key: cord-0767262-te419lw0 authors: Mallucci, Giulia; Zito, Antonio; Fabbro, Beatrice Dal; Bergamaschi, Roberto title: Asymptomatic SARS-CoV-2 infection in two patients with multiple sclerosis treated with fingolimod date: 2020-07-19 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2020.102414 sha: 87c3dde1db680ea17d0e38d15203b9a3f04f1b73 doc_id: 767262 cord_uid: te419lw0 nan Fingolimod is a sphingosine 1 phosphate (S1P) receptor modulator, largely used in Multiple Sclerosis (MS) treatment to reduce clinical and radiological disease activity. Fingolimod, binding to S1P receptors on lymphocytes, leads to receptor internalization and sequesters lymphocytes in lymph nodes, preventing them from contributing to the autoimmune reaction. Under fingolimod treatment lymphopenia is typically observed, and there is a small increase in the risk of herpes virus and respiratory tract infections (Arvin et al., 2015) . The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pertains to the large family of Coronaviridae, which includes also MERS-CoV,SARS-CoV, and it causes a respiratory disease called . Generally, COVID-19 is less severe than SARS, in fact, it can be a self-limiting disease in about 80% of patients, whilst serious bilateral interstitial pneumonia and multi organ failure may complicate the remaining 20% (Onder et al., 2020) . The first COVID-19 Italian case was reported in February 2020 in Lombardy (Northern Italy). Thereafter, it spread vastly and broadly across the country. Currently, we do not know whether people with MS carry a different risk of SARS-CoV-2 contagion and developing serious complications when infected, especially if exposed to immunomodulatory therapies. In this paper, we report two cases of MS patients on fingolimod treatment that were infected with SARS-CoV-2 but did not develop any COVID-19 symptom, sign, or complication. Informed consent was obtained from the subjects. In 2005 (at the age of 22) patient 1 reported hypoesthesia in the right side of the body. Thereafter described two other episodes characterized by sensory impairment. In 2006 the patient was diagnosed with MS and started therapy with interferon-beta 1a, which was substituted with natalizumab in 2007 due to another sensory relapse and increased lesion load in brain MRI. In 2010, due to PML risk, patient 1 decided to stop current treatment and switched to fingolimod, initiated in 2011 and continued until today. From then on, patient 1 has been free from relapses and MRI has detected no new inflammatory lesion. In January 2020 Expanded Disability Status Scale (EDSS) was 2.5, total lymphocytes 0.68 10 3 /mul [normal range between 0.8 10 3 /mul and 4.2 10 3 /mul].]. By end of February 2020, a few days after the first case of COVID-19 in Italy, patient 1 was exposed to COVID-19 cases. Accordingly, the patient was submitted to nasopharyngeal swab specimen that was positive for SARS-CoV-2 using quantitative reverse transcriptase-polymerase chain reaction targeting the In mid-March, patient 2 was exposed to COVID-19 cases. Accordingly, the patient underwent potentially exposing them to the risk of infection and severe complications. In addition, the management of disease modifying treatment (DMT) for MS during COVID-19 emergency is conditioned by uncertainties: whether to start, continue, suspend a DMT, and which types of DMT should be preferred. As per today, the course of COVID-19 in MS patients on fingolimod has been described in at least five other cases: two from USA (Bowen et al., 2020) , one from Germany (Foerch et al., 2020) , one from Iran (Barzegar et al., 2020) and one from Italy (Chiarini et al., 2020) . In detail, the two American and the Italian cases were reported with mild COVID-19 and fully recovered; while the German and the Iranian cases were reported with initially severe COVID-19 requiring admission to intensive care unit; although they had negative prognostic features, they promptly recovered. As the aforementioned five cases, also our two cases have been infected by SARS-CoV-2 but, despite the lymphopenia and the ongoing treatment with fingolimod, they did not develop any sign or symptoms for COVID-19. Of note, once disclosed SARS-CoV-2 infection, fingolimod treatment had been interrupted, both in our cases and in the published ones. However, the elimination half-life is 4-9 days and the lymphopenia last up to 1-2 months from drug withdrawal, thus fingolimod action likely persisted during the active phase of SARS-CoV-2 infection. In summary, MS patients on fingolimod treatment who were infected by SARS-CoV-2 had asymptomatic COVID-19, mild COVID-19 or severe COVID-19 but with a surprisingly rapid recovery. This favourable COVID-19 course, might be partially explained by the fact that all affected individuals were relatively young, which is a good prognostic feature (Kronbichler et al., 2020; Oran and Topol, 2020) . Of note recent papers 4 have highlighted that asymptomatic cases are more frequently young and female (Meng et al., 2020; Peckham et al., 2020) . So far, the use of fingolimod does not seem to expose people to a particular risk of unfavourable COVID-19 evolution. Conversely, fingolimod may even have a protective effect against SARS-CoV-2, both enhancing lung endothelial cell integrity and preventing the reactive cytokine storm thanks to the moderate immunosuppression (Ramanathan et al., 2020 ). An exploratory study to evaluate the efficacy of fingolimod for COVID-19 is undergoing (https://clinicaltrials.gov/ct2/show/NCT04280588). In addition, notwithstanding the low circulating lymphocytes, in fingolimod immunosuppressed patients, T and B cells in the lymphonode may rapidly expand and mount an effective immune response that favours COVID-19 recovery after drug discontinuation (Chiarini et al., 2020) . Note that, after discontinuation of fingolimod, there is a risk of MS relapse due to a 'rebound' effect (Barry et al., 2019) , thus longer fingolimod treatment suspension should be avoided. Based on the above reported experiences, fingolimod therapy is likely safe therapy during COVID-19 outbreak. Although we could argue that continuing fingolimod during in all COVID-19 cases would reasonable, a very recent paper has reported that the onset of COVID-19 symptoms could be delay up to 4 days (range 3-5) in swab SARS-CoV2 positive asymptomatic individuals (Arons et al., 2020) . Thus, in accordance to the international consensus statement (Amor et al., 2020; Giovannoni et al., 2020) , fingolimod should be continued in MS patients but might be stopped in SARS-CoV-2 confirmed cases. 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SSRN Electron Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases