key: cord-1044971-cw7fwu23
authors: Cento, Valeria; Colagrossi, Luna; Nava, Alice; Lamberti, Anna; Senatore, Sabrina; Travi, Giovanna; Rossotti, Roberto; Vecchi, Marta; Casati, Ornella; Matarazzo, Elisa; Bielli, Alessandra; Casalicchio, Giorgia; Antonello, Maria; Renica, Silvia; Costabile, Valentino; Scaglione, Francesco; Fumagalli, Roberto; Ughi, Nicola; Epis, Oscar Massimiliano; Puoti, Massimo; Vismara, Chiara; Faccini, Marino; Fanti, Diana; Alteri, Claudia; Perno, Carlo Federico
title: Persistent positivity and fluctuations of SARS-CoV-2 RNA in clinically-recovered COVID-19 patients
date: 2020-06-20
journal: J Infect
DOI: 10.1016/j.jinf.2020.06.024
sha: 16c50a131730c1a4d17f978424655b6510cf2583
doc_id: 1044971
cord_uid: cw7fwu23

nan

As the COVID-19 pandemic slowly recedes, the number of clinically recovered subjects increases steadily. To minimize the risk of viral transmission in the community, several countries worldwide are currently endorsing a "test-based" strategy for hospital discharge and discontinuation of home-isolation, which requires 2 negative results of RT-PCR for SARS-CoV-2 RNA on nasopharyngeal swabs collected ≥24 h apart. 1 Emerging evidences are indicating that RT-PCR positivity may persist for several weeks after the resolution of symptoms, 2-5 while the decline in viral infectivity occurs rather quickly (i.e. within one or two weeks since symptoms onset). [5] [6] [7] Whether the persistently-positive recovered patients might still shed infectious virus is thus uncertain, and this implies the risk for many of them to remain hospitalized, or in shelter-inplace, for a much longer time than necessary, with significant social distress and economic commitment.

In order to help in estimating the burden, and the temporal extent, of persistent RT-PCR positivity, and thus support the design of sustainable follow-up protocols, we retrospectively analyzed 13,475 longitudinal SARS-CoV-2 molecular tests (performed from March 3 to June 4, 2020), of 7608 laboratory-confirmed and clinically recovered COVID-19 patients. Patients were tested at symptoms resolution while still hospitalized ( N = 501; range of follow-up: 1-53 days), and/or after hospital discharge ( N = 7127; range of follow-up post-discharge: 14-74 days); 50.6% of them were male, and median (IQR) age was 51 (41-59) years.

At symptoms resolution, after a median (IQR) of 21 (15-28) days since their onset, nearly half of the 501 hospitalized patients tested (46.9%, N = 235) had detectable virus in nasopharyngeal swabs, in all cases with cycle-thresholds (Cts) values ≥24 (viral-load < 1 × 10 6 by quantitative droplet-PCR). These patients had higher nasopharyngeal viral-load at hospital-admission, compared to those who tested negative (median [ During follow-up, 2182/2655 patients (82.2%) had 2 consecutive RT-PCR negative results, within a median (IQR) of 16 (16-19) days after hospital discharge, and thus discontinued molecular monitoring.

To the best of our knowledge, none of the patients monitored after hospital discharge have ever shown a resurgence of COVID-19 symptoms, regardless of RT-PCR results.

Overall, our results confirm the prolonged RT-PCR positivity in a significant proportion of recovered COVID-19 patients (46.9% at clinical recovery, 13.7% at day-14 after hospital discharge, and 14.7% between day-41 and day-60 after hospital discharge). By taking into account the non-negligible risk for negative-to-positive fluctuations, as also previously reported, 2-4 these long-term positivity rates could be underestimated.

While considering public-health orders, we should underline that RT-PCR positivity after recovery does not necessarily implies the presence of a viable or transmissible virus. Viral culture attempts from respiratory specimens failed after the first 8-18 days since symptoms onset, 5-7 and/or from respiratory specimens characterized by RT-PCR Ct values > 24. 7 All patients included in our analysis complied with one or both these criteria, ever since their first control after clinical recovery. The data published so far lead us to consider the contagiousness of our persistently positive (and persistently asymptomatic) patients rather unlikely, even if the risk of viral transmission should not be definitely rule out (especially at of few days after the symptoms resolution).

Based on our data, the optimal post-recovery follow-up strategy should include an integrated approach between the exclusively "symptom based" one (as recommended by the CDC 8 ) and the one based only on the evaluation of the negativity of the RT-PCR (as recommended by the ECDC 1 ), possibly by integrating the latter with a quantitative evaluation of the viral load. A pressing clinical and social need to define a maximum time and viral load limit beyond which the positivity of the RT-PCR loses significance, is thus felt now more than ever, as this is the only way to allow their safe return to the community, and not to prolong their isolation beyond clinical and public-health utility. 

European Centre for Disease Prevention and Control. Guidance for discharge and ending isolation in the context of widespread community transmission of COVID-19

Seven discharged patients turning positive again for SARS-CoV-2 on quantitative RT-PCR

Letter to the Editor: three cases of re-detectable positive SARS-CoV-2 RNA in recovered COVID-19 patients with antibodies

COVID-19 follow up testing

Prolonged virus shedding even after seroconversion in a patient with COVID-19

Virological assessment of hospitalized patients with COVID-2019

Predicting infectious SARS-CoV-2 from diagnostic samples

Symptom-based strategy to discontinue isolation for persons with COVID-19

We thank Dr. Silvia Nerini and all the staff of the Microbiology and Virology Laboratory of ASST Grande Ospedale Metropolitano Niguarda for outstanding technical support in processing swab samples, performing laboratory analyses and data management.