Since the first outbreak of SARS-CoV-2 infection in China, COVID-19 epidemic spread throughout the world involving more than 37 million people (14). In Italy, the exponential growth of positive cases, especially in the first weeks, brought a rapid succession of Government policies aiming at controlling the spreading of the disease (15). Prevalent cases account for most of the present cases in Italy, therefore one of the most important questions to answer remains the duration of the disease itself.
This research focused on the evaluation of the interval between the first diagnosis of SARS-CoV-2 infection and both the first negative RT-PCR testing and the double negative result that accounts for the recovery. On total population (n=52186) the analysis showed a CCI for negativity (considering both the single last and the double negative sample) of 16.6%, 31.1%, 45.2% and 56.3% at 2 28, 35 and 42 days from diagnosis respectively.
When the same population is stratified for sex, CCI for women showed a more rapid increase accounting for a higher probability than men of being negative or potentially negative for women, at any time interval. The stratified analysis for age showed a pattern in which younger patients had a consistently higher probability of negative or potentially negative than older patients, especially for higher time intervals. The lowest CCI curve was evident for patients older than 80 yo. As shown in Fig. 2, patients older than 65 yo showed a sensibly lower CCI than any younger age group.
These remarkable differences between age groups are partly motivated by the consistently higher probability of death in these older patients; in fact, CCI refers to the probability that the event verifies as the first event compared to the other events considered, as in this case death.
Patients older than 65 yo showed CCIs for negativity almost halved compared to those of younger age groups, on the contrary, when considering CCI for death, the older age groups showed a significantly higher probability than that of younger age groups.
Our results are in accordance with the work of Mancuso et al. (16) which demonstrated in a sample of 1162 patients that 60,6% of subjects became negative at a median follow up time of 30 days from diagnosis and 36 days from symptoms onset. Moreover, in a recent submitted article, available in pre-print, Lombardi et al. reported a median time from first positive test to a negative test to be 27 days (95% CI: 24-30) (17). The results of our study have been obtained independently of symptoms, therefore the positivity of samples at RT-PCR testing was not related to a clinical correlation and we can’t speculate on the probability of positive patients to be contagious.
This study has a few limitations. In the initial phase of the Public Health Emergency we lacked an official testing protocol for SARS-Cov-2 in Italy (18). As a consequence, data have been recorded without a planned national strategy. A second issue is the absence of a rationale, confirmed by reliable study results, that explains the possibility of occurrence of a positive swab after a first negative result. Thus, the negativity status should be ascertained considering, from the sequence of swabs performed to a single subject, the result of the last one: if the result is negative the subject is considered negative. Although the loss of accuracy, this choice is useful to avoid putative under-estimation of negativization times.
Up to date, SARS-CoV-2 contagiousness has been reported in current literature to be evaluated not only by the positivity to RT-PCR, but also considering the viral replication. In fact, several studies posit that the likelihood of recovering replication-competent virus declines after onset of symptoms. In patients with mild to moderate symptoms, no trace of a replication-competent virus was found after 10 days following symptom onset (19, 20, 21). In patients with severe symptoms, which in some cases were complicated by immunocompromised state, replication-competent virus was isolated between 10 and 20 days after symptom onset (22); even though, 88% and 95% of their biological fluids tested negative for replication-competent virus research after 10 and 15 days, respectively, following symptom onset.
At the same time, it is evident that a high fraction of SARS-CoV-2 positive patients remain positive for a long time span; this implies that, if the test-based criteria is used as the necessary condition to end the isolation, most patients will be isolated for a long time regardless of symptoms resolution.
These considerations need to be done especially due to the impact of containment measures on those activities that would suffer the most from this policy: manufacturing and productive activities, schooling and education. A strict policy of a long quarantine means loss of work hours, and sometimes entire departments will be sent home. The impact of the containment measures will be both short and long time: during the 4th quarter of the 2020 the Gross Domestic Product (GDP) will contract of around 11%, and more than half of it is due to COVID-19 induced uncertainty (23); also, given that every additional year of schooling translates to 8 percent in future earnings, a study demonstrated that the cost of school closures due to earning losses as a percent of GDP will range from 9% in high income countries to 61% in low income countries (24).
The test-based criteria has been discarded by the major scientific organization (WHO, CDC) but it still is the requirements for the community re-admission for many nations. As a consequence, the absence of a single internationally-shared procedure that grants 100% safety causes great uncertainty and confusion, also taking into account that a 60 days long isolation is not easily manageable and maybe not even necessary.
In conclusion, it appears clear that SARS-CoV-2 positivity is a condition that frequently lasts more than 30 days, as we observed in our cohort of patients. To be able to determine the accordance between positivity to the test and being contagious is paramount in order to avoid very long isolation or quarantine which would be unsustainable, but, at the same time, shortening the time span to less than 10-15 days would pose a concrete risk of increasing the virus spreading in the population therefore more solid studies are required in order to determine a single internationally accepted policy regarding the dismission of quarantine and isolation.