key: cord-1001030-42t0zriz authors: Batisse, Dominique; Benech, Nicolas; Botelho-Nevers, Elisabeth; Bouiller, Kevin; Collarino, Rocco; Conrad, Anne; Gallay, Laure; Goehringer, Francois; Gousseff, Marie; Joseph, Dr Cédric; Lemaignen, Adrien; Lescure, François-Xavier; Levy, Bruno; Mahevas, Matthieu; Penot, Pauline; Pozzetto, Bruno; Salmon, Dominique; SLAMA, Dorsaf; Vignier, Nicolas; Wyplosz, Benjamin title: Clinical recurrences of COVID-19 symptoms after recovery: viral relapse, reinfection or inflammatory rebound? date: 2020-06-30 journal: J Infect DOI: 10.1016/j.jinf.2020.06.073 sha: 602f7c6ccf4eebb9086038d1874f82ee91e739a1 doc_id: 1001030 cord_uid: 42t0zriz For the first 3 months of COVID-19 pandemic, COVID-19 was expected to be an immunizing non-relapsing disease. We report a national case series of 11 virologically-confirmed COVID-19 patients having experienced a second clinically- and virologically-confirmed acute COVID-19 episode. According to the clinical history, we discuss either re-infection or reactivation hypothesis. Larger studies including further virological, immunological and epidemiologic data are needed to understand the mechanisms of these recurrences. Abstract: For the first 3 months of COVID-19 pandemic, COVID-19 was expected to be an immunizing non-relapsing disease. We report a national case series of 11 virologically-confirmed COVID-19 patients having experienced a second clinically-and virologically-confirmed acute COVID-19 episode. According to the clinical history, we discuss either re-infection or reactivation hypothesis. Larger studies including further virological, immunological and epidemiologic data are needed to understand the mechanisms of these recurrences. The rapidly spreading COVID-19 pandemic resulted with more than 8.5 million cases diagnosed and 450,000 deaths on June 20 th , 2020. As described with other coronaviruses, SARS-CoV-2 was first expected to induce a monophasic disease with at least transient immunity (1,2). Nevertheless, rare cases of suspected COVID-19 "recurrence" or "reactivation" have been reported, including the description by Ye & Colleagues in this journal of 5 patients with suspected SARS COV 2 reactivation after home discharge (3) (4) (5) (6) . Similarly, the COCOREC (Collaborative study COvid RECurrences) study aimed at summarizing clinical and virological data of patients presenting a second confirmed COVID-19 episode, at least 21 days after the first onset, and after a symptom-free interval [oxygen-free and discharge from acute-care unit (ACU), or return to usual clinical state]. Cases were collected retrospectively at a multicenter observational level through the COCLICO (COllaborative CLInician COVID-19) French study group meeting. A COVID-19 episode was defined by (i) at least one recent major clinical sign of COVID-19 including fever or chills, febrile flu-like-syndrome, dyspnea, anosmia, or dysgeusia; and (ii) a positive SARS-CoV-2 RT-PCR test. Patients were not included if a differential diagnosis (amongst which bacterial, fungal or other viral superinfection, thrombo-embolic complication, secondary organizing pneumonia or interstitial lung disease) could explain the symptom recurrence. After information, all patients agreed with the use of their anonymous medical data. Between April 6 th and May 14 th , 2020, 11 patients were identified (sex ratio M/F 1. 2 comorbidity had a first mild COVID-19 episode with a complete recovery: three returned to work in COVID units, one had possible COVID re-exposure at home (patient 2). All of them experienced a clinical relapse requiring sick-leave but no hospitalization after a median symptom-free interval of 9 [7] [8] [9] [10] [11] [12] [13] [14] days. In contrast, 7 older comorbid patients (patients 5-11, median age 73 [54-91] years) required ACU hospitalization for both episodes, with a clinical recovery of 11 days in the interval. During the first episode, one patient received lopinavir, and three corticosteroids. Six of them required oxygen therapy again during the second episode. Two patients died of ARDS recurrence and another of chronic right heart failure worsening. All patients had a positive SARS-CoV-2 RT-PCR test in respiratory samples for both episodes (Table 2) . They all showed CT scan signs of acute COVID-19 during the second episode, worsening for 4 in 7 when comparison available, including a case of pulmonary embolism without sign of superinfection and no differential diagnosis (supplementary Table) . A SARS-CoV-2 serology was available after D21 for nine patients: five were positive, one slightly positive and three negative. A viral culture was performed on Vero E6 cells from naso-pharyngeal swabs of two patients during the second episode; Immunity to SARS-CoV-2 involves both cell-mediated and humoral responses, but its protective role from re-infection along with definitive viral clearance is uncertain (7) . Our case series of 11 patients having experienced two separate symptomatic COVID-19 episodes, associated with viral detection and no evidence for a differential diagnosis, raises two pathophysiological hypotheses underlying these recurrences: viral reinfection or viral reactivation from sanctuaries. In the case of healthy healthcare workers with mild symptoms at both episodes, a re-infection due to the prolonged exposition can be supposed, given the fact that the immune response may faint in this young population with no invasive infection (8) . The second group included vulnerable persons less likely to have met the virus again and having presented two repeated episodes of hypoxemic pneumonia, fatal in three cases. Recurrence might have occurred due to a suboptimal control of the SARS-CoV-2 infection, allowing a second episode of viral replication. COVID-19 recurrences should be differentiated from secondary complications such as pulmonary embolism or super infection (5) or persistence of traces of viral RNA that can be detected in respiratory samples up to 6 weeks after onset of symptoms in clinically-cured patients (9) . Immunosuppressive factors such as drugs or pathological conditions could contribute to impair viral clearance and favor SARS-CoV-2 reactivation (10). Three of the 7 severe patients of our series, and 3 of 4 patients reported by Ye (3) received corticosteroids during the first episode. Furthermore, from our 3 patients who developed no SARS-CoV-2 antibodies more than 21 days after severe symptoms, two received recent chemotherapy and/or rituximab.. This work has some limitations. In addition to the limited number of observations, the cure between episodes was only clinically-defined (except for patient 6) because iterative RT-PCR controls were not recommended by French guidelines. Finally, viral culture could be performed only for two patients, with no phylogenic sequence comparison at this time. In conclusion, the fact that patients could experience re-activation of a long-lasting virus carriage or might be re-infected, as well as potential long-term effects of drugs or diseases that hamper the immune response, constitutes a substantial point of vigilance for the management of the pandemic at the individual and collective levels. Studies including genomic comparisons of viral strains involved in both episodes, determination of RNA infectivity by viral culture, as well as assessment of innate and adaptive immunity and monitoring inflammatory targets, would be of great value for further understanding the underlying pathophysiology of these COVID-19 recurrences. Human Coronavirus NL63 Molecular Epidemiology and Evolutionary Patterns in Rural Coastal Kenya Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation Reactivation of COVID-19 pneumonia: A report of two cases Recurrence of COVID-19 after recovery: a case report from Italy. Infection Cause analysis and treatment strategies of "recurrence" with novel coronavirus pneumonia (COVID-19) patients after discharge from hospital Zhonghua Jie He He Hu Xi Za Zhi Zhonghua Jiehe He Huxi Zazhi Chin J Tuberc Respir Dis Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019 Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19 patients Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients This work had no financial support. None of the authors has any conflict of interest to declare regarding this subject.