With Covid-19 patients flocking to hospitals across the country, doctors face an impossible question. Which patients in the emergency room are more likely to get worse quickly and which are most likely to fight the virus and recover?
As it turns out, there may be a way to differentiate these two groups, although it’s not yet widely used. Dozens of research published in the past few months found that people with bodies full of coronaviruses were more likely to get seriously ill and die more often, compared to people who carried much fewer viruses and were more likely to be relatively unharmed.
The results suggest that knowing what is known as viral load – the amount of virus in the body – could help doctors predict a patient’s course and more accurately distinguish those who may only need an oxygen check once a day from those who need it monitored, said Dr. Daniel Griffin, an infectious disease doctor at Columbia University in New York.
Tracking viral load “can actually help us stratify risk,” said Dr. Griffin. The idea is not new: viral load management has long been the foundation of caring for people living with HIV and stopping the transmission of this virus.
Little effort has been made to track viral loads in Covid-19 patients. However, earlier this month the Food and Drug Administration announced that clinical laboratories may report not only whether a person was infected with the coronavirus, but also how much virus was transmitted in their body.
This is not a change in policy – laboratories could have reported this information all along, according to two senior FDA officials, who spoke on condition of anonymity for not having the authority to speak publicly on the matter.
Still, the news came as a welcome surprise to some of the experts who have spent months pushing laboratories to record this information.
“This is a very important step by the FDA,” said Dr. Michael Mina, epidemiologist at Harvard TH Chan School of Public Health. “I think it’s a step in the right direction to make the most of one of the little pieces of data we have for a lot of positive people.”
The FDA change followed a similar move by the Florida Department of Health to require all laboratories to report this information.
Omitting viral load from test results was a missed opportunity not only to optimize strained clinical resources but also to better understand Covid-19, experts say. For example, an analysis of viral load shortly after exposure could reveal whether people who die of Covid-19 are more likely to have high viral loads at the onset of their illness.
And a study published in June showed that the viral load decreased as the immune response increased, “just as you would expect from an old virus,” said Dr. Alexander Greninger, a virologist at the University of Washington in Seattle. who directed the study.
An increase in the average viral load across communities could indicate an increasing epidemic. “We can get an idea of whether the epidemic is growing or decreasing without relying on the number of cases,” said James Hay, postdoctoral fellow in Dr. Mina’s laboratory.
Fortunately, viral load data – or at least a rough approximation of it – is readily available to feed into the results of the PCR tests that most laboratories use to diagnose coronavirus infection.
A PCR test is performed in “cycles”, doubling the amount of viral genetic material originally taken from the patient sample. The higher the initial viral load, the fewer cycles the test takes to find genetic material and generate a signal.
A positive result at a low cycle threshold or Ct implies a high viral load on the patient. If the test is positive after completing many cycles, the patient is likely to have a lower viral load.
Researchers at Weill Cornell Medicine in New York recorded the viral load of more than 3,000 hospitalized Covid-19 patients on the day they were admitted. They found that 40 percent of patients with high viral loads – whose tests were positive at a Ct of 25 or less – died in the hospital, compared with 15 percent of those who tested positive at higher Ct and presumably lower viral loads.
In another study, the Nevada Department of Health found an average Ct of 23.4 in people who died from Covid-19 compared to 27.5 in people who survived their diseases. People who were asymptomatic had a mean of 29.6, suggesting they carried much fewer viruses than the other two groups.
These numbers seem to vary very little, but they represent millions of virus particles. “These are not subtle differences,” said Dr. Greninger. A study from his lab showed that patients with a Ct less than 22 were more than four times as likely to die within 30 days as compared to those with a lower viral load.
However, using Ct values to estimate viral load is a difficult practice. Viral load measurements for HIV are highly accurate because they are based on blood samples. Tests for the coronavirus rely on wiping your nose or throat – a process that is subject to user error and the results of which are less consistent.
The amount of coronavirus in the body changes drastically as the infection progresses. The levels go from undetectable to positive test results in just a few hours, and the viral load continues to rise until the immune response sets in.
Then the viral load decreases rapidly. However, viral fragments can remain in the body and produce positive test results long after the patient is no longer infectious and the disease has resolved.
Given this variability, capturing viral load at a given point in time may not make sense if there is no more information about the progression of the disease, said Dr. Celine Gounder, Infectious Disease Specialist at Bellevue Hospital Center and a member of the Coronavirus Inbound Management Advisory Group.
“When do you measure the viral load on this curve?” Asked Dr. Gounder.
The exact relationship between a Ct value and the corresponding viral load can vary between tests. Instead of validating this quantitative relationship for each machine, the FDA authorized the tests to provide diagnoses based on a limit value for the cycle threshold.
Most manufacturers conservatively set the thresholds for diagnosing their machine between 35 and 40. These values generally correspond to an extremely low viral load. However, the exact threshold for a positive result or for a certain Ct as an indication of infectivity depends on the instrument used.
“So I’m very concerned about many of these Ct-based ratings,” said Susan Butler-Wu, director of clinical microbiology at the University of Southern California.
“Of course it is a value that can be useful in certain clinical circumstances,” said Dr. Butler-Wu, “but the idea that you can have a unicorn Ct that correlates perfectly with an infectious or non-infectious condition makes me very nervous.”
Other experts recognized these limitations, but said that the benefits of collecting Ct values outweighed the concerns.
“All of these are valid points when looking at the test results of an individual patient, but they don’t change the fact that, on average, looking at the results of the admission tests of these Ct values, actually identifies patients at high risk of decompensation will and die, “said Dr. Michael Satlin, an infectious disease physician and lead researcher on the Weill Cornell Study.
Dr. Satlin said adjusting his team’s results for duration of symptoms and various other variables did not change the high risk of death in high viral load patients. “Regardless of how you try to statistically adjust, that association is extremely strong and won’t go away,” he said.
At the population level, too, Ct values can be valuable during a pandemic, said Dr. Hay. High viral loads in a large group of patients may indicate recent exposure to the virus, suggesting an incipient increase in community transmission.
“This could be a great monitoring tool for less well-equipped facilities that need to understand the course of the epidemic but are unable to conduct regular, random tests,” said Dr. Hay.
Overall, information on the viral load is too valuable to be ignored or discarded without analysis.
“One of the things that has been difficult with this pandemic is that everyone wants to do evidence-based medicine and do it at the right pace,” said Dr. Greninger. “But we should also expect certain things to be true, like that more viruses are usually not good.”
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