key: cord-0056393-0kwm48m7 authors: Yamada, Eijiro; Ishida, Emi; Nakajima, Yasuyo; Horiguchi, Kazuhiko; Matsumoto, Shunichi; Okada, Shuichi; Kamitani, Wataru; Yamada, Masanobu title: The long-quarantined case of COVID-19 with prolonged viral shedding and intermittent fever for more than 70 days date: 2021-02-09 journal: nan DOI: 10.2217/fvl-2020-0423 sha: 5ef575fe7873ff1a80276e4598bed01db4cde7e2 doc_id: 56393 cord_uid: 0kwm48m7 A 79-year old Japanese woman was diagnosed with coronavirus disease (COVID-19), caused by SARS coronavirus 2 (SARS-CoV-2), based on a positive reverse transcription-PCR (RT-PCR) test result. Chest computed tomography revealed mild interstitial pneumonia. She had intermittent persistent inflammatory reactions with fever. Laboratory findings and RT-PCR test results showed SARS-CoV-2 positivity for more than 70 days. To the best of our knowledge, this relatively mild case has the longest duration of viral shedding recorded, as confirmed by RT-PCR analysis. This case demonstrates that the viral shedding in COVID-19 can be prolonged, even in mild disease, and highlights the difficulties in distinguishing viral shedding from SARS-CoV-2 infectivity. oxygenation capacity was well maintained on room air. While a chest radiograph revealed a few inflammatory changes, computed tomography showed mild interstitial pneumonia ( Figure 1 ). Her clinical course is shown in (Figures 2 & 3) . On diagnosis, she was administered favipiravir, which is used for the treatment of COVID-19 in Japan. However, we were forced to discontinue the administration of all oral drugs, including favipiravir, due to dysphagia on day 10. Although, her fever and laboratory results improved after treatment with favipiravir, she aspirated several times and had intermittent fever, indicating possible aspiration pneumonia. Therefore, she underwent fasting management and was administered peripheral parenteral nutrition. After favipiravir treatment, RT-PCR tests were occasionally conducted to examine for viral shedding, but it showed positive results for more than 60 days after diagnosis. In Japan, the guidelines for the discharge of symptomatic patients with COVID-19 have been frequently revised according to WHO standards [6] . The guidelines allowed the discharge of patients 10 days after symptom onset and 72 h after symptoms resolution. Since she had intermittent fever, she could not be discharged until two RT-PCR tests using nasal swab samples confirmed the absence of viral shedding. Finally, RT-PCR performed 73 days after her first positive test revealed negative results. Prolonged SARS-CoV-2 RNA shedding is not a rare phenomenon. The longest duration of viral shedding reported for mild cases without invasive mechanical ventilation is 60 days from the first positive RT-PCR result [4] . Additionally, we found another case report that described more than 70 days of viral shedding from symptoms onset, but more than 60 days after obtaining positive PCR results [7] . Here, we have reported a case of confirmed persistent viral shedding of SARS-CoV-2 based on RT-PCR testing for more than 70 days, which, to the best of our knowledge, is the longest duration reported to date for mild cases. The following factors are associated with prolonged viral shedding in patients with COVID-19: male sex; delayed hospital admission after illness onset and; invasive mechanical ventilation [8] . Surprisingly, none of these factors were applicable in our case, which pertained to a woman who was admitted on the day of fever onset and did not require invasive mechanical ventilation. Moreover, while prolonged viral shedding has been observed in severe cases, our case was a mild case with only a high fever and no respiratory symptoms, despite abnormal laboratory and chest computed tomography findings [8] . Additionally, despite being frail, she had no complications such as respiratory diseases or diabetes mellitus, which are now considered risk factors for severe COVID-19 [5, 6] . This indicates that prolonged viral shedding in patients with COVID-19 is unpredictable and may even occur in mild cases. Old age is a significant factor associated with prolonged viral shedding [9] . Although, prolonged viral shedding has been observed in many cases, limited information is available on prolonged viral shedding in immunocompromised patients. It has recently been reported that prolonged viral shedding can be observed after immunosuppressive therapy for cancer [10] . Moreover, it was noted that a diminished CD8 + T-cell response, which is seen in people with frailty [11] , correlates with prolonged viral shedding [12] . Therefore, frailty might explain the prolonged viral shedding in our case. The duration of viral shedding is often considered to determine the appropriate period of isolation as it could be a marker of infectivity [13] . Considering this, the Japanese guidelines previously mandated two negative RT-PCR tests using nasal swabs samples 24 h apart in accordance with the WHO standards. However, a positive RT-PCR result does not necessarily indicate the potential for viral transmission because the amount of SARS-CoV-2 viral RNA detected does not always indicate greater infectivity. Therefore, the conditions for discharge were revised as follows: 10 days after the symptom onset and 72 h after the symptom resolution. Since our patient had frequent aspirations and fever, indicating possible aspiration pneumonia, it was difficult to distinguish pneumonia from COVID-19 and aspiration. Therefore, although the Japanese guidelines for quarantine were revised, two negative RT-PCR test results using nasal swab samples were required to confirm the absence of viral shedding. There is limited understanding of the significance of viral shedding of SARS-CoV-2 with respect to its infectiousness and reactivation. This has resulted in a clinical dilemma. It is crucial to have a clearer understanding of these fundamental concepts considering the multiple waves of COVID-19 worldwide, including in Japan [1] . Detecting seroconversion onset could be a clue to overcoming these problems. Recently, it has been reported that viral shedding of SARS-CoV-2 drops rapidly to undetectable levels on seroconversion and a serum neutralizing antibody titer is independently associated with noninfectious SARS-CoV-2 [14] . Our patient had both increased IgG and IgM levels, indicating seroconversion. Further studies are needed to confirm this hypothesis. On diagnosis, our patient was administered favipiravir, which is regularly used for the treatment of COVID-19 in Japan. However, we were forced to discontinue the medication due to dysphagia on day 10. Favipiravir is a new type of RNA-dependent RNA polymerase inhibitor that has been approved for influenza treatment [15] . Theoretically, it has potential antiviral action against the RNA virus SARS-CoV-2. Although, clinical trials of favipiravir for COVID-19 treatment are ongoing, its efficacy is not yet confirmed. However, some reports have demonstrated its effectiveness, particularly in increasing the cumulative virus elimination rate. However, in our case, no obvious effect on virus elimination was observed; therefore, more studies are needed to understand COVID-19 treatment with favipiravir and other potential drugs. In summary, we have presented a case of persistent viral shedding of SARS-CoV-2 based on RT-PCR testing for more than 70 days. To the best of our knowledge, this is the longest duration of viral shedding reported worldwide thus far. More importantly, our case was a mild case with no complications. The patient was quarantined for more than 70 days since she had fever that could not be distinguished from aspiration pneumonia. It is critical to understand the mechanisms behind persistent viral RNA shedding and the possibility of viral reactivation to help manage COVID-19 effectively. This case demonstrated that the viral shedding in coronavirus disease can be prolonged and that there are difficulties in distinguishing viral shedding from SARS-CoV-2 infectivity. While there is a persistent lack of understanding of the significance of shedding of SARS-CoV-2 with respect to its infectiousness and reactivation, clinical problems will ensue. • Coronavirus disease (COVID-19), caused by SARS-coronavirus-2 (SARS-CoV-2), has become a public health emergency in all countries worldwide, including in Japan. • Viral shedding, which is often considered to determine the period of isolation as it could be a marker of infectivity, is considered to last for an average of 12-20 days; the longest duration of viral shedding for mild cases reported to date is 60 days. Case summary • A 79-year old Japanese woman was diagnosed with COVID-19 using reverse transcription-PCR (RT-PCR) tests. Chest computed tomography revealed mild interstitial pneumonia. She had persistent mild inflammatory reactions with fever, but she did not require invasive mechanical ventilation. Laboratory findings and RT-PCR test results showed SARS-CoV-2 positivity more than 70 days. • To the best of our knowledge, this case reports the longest duration of viral shedding in mild cases. This case demonstrates that viral shedding in COVID-19 can be prolonged, even in mild cases and highlights the difficulties in distinguishing viral shedding from SARS-CoV-2 infectivity. Author contributions E Yamada contributed to the care of the patient, data collection, the literature review and drafting the manuscript; E Ishida contributed to the care the patient, data collection and the literature review; Y Nakajima, K Horiguchi, S Matsumoto contributed to the care of the patient; S Okada, W Kamitani and M Yamada did critical revisions to the manuscript. All authors issued final approval for the version to be submitted. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. The principles outlined in the Declaration of Helsinki were followed, and the subjects provided informed consent prior to relevant data collection and publication. future science group 10.2217/fvl-2020-0423 World Health Organization. WHO coronavirus disease (COVID-19) dashboard Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical characteristics and factors associated with long-term viral excretion in patients with severe acute respiratory syndrome coronavirus 2 infection: a single-center 28-day study Case report: viral shedding for 60 days in a woman with COVID-19 Clinical characteristics of coronavirus disease 2019 in China Clinical management of COVID-19 interim guidance Persistent viral RNA positivity during the recovery period of a patient with SARS-CoV-2 infection Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19) Insight into the reason of prolonged viral RNA shedding in patients with COVID-19 infection • Where old age as a significant factor associates with prolonged viral shedding was mentioned Shedding of viable SARS-CoV-2 after immunosuppressive therapy for cancer • Where prolonged viral shedding seen after immunosuppressive therapy for cancer was mentioned T-cell phenotypes predictive of frailty and mortality in elderly nursing home residents • Where frailty correlating with impaired CD8 + T-cell response was mentioned SARS-CoV-2 Viral RNA shedding for more than 87 days in an individual with an impaired CD8 + T-cell response • Where prolonged viral shedding correlating with impaired CD8 + T-cell response was mentioned • Where the duration of viral shedding is often considered to determine the period of isolation was mentioned Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19) • Where the relationship between seroconversion and infectivity was mentioned Favipiravir (T-705), a novel viral RNA polymerase inhibitor