Research highlights challenges in utilizing Ct data to guide COVID-19 clinical planning

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high global morbidity and mortality risk among patients who have comorbidities. In COVID-19 patients, hypertension, obesity, and diabetes mellitus were found to be the most prevalent comorbidities

The majority of patients who have been infected with SARS-CoV-2 test negative 14-days following initial infection, whereas some patients can remain RNA positive for months. The recent emergence of re-infections, vaccine-breakthrough cases, and variants of concern VOC, such as the Delta variant, which has been observed to rise to higher virus titers, underscore the clinical imperative to interpret positive SARS-CoV-2 results from the same person.

The current gold-standard test for SARS-CoV-2 is the RT-PCR clinical diagnostic test, however, this test is not quantitative. The Ct values gained from the RT-PCR test are inversely correlated with the RNA amount present in a sample, but they are influenced by specimen, patient and diagnostic test characteristics.

In a new study, a collaboration of researchers from various institutes described the natural history of SARS-CoV-2 testing, which includes Ct values among patients who had tested positive multiple times, prior to the emergence of VOCs in the vaccine roll-out. In addition, the authors analyze the timescale of positivity and clinical features of the population of patients with prolonged SARS-CoV-2 positivity.

A preprint version of this study, which is yet to undergo peer review, is available on the medRxiv* preprint server.

Diagnostic testing characteristics of patients with multiple positive SARS-CoV-2 tests

Of the 207 patients who had multiple positive tests in this study who did not display prolonged positivity, 17 showed patterns of intermittent positivity due to having at least one negative test between their first and last positive test. This intermittent positivity was seen over three times more among the 57 patients who displayed prolonged positivity in this study.

Ct values from RT-PCR tests commonly decline over time, but variable rates of decline were observed from the patients within this study. Of patients who had displayed prolonged positivity, 123 of them had Ct values available, obtained from their first and last positive tests.

Among these patients, final positive tests were median 9.8 cycles higher when compared to the first time they tested positive, which indicates lower amounts of RNA were detected. However, 11 of these patients displayed more elevated amounts of RNA in their last positive test when compared to their first.

Overall, final positive tests ranged from 22.5 cycles lower to 31.8 cycles higher, with final positives testing near the detection limit (>35) for 21 patients. The first and last test Ct data was available for 36 of the patients who had prolonged positive tests. Final positive tests were a median of 14 cycles higher than the first positive tests.

As opposed to patients without prolonged positivity, there were no patients with prolonged positivity who had terminal test Ct values lower than their first positive test.

From the prolonged positive patients, 33 had positive tests close to the limit of detection (>35Ct), which is consistent with the decline of viral DNA over time. However, after the first positive test, by day 40, 5 patients still displayed Ct values of <35, and one patient tested positive, exhibiting a Ct value of <35 109 days after the initial positive test.

Summary of time between first and last positive test for patients with multiple positive tests. Y-axis indicates days between first and last positive test, individual dots indicate individual patients. Blue indicates prolonged positive patient defined at natural breakpoint of 3rd quartile duration, grey indicates short-term positive patient. Violin and box plot indicate overall distribution of days between first and last positive test." height="775" src="/image.axd?picture=2021%2f10%2fA12.jpg" title="Summary of time between first and last positive test for patients with multiple positive tests. Y-axis indicates days between first and last positive test, individual dots indicate individual patients. Blue indicates prolonged positive patient defined at natural breakpoint of > 3rd quartile duration, grey indicates short-term positive patient. Violin and box plot indicate overall distribution of days between first and last positive test." width="1009">
Summary of time between first and last positive test for patients with multiple positive tests. Y-axis indicates days between first and last positive test, individual dots indicate individual patients. Blue indicates prolonged positive patient defined at natural breakpoint of > 3rd quartile duration, grey indicates short-term positive patient. Violin and box plot indicate overall distribution of days between first and last positive test.

Implications

The results from 8% of the patients showing intermittent positivity with multiple positive SARS-CoV-2 tests before sustained VOC transmission suggest that the samples' quality plays a significant role in Ct results.

Interestingly, it was three times more likely for a prolonged positive patient to display intermittent positivity. Thus, the intermittent negative results from some patients may be due to therapeutic interventions, variable shedding dynamics, among other variables, which should be explored within future studies.

As the pandemic continues to progress and VOCs capable of higher titers and vaccine breakthroughs such as the Delta variant become more prevalent, longitudinal testing information with variability in CT values will be more accessible for a more significant number of patients.

Due to the addition of novel variants in circulation, it will become vital to be mindful of the possibility of variable shedding at any stage of infection and be cautious when interpreting Ct values as proxy measures for severity and infectivity.

It is of great urgency that diagnostic tests are developed and deployed that can discriminate between re-infection and prolonged shedding, which will provide insight into infectiousness and help with the future stages of the pandemic.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

References

Journal reference:
Colin Lightfoot

Written by

Colin Lightfoot

Colin graduated from the University of Chester with a B.Sc. in Biomedical Science in 2020. Since completing his undergraduate degree, he worked for NHS England as an Associate Practitioner, responsible for testing inpatients for COVID-19 on admission.

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