoculum, or the initial dose of virus that a patient takes in, is one likely determinant of ultimate illness severity. That's separate from patients' subsequent viral load, the level of replicating virus as measured by copies per mL.
The "variolation" hypothesis holds that, at some level, the inoculum overwhelms the immune system, leading to serious illness. With less than that (and the threshold may vary from one person to the next), the individual successfully fights off the infection, with mild or no clinical illness.
"Diseases in which your immune system has a big role to play in how sick you get -- and your immune system contributes to pathogenesis -- do not seem to be able to handle a large viral inoculum," Gandhi said in an interview.
Severe COVID-19 may be caused by a reaction known as the cytokine storm, an immune response in which the body attacks its own cells and tissues as opposed to the virus itself. Although this theory has yet to be proven (and other theories, such as the bradykinin storm, have been suggested), a large initial dose of SARS-CoV-2 may be the trigger.
Trials that give humans different doses of viral RNA are not ethical, of course. But animal studies provide preliminary evidence that viral inoculum could impact disease severity, Gandhi noted. In a , for example, those infected with a higher dose of SARS-CoV-2 had worse outcomes compared to those infected with smaller amounts of virus.
Masked hamsters were also shown to be less likely to get COVID-19 illness than those without masks, . And if they did acquire the illness, it was more mild.
"We know that a higher inoculum of an infectious agent generally makes people sicker," said Peter Katona, MD, an infectious disease specialist and professor at the University of California in Los Angeles.
While there is some emerging research that viral inoculum may play a role in disease severity in COVID-19, other infectious disease specialists have explored how viral load -- the amount of viral RNA present in the bloodstream -- may also be a factor in illness severity.
In the , a group led by Carlos Cordon-Cardo, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, reported that the viral loads of patients who died from COVID-19 illness were significantly higher than those of patients who survived (mean log10 6.4 copies per mL vs 5.2 copies per mL, respectively). In addition, for each additional unit of viral RNA detected, researchers observed a 7% increased risk of mortality.
An earlier study published in also found that the mean viral load in severe coronavirus cases was more than 60 times that of mild cases, according to Yang Liu, MD, of Nanchang University in China, and colleagues.
Cordon-Cardo's group wrote that while categorizing COVID-19 patients is still a challenge, "transforming qualitative testing into a quantitative measurement of viral load will assist clinicians in risk-stratifying patients and choosing among available therapies and trials."
Ravina Kullar, PharmD, MPH, an infectious disease expert and epidemiologist speaking on behalf of the Infectious Disease Society of America, said that the question of how providers should treat patients with a high viral load is a critical one.
Patients with a higher viral load "should potentially be put on the steroid dexamethasone from the get go, rather than an antiviral, to help prevent that cytokine storm that might lead to worse outcomes," Kullar said.
But the research investigating whether or not patients with a higher viral load will suffer worse outcomes is not conclusive. A South Korea-based study published in found that viral load was no different in asymptomatic patients versus those with symptoms.
While experts believe there is evidence that viral load could indicate how severe COVID-19 could be, they also don't think it's the only factor that contributes to severe illness.
"I think it's all dependent on someone's immune system," Kullar said. "Viral load is a part of the picture, but it's not the full picture."
Patients who are older, have pre-existing conditions such as cardiovascular diseases or cancer, or immune system deficiencies, are still at risk of severe disease, and viral load in isolation may not be an accurate predictor.
Katona said many questions remain unanswered about viral load and disease severity: how it relates to transmissibility, for example, as well as the best way to measure it (saliva vs nasopharyngeal samples).
"We know some of the unknowns, but there are also a lot of unknown unknowns," Katona said. "I'm convinced that the viral load makes a difference. We just haven't been able to show that consistently."