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Delayed Covid-19 Viral Loads Have Implications for Testing, Treatment

Remember the early days of the Covid pandemic when a rapid test could quickly determine if patients were infected as soon as they exhibited symptoms? A new study points out how much the situation has changed, with peak viral loads now occurring as late as the 4^th or 5^th day. Here is more information on that and what it means for testing.

ATLANTA – When the COVID-19 pandemic began, peak viral loads appeared to coincide with symptom onset. Now, more than 3 years later, viral loads apparently are peaking later.

“Our data suggest that the relationship between SARS-CoV-2 Ct value distributions (as a well-established proxy for viral load distributions) and the timing of symptom onset in a highly immune population is very different than the relationship between these parameters observed early in the pandemic—a finding with major implications for testing practice going forward,” write Emory University-led researchers.

The preprint study in medRxiv, adds, “Early in the COVID-19 pandemic, peak viral loads coincided with symptom onset. We hypothesized that in a highly immune population, symptom onset might occur earlier in infection, coinciding with lower viral loads.”.

To demonstrate that, the study team assessed SARS-CoV-2 and influenza A viral loads relative to symptom duration in symptomatic adolescents and adults over the age of 16 who presented for testing in Georgia. During that time period, April 2022 to April 2023, the Omicron variant of SARS-Cov-2 was predominant.

Of 348 newly diagnosed SARS-CoV-2 PCR-positive patients (65.5% women, median age of 39.2), 91.1% had a history of vaccination, natural infection, or both

Information on symptom duration and recent testing history was obtained from participants, while the presence of infection was tested using established assays. To estimate hypothetical antigen rapid diagnostic test (Ag RDT) sensitivity on each day after symptom onset, percentages of individuals with Ct value <30 or <25 were calculated.

Results indicate that, by both Ct value and antigen concentration measurements, median viral loads rose from the day of symptom onset and peaked on the fourth/fifth day. “Ag RDT sensitivity estimates were 30.0-60.0% on the first day, 59.2-74.8% on the third day, and 80.0-93.3% on the fourth day of symptoms,” the researchers report.

In 74 influenza A PCR-positive individuals (55.4% women; median age 35), median influenza viral loads peaked on the second day of symptoms.

“In a highly immune adult population, median SARS-CoV-2 viral loads peaked around the fourth day of symptoms, according to the study. “Influenza A viral loads peaked soon after symptom onset. These findings have implications for ongoing use of Ag RDTs for COVID-19 and influenza.”

Early in the COVID-19 pandemic, SARS-CoV-2 viral loads tended to peak at the onset of symptoms, steadily decreasing afterward, according to the report, which added, Subsequently, multiple evaluations of the first commercially available antigen rapid diagnostic tests (Ag RDTs) indicated that viral loads in symptomatic adults within the first 7 days of symptoms were reliably high enough to be detected in most individuals by the Ag RDTs with strongest performance.

“Accordingly, initial FDA-approved instructions for use of Ag RDTs utilized only a single test in symptomatic individuals within the first week of symptoms. Early Ag RDT deployment across the United States similarly utilized only one test per symptomatic individual, though the utility of backup molecular testing in those with negative Ag RDT results was simultaneously emphasized.”

The situation has changed, however. The researchers advise, “More recently, and particularly during the SARS-CoV-2 Omicron variant surge in early 2022-- which overlapped with markedly increased consumer access to home Ag RDTs-- increased uncertainty emerged regarding the negative predictive value of Ag RDTs in newly symptomatic individuals and how to guide consumers now in charge of interpretation of their own testing results. “

For example, studies of home Ag RDT performance documented improvement of sensitivity with serial testing. In November 2022, the Food and Drug Administration adjusted recommendations for home Ag RDT use to include guidance to repeat testing in symptomatic individuals 48 hours after an initial negative test, for a total of at least two tests.

“Despite the shift over time towards use of serial Ag RDTs in symptomatic individuals to exclude COVID-19, the reasons for the apparent change in clinical performance of Ag RDTs in symptomatic individuals between early and late in the pandemic have not been a major focus of investigation,” the study authors point out.

That is important because those who test negative on antigen tests on the first few days of symptoms and remain symptomatic might not realize that Covid has not been excluded, they add.

“Serial testing recommendations should be updated to clarify the timing of repeat testing (potentially including a third test if tests are negative on the first and third days of symptoms) and the need to take precautions around others through at least the fourth day of symptoms, including masking when feasible,” according to the study. “Moreover, though challenging, it will be important to find ways to educate home antigen test users about these updated recommendations.”

The researchers add that their findings also have implications for test-to-treat programs that combine home Ag RDT use with prescriptions of antiviral treatment “given that treatment is optimally given as early in the course of infection as possible.”