Longitudinal SARS-CoV-2 Testing among the Unvaccinated Is Punctuated by Intermittent Positivity and Variable Rates of Increasing Cycle Threshold Values

The coronavirus disease 2019 (COVID-19) pandemic is complicated by cases of vaccine breakthrough and reinfection and widespread transmission of variants of concern (VOCs). Consequently, the need to interpret longitudinal positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests is crucial in guiding clinical decisions regarding infection control precautions and treatment. Although diagnostic real-time reverse transcription (RT)-PCR tests yield <em>C_T</em> values that are inversely correlated with RNA quantity, these tests are only approved for qualitative interpretation. In this study, we performed a retrospective review of 72,217 SARS-CoV-2 positive tests and identified 264 patients with longitudinal positivity prior to vaccination and VOC circulation. Patients with longitudinal positivity fell into two categories: short-term (207, 78%) or prolonged (57, 22%) positivity, defined as &le;28 (range, 1 to 28; median, 16) days and &gt;28 (range, 29 to 152; median, 41) days, respectively. In general, <em>C_T</em> values increased over time in both groups; however, 11 short-term-positive patients had greater amounts of RNA detected at their terminal test than at the first positive test, and 6 patients had RNA detected at <em>C_T</em> values of &lt;35 at least 40&thinsp;days after initial infection. Oscillating positive and negative results occurred in both groups, although oscillation was seen three times more frequently in prolonged-positive patients. Patients with prolonged positivity had diverse clinical characteristics but were often critically ill and were discharged to high-level care or deceased (22%). Overall, this study demonstrates that caution must be emphasized when interpreting <em>C_T</em> values as a proxy for infectivity, a predictor of severity, or a guide for patient care decisions in the absence of additional clinical context, particularly among the unvaccinated population. <strong>IMPORTANCE</strong> We describe the duration of positivity and the COVID-19 treatment and outcome characteristics of an unvaccinated population of patients with prolonged SARS-CoV-2 positivity. This investigation serves to highlight challenges in using <em>C_T</em> values to guide clinical decisions among unvaccinated individuals.