Doctor, how long should I isolate myself?

Recommendations on the duration of isolation for patients with Covid-19 continue to evolve with an increased understanding of the transmission dynamics of SARS-CoV-2. At the start of the Covid-19 pandemic, recommendations from the Centers for Disease Control and Prevention (CDC) included interrupting isolation when there was clinical improvement and a negative SARS-CoV-2 molecular test. This recommendation was replaced by a time-based approach (instead of a test-based one) when it became apparent that the elimination of unworkable SARS-CoV-2 RNA in the upper respiratory tract can continue for days to weeks after recovery from the disease .¹ Initial studies, although small, showed that SARS-CoV-2 detected by PCR in respiratory samples beyond day 10 after the onset of symptoms did not grow in cell culture and was probably not transmissible.^2.3 Large population studies conducted by CDC South Korea indicate that the infectious potential of SARS-CoV-2 decreases after the first week after the onset of symptoms, regardless of symptom resolution.⁴

However, some studies have recently challenged this concept. One study showed viable virus by in vitro growth in cell culture in 14% of patients (4 out of 29) with persistent positive SARS-CoV-2 PCR tests from upper respiratory samples obtained after the first week after the initial positive PCR test ; one patient was never hospitalized and one was hospitalized with mild symptoms.⁵ The complete sequencing of the viral genome indicated that these cases represented the same infection, rather than reinfection. Age, immunocompromised status and severe illness have been associated with prolonged SARS-CoV-2 RNA release¹; however, the data are insufficient in relation to the factors associated with the prolonged elimination of viable SARS-CoV-2. A recent study showed that some patients with immunosuppression after cancer treatment can eliminate viable SARS-CoV-2 for at least 2 months.⁶ A study of 129 serious cases of Covid-19 showed that the probability of detecting viable viruses beyond the 15th day after the onset of symptoms was 5% or less.⁷ The CDC currently recommends isolation precautions for 10 days after the onset of symptoms (with fever resolution lasting at least 24 hours without the use of fever-reducing drugs), with a 20-day extension for immunocompromised patients or those with severe illness. The patient described in the clinical vignette had severe infection according to the World Health Organization’s severity scale and the CDC criteria; therefore, continuing isolation for a total of 20 days seems reasonable and in line with current evidence. No study to date has reported the occurrence of person-to-person transmission from the observed late elimination of viable SAR-CoV-2; therefore, it may be reasonable to customize decisions regarding the duration of isolation based on individual circumstances. In the current case, a family member is a kidney transplant recipient, a condition in which Covid-19 infection is associated with high morbidity and mortality, which further justifies a 20-day isolation period.

Repeating the SARS-CoV-2 PCR test to determine the duration of isolation should not be recommended for this patient because, as noted, a positive PCR test does not mean that she is infectious and viral tissue culture is not available. to assess the existence of viable viruses in clinical laboratories. Repeating the CRP test can result in unnecessarily prolonged isolation and anxiety for patients and medical staff. Making the public aware of the deficiencies of Covid-19 diagnostic tests and the distinction between viral RNA release and viable virus is essential to ensure that patients and healthcare professionals feel comfortable with our current isolation precautions approach to patients with Covid-19.

This article was published on March 10, 2021, at NEJM.org.

The vignette scenario focuses on the question of how long after the onset of symptoms a patient with Covid-19 can transmit the virus, SARS-CoV-2. Behind this question are additional questions that highlight current test deficiencies. First, is the result of a PCR test with reverse transcriptase a valid substitute for the presence of a transmissible virus? Second, does the in vitro growth of the virus from respiratory samples predict transmission to people?

I will argue that the answer to the first question is “no” and the last “probably”, although we do not know the infective dose for transmission.

Fourteen days after the onset of symptoms, a 24-year-old woman with no underlying coexisting illnesses is under discharge planning. Although she spent several days in the ICU, her course was moderate, not severe: she was persistently afebrile, was never intubated and had only moderate changes on the chest X-ray.

Some reports suggest that patients with Covid-19 who are older, male or obese, who are immunosuppressed or who have severe illness have longer-than-average periods of virus spread. This patient has none of the above characteristics and would not be expected to have a prolonged viral spread.

In a retrospective cross-sectional study of 90 patients with confirmed Covid-19 (severity not described), the researchers placed respiratory samples in African green monkey (Vero) cell lines. In vitro infectivity was observed in 29%, and the odds ratio for viral growth decreased by 37% for each additional day after the onset of symptoms. No growth was detected in the samples collected more than 8 days after the onset of symptoms.⁸

A detailed virological analysis of nine cases of mild Covid-19 in young and middle-aged professionals showed no isolation of the virus in serial samples of blood, urine or faeces. Viral growth was found in oropharyngeal or nasopharyngeal smears in all patients from the 1st to the 5th day after the onset of symptoms. Although viral RNA was detected in 40% of patients after day 5, and even been detected up to 28 days, viral growth was not detected after day 8.^two

Cheng and colleagues prospectively enrolled 100 patients with confirmed Covid-19 and 2761 contacts. The attack rate for 1,818 contacts who were exposed within 5 days after the onset of symptoms in the primary group of patients was 1% (confidence interval of 95% [CI], 0.6 to 1.6), but the attack rate among 852 contacts subsequently exposed was 0% (95% CI, 0.0 to 0.4).⁹

A systematic review and meta-analysis of case series, cohort studies and randomized trials of SARS-CoV-2 showed RNA release for 17 days after the onset of symptoms (95% CI, 15.5 to 18.6) in upper respiratory samples among a total of 3,229 participants in 43 studies and for 14.6 days (95% CI, 14.4 to 20.1) in samples of the lower respiratory tract among a total of 260 participants in 7 studies. Although RNA can be detected up to 83 days and 59 days in upper and lower respiratory samples, respectively, no study has detected live viruses beyond day 9 of the disease.¹

In February 2021, the CDC, citing its own unpublished data and data from other sources, stated that in patients with mild or moderate Covid-19, the virus competent for replication was not recovered after 10 days after the onset of symptoms. Even in severe illnesses (the vast majority of patients admitted to the ICU had been intubated), the probability of isolating the virus after 15 days was 5%.¹⁰

In summary, a 24-year-old woman with moderate Covid-19 infection and no marker for prolonged viral spread has positive RNA detection, but probably has no competent virus for replication. She is unlikely to transmit SARS-CoV-2 to an immunosuppressed family member at home.

This article was published on March 10, 2021, at NEJM.org.