Since the first outbreak of SARS-CoV-2 infection in China, COVID-19 epidemic spread throughout the world involving more than 37 million people . In Italy, the exponential growth of positive cases, especially in the first weeks, brought a rapid succession of Government policies aiming at controlling the spread of the disease . 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 ascertainment of SARS-CoV-2 infection and the last test result that accounts for the recovery. It is worth recalling that the dataset includes all the tests performed from the very beginning of the outbreak until, approximately, the beginning of phase 2. In the earliest period there was no guideline either for the diagnosis of recovery or the conversion to negative status. Several communications by international and national sources have been published in the following period: for example, the first regulatory instructions about the assessment of negative status by two negative swabs in Italy can be dated to February 22th by Italian Ministry of Health (circolare N. 5443). In this situation the administration of diagnostics tests was perfomed with heterogeneous rules throughout the majority of the time period covered by our data. In view of this, we preferred to perform a reconstruction of negative status by referring to the latest available swab, which represents the current-period knowledge (referred to the end of the study) about health status of all positive subjects in the territory. Of course, some limitations are implied, as discussed below. Up to date, the national guidelines have changed and a symptomatic patient is considered “recovered” and can go back to society after at least 10 days from the appearance of symptoms and at least 3 days from the clinical recovery if a RT-PCR test performed on the 10th day yields a negative result, while for asymptomatic cases it is possible to discontinue quarantine and isolation after 10 days from the first positive RT-PCR test result if a negative one is yielded on the 10th day.
Another major difference that has been introduced in the latest national guidelines and that doesn’t apply for our study is that, individuals that came in contact with a case of COVID-19 can either be quarantined for 14 days and released at the end of the two weeks without undergoing a RT-PCR test or they can be quarantined for 10 days if a RT-PCR test performed on the last day yields a negative result. If the individual becomes symptomatic he will be isolated, a nasopharyngeal swab will be performed immediately and isolation will be continued at least until the end of symptoms. Isolation will only be discontinued after one negative result of RT-PCR test. A patient that shows no symptoms but is persistently positive to RT-PCR test after at least one week from his clinical recovery, will be able to go back to the community after 21 days from symptoms appearance without the need to perform another nasopharyngeal swab.
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. 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) . 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.
The major limitations of the study stem from the fact that in the period under investigation data have been recorded without a planned national strategy, because of the lack of a unique testing protocol for SARS-Cov-2 . Although, the loss of accuracy for the reconstruction of the time of conversion into negative status, this choice is useful to avoid putative under-estimation of negative conversion time. A further issue that justifies the use of the last swab to ascertain the negative status is the absence of a rationale, confirmed by reliable study results, that explains the possible factors that could determine of occurrence of a positive swab after a first negative result. In particular at the time of the study it was not clear if, and to what extent, subjects recovered from coronavirus could be again infected by the virus.
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 [23, 24, 25]. 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; 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 being 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 by about 11%, and more than half of it is due to COVID-19 induced uncertainty ; 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 .
The test-based criteria have been discarded by the major scientific organizations (WHO, CDC) but it still is the requirement for re-admission in the community in 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.