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

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with a high overall risk of morbidity and mortality in patients with co-morbidities. In COVID-19 patients, hypertension, obesity and diabetes mellitus were found to be the most common comorbidities

The majority of patients who have been infected with SARS-CoV-2 test negative 14 days after the initial infection, while some patients may remain RNA positive for months. The recent emergence of re-infections, vaccine discovery, and VOC variants of concern, such as the Delta variant, with increased viral titers observed, underscores the clinical imperative to interpret positive SARS results. CoV-2 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 ​​obtained from the RT-PCR test are inversely correlated with the amount of RNA present in a sample, but they are influenced by the characteristics of the sample, the patient and the diagnostic test.

In a new study, a collaboration of researchers from various institutes described the natural history of the SARS-CoV-2 test, which includes Ct values ​​in patients who had tested positive multiple times, before the emergence of VOCs. in the deployment of the vaccine. In addition, the authors analyze the timescale of positivity and clinical characteristics of the patient population with prolonged positivity for SARS-CoV-2.

A pre-printed version of this study, which is yet to be peer reviewed, is available on the website medRxiv* preprint server.

Characteristics of diagnostic tests for patients with multiple positive tests for SARS-CoV-2

Of the 207 patients who had multiple positive tests in this study and 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 observed three times more among the 57 patients who displayed prolonged positivity in this study.

RT-PCR Ct values ​​generally decrease over time, but varying rates of decline were observed in patients in this study. Of the patients who had shown prolonged positivity, 123 had available Ct values, obtained from their first and last positive tests.

Among these patients, the final positive tests were above the median of 9.8 cycles compared to the first positive test, indicating that lower amounts of RNA were detected. However, 11 of these patients had higher amounts of RNA in their last positive test compared to their first.

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

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

Of the prolonged positive patients, 33 had positive tests near the limit of detection (> 35Ct), which is consistent with the decline of viral DNA over time. However, after the first positive test, on day 40, 5 patients still had Ct values ​​

Summary of time between first and last positive test for patients with multiple positive tests.  The Y axis indicates the days between the first and last positive test, individual dots indicate individual patients.  Blue indicates a prolonged positive patient defined at the natural breaking point of Duration of the 3rd quartile, gray indicates a short-term positive patient. The violin and boxplot indicate the overall distribution of days between the first and the last positive test. “Height =” 775 “src =” https://www.news-medical.net/image.axd?picture=2021 % 2f10% 2fA12.jpg “title =” Summary of time between first and last positive test for patients with multiple positive tests. The Y axis indicates the days between the first and last positive test, individual dots indicate individual patients. Blue indicates a prolonged positive patient defined at the natural stopping point of duration> 3rd quartile, gray indicates a short-term positive patient. The violin and boxplot indicate the overall distribution of days between the first and the last positive test. “Width =” 1009 “>

Summary of time between first and last positive test for patients with multiple positive tests. The Y axis indicates the days between the first and last positive test, individual dots indicate individual patients. Blue indicates a prolonged positive patient defined at the natural stopping point of duration> 3rd quartile, gray indicates a short-term positive patient. The violin and boxplot indicate the overall distribution of days between the first and the last positive test.

Implications

Results from 8% of patients showing intermittent positivity with multiple positive tests for SARS-CoV-2 prior to sustained VOC transmission suggest that sample quality plays an important role in Ct results.

Interestingly, a prolonged positive patient was three times more likely to display intermittent positivity. Thus, intermittent negative results in some patients may be due to therapeutic interventions, varying excretion dynamics, among other variables, which should be explored in future studies.

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

Due to the addition of new circulating variants, it will become essential to keep in mind the possibility of variable excretion at any stage of infection and to be careful in interpreting the values. Ct as proxy measures of severity and infectivity.

There is an urgent need for diagnostic tests to be developed and deployed that can distinguish between reinfection and prolonged shedding, which will provide insight into infectivity and aid in future stages of the pandemic.

*Important Notice

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

The references

Journal reference:

  • Longitudinal tests for SARS-CoV-2 are punctuated with intermittent positivity and varying rates 3 of cycle threshold decline, Shawn E. Hawken, Subhashini A. Sellers, Jason R. Smedberg, Jeremy D. Ward, Herbert C. Whinna , William Fischer, Melissa B. Miller, medRxiv, 2021.10.01. https://doi.org/10.1101/2021.10.01.21264373, https://www.medrxiv.org/content/10.1101/2021.10.01.21264373v1


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