key: cord-0868506-6pz1zwms authors: Meca-Lallana, Virginia; Aguirre, Clara; Cardeñoso, Laura; Alarcon, Teresa; Figuerola-Tejerina, Angels; del Río, Beatriz; Álvarez, Miguel Ruiz; Vivancos, José title: ESTABLISHMENT OF A SAFETY PROTOCOL FOR THE ADMINISTRATION OF TREATMENTS IN MULTIPLE SCLEROSIS DURING THE SARS-CoV-2 PANDEMIC date: 2020-06-02 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2020.102244 sha: 8092e3b9022d2ac3c0da17cd01403ee3054cc9ba doc_id: 868506 cord_uid: 6pz1zwms nan changing reality, forcing us to make decisions quickly with a lack of available evidence. It is currently unclear whether MS patients are exposed to a greater risk of severity upon SARS-CoV-2 infection 2, 3 , although the use of some disease-modifying drugs may entail an additional infection risk for these patients 4 and many of these drugs are also contraindicated in cases of active infection. In order to minimize the risk associated with administering immunosuppressive treatments, it has been proposed to postpone as long as possible the use of those with a higher risk of inducing lymphopenia in the short to medium term and to use extended administration for other drugs 2, 5 . In patients treated with these drugs or patients with a possible MS relapse, SARS Cov2 infection should also be carefully ruled out as a cause of clinical deterioration and the use of steroids should be considered only in those patients with relapses leading to increased disability 2, 5 There are a number of reasons why protocols are needed for safe administration of MS treatments: -The COVID-19 incubation period is variable, ranging from 0 to 24 days 6 -Asymptomatic carriers can spread the virus. Immunosuppressive treatments, by modifying the immune response, could activate asymptomatic infections or those in the incubation period. Although such cases are yet to be described, we must take this theoretical concept into account 7, 8 -Clinical reactivation of infection, i.e. the reappearance of a new infectious case, has been described 8 . These patients presented negative PCR following the first clinical picture, with a reactivation window period from negative to positive SARS-CoV-2 and a new clinical picture within 4 to17 days. Corticosteroids were used in most of this reactivated patients. This suggests that recovered patients may still carry the virus, which could be reactivated by certain conditions, such as immunosuppression 8 . The existence of false negatives could lead to these presumed 'reactivations' being interpreted erroneously. Perhaps these patients are still convalescing from their first clinical symptoms 9 . In any case, the detection of such cases is important. We have had a similar experience with clinical reactivation of a patient after taking a dose of immunosuppressant. This is one of the things that led us to conduct the current work. Despite all this, we must bear in mind that it is unproven 3 whether patients receiving immunosuppression are at greater risk in this pandemic because of the differential characteristics of COVID-19. It is thought that this disease develops in different phases, with the most severe caused by cytokine release syndrome and hyper-inflammatory state, as well as changes resulting from vascular pathology and thrombosis 10 . In reference to hyper-inflammation, it has been postulated that the previous use of selective immunosuppressive drugs could even offer a protective mechanism 5, 6, 11 . Until the evidence increases, however, and in our experience of patient management, our action protocol must focus on safety. The most commonly used technique for diagnosing SARS-CoV-2 infection is to detect viral RNA using RT-PCR in nasopharyngeal swabs 7 . The positive results of this technique depend on the presence of sufficient quantity of viral genome at the sample extraction site, as well as on the sample collection technique, which can lead to false negatives 12 . Negative results may also be obtained when the virus cannot be detected in the exudate because the patient is at an early stage of the disease (window period), the host's immunity has suppressed it, or if samples are obtained late in the course of infection 13 . Blood testing for IgM against the virus, a marker of acute infection, can increase diagnostic sensitivity from 51.9% to 98.6%. It also seems that IgM can remain detectable for longer than viral RNA 12 . IgM testing may, however, give false negatives if the samples are taken at the beginning of infection, since IgM has been observed from the fifth day of infection 12 . IgG, on the other hand, a marker of late immunity, appears around day 14 12, 13 , with levels increasing until around day 21, when a sustained 'plateau' can be reached 12 . ELISA IgM and IgG testing has greater than 95% specificity and the use of this technique together with PCR at the onset and in the following two weeks can further increase diagnostic accuracy 14 . This increased diagnostic sensitivity using both PCR and serology has been confirmed in various recent works 15 , reaching sensitivity and specificity levels of up to 100% 16 . In general, most antibodies are produced to combat the most abundant viral protein, NC, and these tests are therefore the most sensitive 14. There are several rapid tests of varying quality available on the market that do not in some cases detect precisely the antigens used 14 . We present the safety protocol for treating MS patients established in our MS Unit and its development over the pandemic period. Our aim is not to establish the sensitivity and specificity of the tests used; these findings could be presented in a subsequent broader. Our aim, instead, is to present the safety protocol used in MS patients. We have used a dynamic protocol adapted to the development of the pandemic. During the early days of the pandemic, the first measure was to postpone doses of certain immunosuppressive treatments due to rapid spread of the virus and saturation of emergency services. The need to avoid MS reactivation in our patients, however, led us to implement several protocols for administering treatments as safely as possible. The protocol applies to administering initial doses and all re-doses of natalizumab, ocrelizumab, rituximab, cladribine and alemtuzumab, as well as initial doses of teriflunomide, dimethyl fumarate, fingolimod, and methyl prednisolone in relapses. Injectables are excluded because of their reduced impact on the immune system 15 . We stop the protocol in patients where recovery from COVID-19 has been demonstrated. Finally, it is crucial to individualize treatment in each patient. Treatment decisions (maintaining, suspending or delaying treatment) must be individualized and take into account associated risk factors (age, comorbidities, etc.) 2,5 . We consider that the ideal scenario would be to perform PCR together with IgG and IgM serology testing in all patients scheduled to receive immunosuppressive treatment. We do not currently have a way of interpreting serology tests with absolute certainty. Nevertheless, in addition to increasing diagnostic sensitivity in negative cases 12, 16, 17 , this could increase the safety with which treatments are initiated by reducing the possibility of reactivating the virus after treatment. Our protocol offers safety to our MS patients. The simplicity and versatility of our protocol allows it to be applied in different regions with differing pandemic statuses. 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