Can I see your #MSCOVID19 paper?


I few days ago I mentioned not wanting to review someones COVID-19 and MS review, because it was missing published information and so I did not want to write their review. I submitted my constructive review of the paper for the authors benefit and then bowed out of the referering process.

You said that I should put my review online. However, that review was a critique of their paper, not a review of the literature. However, you spurred me into action.

You asked for it and now you’ve got it. We have written a review. Make a big mug of tea, sit back and have a read.

It is meant to be scientific and it is not a sound bite.

It may not be completely correct and will be revised as you spot any howlers or as new information arises. There are currently 200-500 papers a day to scan on COVID-19, in addition to the MS stuff. So forgive me if I missed some. Again the confusion lies in the pathology. I expected the lungs to full of CD8 cells , but of the pathology studies surfacing this does not appear to be the case. I think it also needs a couple of sentences on the thrombi (clots) and haemorrages, which if they are the major issue may not have much to do with most MS treatments. This version has now been submitted to a Journal, as not everyone reads the blog and it is aimed to be scientific. Whilst BioRXiv and MedRXiv is a place were preprints can be put before publication they don’t do reviews. However, it will never see the light of day as it is today , because it is already out of date and will need to be revised. The reviewers may have different opinions that need to be incorporated. Within a Week there will be 1,000-2,000 more papers to accomodate and within a month perhaps 5,000 papers to accomodate, so I hope the reviewers are quick. Maybe they will think it is too boring to publish.

Not all the source information has been peer-reviewed, but as we know that process is not infallible. However most statements are supported by more than one published paper

You can be the reviewers. This has not been peer-reviewed

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.

David Baker1, Sandra Amor1,2, Angray S. Kang1,3, Klaus Schmierer1,4, Gavin Giovannoni1,4

1Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom,

2Pathology Department, VUmc, Amsterdam UMC, Amsterdam, The Netherlands

3Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.

4Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.

ABBREVIATIONS: ACE2 angiotensin converting enzyme two, ARDS acute respiratory distress syndrome, ASC antibody secreting cells, CNS central nervous system, DMT, disease modifying therapies, haematopoietic stem cell therapy (HSCT), IRT immune reconstitution therapies, MS multiple sclerosis, RBD receptor binding domain, RNA ribonucleic acid, SARS Severe acute respiratory syndrome,


Background: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS.

Objective: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis.

Observations:  Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia coupled with apparent CD8 T cell exhaustion coupled with a cytokine storm appears to contribute to the damage in ARDS.

Implications: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic.

SARS-Cov-2 and COVID-19 a new pandemic. COVID-19 is the disease caused by infection with the severe acute respiratory syndrome (SARS) coronavirus two (SARS-CoV-2) that is causing a pandemic resulting in the death of thousands of humans (Zhu et al. 2020a; Zhou et al. 2020; Gabutti et al. 2020). It seems that a majority, perhaps up to 80% of people (Day. 2020) infected with SARS-CoV-2 results in a mild a self-limiting illness. However, about 20% of individuals required hospitalisation due to cardiovascular issues and respiratory tract distress (Kimball et al. 2020; Day. 2020), and about a quarter of these hospitalised patients require critical care and potential ventilatory support. The mortality in those who require ventilatory support is about 40-50% (Weiss & Murdoch 2020; Zhu et al. 2020b). Death from COVID-19 is associated with older age and the presence of comorbidities such as cardiovascular disease, smoking, lung disease, obesity and diabetes (Zhu et al. 2020a; Li et al. 2020, Lippi et al. 2020; Gabutti et al. 2020). Mortality in young people and those without comorbidities may well be related to excessive viral load (Lui et al 2020a; Chen et al. 2020a; To et al. 2020), possibility explaining the deaths in the critical care medical personnel. Whilst the typical clinical features requiring self-isolation, and potentially hospitalization, are fever, dry cough and shortness of breath related to upper and lower respiratory tract infection (Zhu et al. 2020a; Zhu et al. 2020b), many other symptoms such as headache and gastrointestinal symptoms may go unnoticed or under-appreciated leading to spreading of the virus (Zhu et al. 2020b; Kimball et al. 2020; Huang et al. 2020). People shed infective virus days before symptoms occur and continue to shed virus via the lungs and faeces whilst symptoms develop and resolve, often for more than 7 days (Pung et al. 2020, Lauer et al. 2020; Xu et al. 2020a; He et al.2020a), indicating the need to self-isolate for more than 7 days after symptom onset to avoid infecting others.

The SARS-CoV-2 is a betacoronavirus (lineage B) that originated in wild animals prior to transmission to humans, in which the viral ribonucleic acid (RNA) is bound by the nucleocapsid protein and encapsulated in a lipid envelope formed by the host cell membrane that contains the viral structural spike, envelope and membrane proteins (Chen et al. 2020b, Lu et al. 2020). The spike protein contains the receptor binding domain (RBD) that is important for binding to the angiotensin converting enzyme two (ACE2) cell receptor and thus key to the cellular target, host range and viral infection (Zhou et al. 2020; Shi et al. 2020. Figure 1). The nucleocapsid protein is highly immunogenic, as is the spike protein that can be neutralised by antibodies, that are distinct from SARS-CoV neutralisation, the closely related virus that caused the SARS outbreak in 2002-2004 (Haveri et al. 2020; Ou et al. 2020; Okba et al. 2020; de Assis et al. 2020). The cell entry of SARS-Cov2 depends on binding of the viral spike proteins to the ACE2 receptor as well as host cell serine proteases such as TMPRSS2 necessary to prime the spike protein (Zhou et al. 2020; Hoffman et al. 2020; Tai et al. 2020; Gabutti et al. 2020). The ACE2 receptor is expressed on the vasculature and is present in many tissues, such as the kidney, gut, renal tubules, seminal vesicles, cardiomyocytes as well as lung epithelia (Hamming et al. 2004; Lukassen et al. 2020). There is very low expression of ACE2 on immune cells, but other receptors may be important in SARS-Cov-2 uptake and appears to involve other co-receptors and proteases (Letko et al 2020) and include CD147 on monocytes/macrophages and T cells (Chen et al 2005, Wang et al 2020a) as well as lectins as evidenced by similarities with the SARS-CoV virus (Yang et al. 2004; Marzi et al. 2004; Granberg et al. 2005).

Immune response against SARS-CoV-2 virus. As the immune system is vital defence against viral infection, it has led to concern for people taking immunosuppressive agents or treatments such as haematopoietic stem cell therapy (HSCT), as immune compromised people are particularly vulnerable to infection (Coles et al. 2020; Willis & Robertson 2020). Such vulnerable people have been advised to self-shield and socially distance themselves to avoid infection until herd immunity, anti-viral agents or effective vaccines have been developed (Kwok et al. 2020; Stein 2020). Multiple sclerosis (MS) is a major neurological disease that causes disability and can require hospitalisation for uncontrolled disease activity (Compston & Coles 2008). MS is currently managed with a variety of different immunomodulatory drugs (Pardo & Jone 2017). This has led neurologists to recommend maintaining the status quo or curtailing the use of certain disease modifying treatments (DMT) in a pragmatic or in a non-pragmatic way (Coles et al 2020, Giovannoni et al. 2020; Brownlee et al. 2020. Table 1). It is therefore important that such recommendations are made on a rational basis using knowledge on the mode of actions of the various agents and their ability to impact on the functioning of the various components of the immune system.  This is important as there is no evidence that immunosuppressed people are at increased risk to other coronavirus infections (D’Antiga 2020). To understand the risks posed to people with MS using DMT, it is important to understand the mechanisms of action and the impact of the treatments on the risk of infections, vaccination responses to fight infections and the mechanisms of pathology and immunity to SARS-CoV-2. Although there are many gaps in our knowledge of the pathogenesis of COVID-19, understanding can be gained from the study of SARS-CoV infection that was epidemic in 2002/2003 as well as other coronaviruses and lower respiratory tract infections (Channappanavar et al. 2014; Prompetchara et al. 2020; Rokni et al. 2020, Sarzi-Puttini et al. 2020). 

Protective immunity against coronaviruses involves both the innate and the adaptive immune response as is typical for most viral infections (Yen et al. 2006; Prompetchara et al. 2020). However, consistent with SARS, some influenza infections and COVID-19, it appears to be the immune response and destruction of virally-infected cells and lung epithelial tissue that cause the acute respiratory distress syndromes (ARDS) and the resultant pneumonia that leads to fluid accumulation in the lungs and respiratory failure, which lead to death in a significant number of people (Chen et al. 2020b; Zhang et al. 2020a; Li et al. 2020). It appears that the immune response to SARS-CoV-2 occurs in two phases involving an immune and a lung tissue damaging phase. 

Figure 1. The protective and destructive immune response against the SARS-CoV-2 virus

Immune cells target the SARS-CoV-2 virus that initially involves the innate immune response, which is then supplemented with anti-viral cytotoxic T cell responses and neutralizing and binding antibodies. 

Immune Phase. Following infection there is an asymptomatic period reported to be a median of 4-5 days, although some reports indicate this can be up to 3 weeks (Pung et al. 2020, Lauer et al. 2020; Lai et al. 2020), during which time the virus attempts to escape immune surveillance through the inhibition of interferon production and blockade of interferon receptor signalling activity, similar to SARS-CoV (Prompetchara et al. 2020; Chu et al. 2020; O’Brien et al. 2020). There is an early phase of the immune response where the innate and then the adaptive immune response eliminates the virus as seen in non-human primates and by inference in humans (Bao et al. 2020; Thevarajan et al. 2020). Given that the majority of infections appear to be asymptomatic (Kimball et al. 2020; Day 2020) indicates that this is a dominant mechanism in most people with COVID-19. In vitro data suggest that there could be an early innate response, notably from the alveolar macrophages and/or monocytes that may be recruited from the circulation (Yen et al. 2006; Thevarajan et al. 2020). Histological studies of cancerous lungs of people subsequently found to have COVID19, exhibited significant macrophage activity (Cai et al. 2020; Tian et al. 2020a). Macrophages as opposed to neutrophils appear important as an early defence mechanism, which are limited in SARS and COVID-19 lesions (Prompetchara et al. 2020; Tian et al. 2020a; Cai et al. 2020). This is probably followed by a CD8 cytotoxic T cell response that is generated within days of infection (Channappanavar et al. 2014; Prompetchara et al. 2020; Thevarajan et al. 2020).

The SARS-CoV-2 may be eliminated before significant peripheral blood antibody titres are generated as seen in non-human primate infections and case reports (Figure 2. Thevarajan et al. 2020, Bao et al. 2020). These antibody responses are generated by about 12 days (IgM) and 14 days (IgG), although this is earlier in some individuals (Zhoa et al. 2020, Guo et al. 2020; Okba et al. 2020; Xiang et al. 2020). Antibodies are predominantly generated against the nucleocapsid and spike proteins (Leung et al. 2020; Okba et al. 2020, de Assis et al. 2020). Antibodies against the RBD of the spike protein are clearly neutralizing, are able to prevent infection (Okba et al. 2020, Tai et al. 2020; Tian et al. 2020b) and appear to be protective, as evidenced by the use of convalescent sera to protect against severe COVID-19 (Duan et al. 2020; Pei et al. 2020; Shen et al. 2020; Bloch et al. 2020). Although CD8 T cells are important in viral immunity, antibodies will be an essential part of the vaccination response to prevent primary infection and reinfection as most infected subjects will develop an immunoglobulin anti-viral response within 1 month (Zhoa et al. 2020, Okba et al. 2020; de Assis et al. 2020). This appears to prevent re-infection as shown in non-human primates (Bao et al. 2020. Figure 2). However, immunity may not be completely protective since people with COVID-19 can rarely present with SARS-CoV-2 re-activation (Ye et al. 2020a; Chen et al. 2020c). However, as the virus may persist in many sites and may not be eliminated at the same rates can explain why viral RNA can be detected in faeces when nasopharyngeal swabs become negative (Chen et al. 2020d). There are clearly viral variants (Foster et al. 2020; Yao et al. 2020) and may be important as vaccines will need to target disease-causing pathogenic variants. This data suggests that immunosuppression of macrophage function and probably CD8 activity may limit anti-viral protection while blunting or inhibition of antibody formation may limit immunity to reinfection.

Figure 2. Removal of the SARS-CoV-2 virus occurs before a significant anti-viral antibody response is generated.

Rhesus macaques were infected with coronavirus and the viral titre was assessed using nasal swabs. Animals were re-infected one month later. The results show the responses of two individual monkeys relating to viral titre and anti-viral antibody response. Adapted from Bao et al. 2020.

Destructive Phase. Although most people appear to tolerate COVID-19 a significant number of people experience respiratory distress (Chen et al. 2020e; Zhu et al. 2020b). Severe disease is associated with peripheral blood neutrophilia and notably lymphopenia (Chen et al. 2020e, Lui et al. 2020b, Wang et al. 2020b), where it seems that viral load relates to the severity of lymphopenia (Lui et al. 2020c). The lymphopenia could relate to extravasation or sequestration of cells into the infected tissues as part of the anti-viral response. Post-mortem histology demonstrates significant mononuclear infiltration into the lung and often, but not always, a paucity of natural killer cells and neutrophils, unless associated with secondary infection (Xu et al. 2020b; Fox et al. 2020; Yoa et al.2020; Magro et al. 2020). There is a paucity of B cells and perhaps of relevance is that the lymphocytes are predominantly CD4 T cells (Xu et al. 2020b; Yoa et al. 2020b). Low peripheral blood CD8 T cell numbers are a poor prognostic feature (Du et al. 2020) and this is consistent with a common feature of the COVID-19 lung pathology, where there is a paucity of CD8 T cells (Xu et al. 2020; Yoa et al. 2020; Zhang et al. 2020b). This may reflect senescence and exhaustion of the anti-viral CD8 response contributing to pathology (Zheng et al. 2020; Cossarizza et al. 2020). Whether this contributes to severe disease and fatality remains to be established. However, this would be consistent with age being a major poor prognostic feature (Huang et al. 2020). It appears that T cells can be infected via CD147 (Wang et al. 2020c). In addition, infection and expression of envelope protein and Open Reading Frame protein sequestration that has been shown to have an apoptotic effect at least after SARS-CoV infection (Yang et al. 2005). This may play a role in the lymphopenia and immune suppression of the anti-viral response. There is marked atrophy of lymphoid tissues that may contribute to the lymphopenic state (Zhang et al. 2020b, Yoa et al.2020, Chen et al. 2020f). Macrophages may also become infected and can take-up the virus due to expression of CD147 (Wang et al 2020a), lectins (Yang et al 2004; Marzi et al 2004; Granberg et al 2005) as well as expression of Toll-like receptors known to recognize SARS-CoV pathogen associated molecular pattern recognition elements such as single stranded viral RNA (Li et al 2013). Macrophage derived cytokines are produced, which lead to cytokines storms associated with worse prognosis (Chen et al. 2020c; Ye et al. 2020b; Herold et al. 2020; Wen et al. 2020). Therefore, agents such as interleukin-6 receptor and IL-1 blockers used in rheumatoid arthritis, and the case of IL-6R off-label in neuromyelitis optica, are being used to limit severe COVID-19 (Luo et al. 2020). Plasma cell-supporting cytokines such as TNFSF13 may be associated with recovery (Wen et al. 2020), however, the antibody response may contribute to macrophage hyper-activation. As such, severe disease is associated with the highest titres of antibodies (Liu et al. 2019; Zhoa et al. 2020) and antibody-dependent enhancement of disease may occur (Iwaski & Yang Y 2020). There is complement activation and microthrombi that develop indicative of damage consistent with IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils (Magro et al. 2020; Zhang et al. 2020b). Interestingly it has been shown that spike-specific antibody may promote interleukin-8 and macrophage chemotactic protein one (CCL2) production that skews macrophage accumulation towards a destructive phenotype (Liu et al 2019).  As such in other lower respiratory tract infections antibodies can sometimes have destructive potential (Kim et al. 1969), therefore immunomodulation during periods of lung damage may offer some benefit. 

Multiple sclerosis agents. Shortly after the outbreak of COVID-19 in Europe, where multiple sclerosis (MS) is more prevalent than Far East Asia (Compston & Coles 2008), concern about loss of viral immunity in immunosuppressed people, lead to a number of guidelines recommending limitation of use of DMT in autoimmune central nervous system disease (Coles et al. 2020) (Figure 2). People with MS may have a modest increased risk of infection. This is clearly the case when you examine people taking DMT, notably the more effective DMT (Willis & Robertson 2020). However, it is important to recognize the risks of poorly controlled MS may outweigh the perceived risks from COVID-19 (Giovannoni et al. 2020; Brownlee et al. 2020) and an essential goal of MS care must be to limit exposure to SARS-COV-2 infection. Therefore, care must be to prevent disease activation and limit the need for hospitalization that could potentially increase the risk of exposure to people with COVID-19. This must be balanced by the requirement of hospitalization for infusion treatments and the level of monitoring that each agent requires, that is particularly arduous with alemtuzumab, but minimal with ocrelizumab and glatiramer acetate (Pardo & Jones 2017).

Table 1. Initial recommendations use of MS-related DMT by some European neurological associations 

Composite guidelines generated from recommendations to treat MS from the Society of Italian Neurologists (SIN) and the Association of British Neurologists (Coles et al. 2020).

Mechanisms driving multiple sclerosis may be distinct from COVID-19 protection and pathogenesis. Although it is widely considered that CD4, TH17 T cells are the central mediators of MS (Kunkl et al. 2020), control of MS is highly consistent with observation that therapeutic agents that block memory B cell function with high efficacy are those most effective in MS (Baker et al. 2017a; Baker et al. 2018), possibly secondary to inhibition of T cell function (Sabatino et al. 2019a, 2019b). Although there are many different mechanisms of action ascribed to the different disease modifying treatments used in MS (Pardo & Jones 2017), all active DMT inhibit memory B cell function (Baker et al. 2017a) and notably there is a treatment hierarchy, unrelated to CD4 or CD8 activity, which correlates well with memory B cell inhibition and relapsing disease (Baker et al. 2017a; Baker et al. 2018). Targeting the memory B cell subsets, and possibly CD4, Th17 T cells, is not likely to prevent SARS-Cov-2 elimination by CD8 T cells and the innate immune responses. Targeting memory B cells may only be relevant if treatment is continuous or long lasting such as with CD20-depleting antibody therapies that maintains peripheral B cells in a nadir state (Sabatino et al. 2019a; Baker et al. 2020a) and may prevent the formation of antibody secreting cells (ASC). However, ASC can be generated by germinal centre cells independent of the CD27+, memory B cell pathway (Baker et al. 2018; Hammarlund et al. 2017; Khodadadi et al. 2019). An example of this is observation that 60-85% of people receiving alemtuzumab produce anti-drug antibody responses within the first month of treatment, despite the essential absence of peripheral blood T and B cells (Baker et al. 2017b, Baker et al. 2020b). This would indicate that peripheral B-cell depletion is unlikely to prevent the generation of SARS-CoV-2 anti-viral responses. Novel vaccine responses will be generated from the immature/naïve B cell compartments that regenerate following B cell depleting therapies such as alemtuzumab, ocrelizumab and cladribine (Baker et al. 2017b, Baker et al. 2019, Baker et al. 2020a). Once formed, anti-viral responses will reside within the long-lived plasma cell pool with lymphoid tissue and bone marrow (Khodadadi et al. 2019; Baker et al. 2018). As such, plasma cells are relatively quiescent (Khodadadi et al. 2019) and thus avoid the action of agents that target proliferating cells and express low levels of the targets for current DMT, including CD52, deoxycytidine kinase and CD20 (Baker et al. 2020b; Sabatino et al. 2019a, Baker et al. 2019). Furthermore, they reside predominantly in the bone marrow, a site that may not be effectively targeted by depleting antibodies as cell elimination would require entry of antibodies, complement components and effector accessory cells required for depletion (Baker et al. 2018). Once plasma cells have formed they are not particularly well targeted by any of the current DMT, except HSCT that purges the lymphoid tissues and bone marrow. Therefore, it will be important to consider how best to deliver a SARS-CoV-2 vaccine in the future, once developed and shown to be active (Amanat & Krammer 2020; Chen et al. 2020g). Strategies could be developed for the highly active agents that accommodate the long-depletion of memory B cells and the more rapid population of naïve cells to create a potential for vaccination against SARS-Cov-2 whilst maintaining protection against MS. 

Low efficacy MS immunomodulators are unlikely to limit anti-viral immunity. The components of the immune response that drive autoimmunity and control infections use overlapping cellular mechanisms and therefore removal of significant immune subsets may have the capacity to reduce anti-viral responses, in a manner that reflects their immunosuppressive potential. Low treatment-efficacy agents such as glatiramer acetate, beta interferons and teriflunomide (Table 1) are not associated with significant immunosuppression, notable increased risk of viral infections, nor lack of responsiveness to vaccines (Pardo & Jones 2017; Comi et al. 2019a; Wijnands et al. 2018; Olberg et al. 2018; Hauser et al. 2019). Indeed, interferon beta and teriflunomide may have anti-viral activity that could be beneficial (Hensley et al. 2004; Bilger et al), as such beta interferon has been shown to inhibit SARS-CoV replication and is currently being trialled in COVID-19 (Dahl et al. 2004; Hensley et al. 2004; NCT04350671; NCT04343768). However, these agents have a downside in that they are not that effective in controlling MS disease activity.

Moderate efficacy MS immunomodulators carry higher, but modest infection risks. Dimethyl fumarate is modestly immunosuppressive and targets lymphocytes rather than monocytes (Pardo & Jones 2017; Diebold et al. 2018). Immature/transitional B cells are less affected compared to memory B cell targeting (Mehta et al. 2019). Although plasmablasts and plasma cells can be affected by dimethyl fumarate therapy (Mehta et al. 2019), immunoglobulin levels are not unduly affected (Diebold et al. 2018). Importantly, vaccine responses on dimethyl fumarate were no different to that occurring in people treated with beta interferons (von Hehm et al. 2017). However, in some individuals persistent lymphopenia has been reported (Mehta et al. 2019; Diebold et al. 2018), notably about 20% of people will exhibit CD8 T cell levels below the lower limit of normal (Mehta et al. 2019). Although this is not generally associated with increased infection rates (Boffa et al. 2020), viral infections, including upper respiratory and lung infections occur with the monomethyl fumarate producing compounds (Pardo & Jones 2017; Diebold et al. 2018; Perini et al. 2018; Fernández et al. 2017; Naismith et al. 2019). 

Functional lymphopenia occurs with sphingosine-1-phosphate receptor modulators such as fingolimod (Pardo & Jones 2017; Diebold et al. 2018) and appears to modestly elevate efficacy and infection risks (Pardo & Jones 2017; Kalincik et al. 2019). Agents such as fingolimod and siponimod are reported to sequester lymphocytes within lymphoid tissues and exhibit limited activity on the innate immune response (Kowarik et al. 2012; Pardo & Jones 2017; Thomas et al. 2017; Angerer et al. 2018). This targets CD4 more than CD8 T cells and notably the naïve and central memory T cell subsets to retain them in lymphoid tissues where anti-viral responses would be generated (Kowarik et al. 2012; Angerer et al. 2018; Hjoorth et al. 2020) and exhibits a more modest decrease in effector memory CD4 and CD8 T cells that will enter inflamed tissues (Angerer et al. 2018). Infections rates are modest (Diebold et al. 2018), but some bacterial and viral, infections such as herpes and varicella, are marginally more common after fingolimod treatment (Calibresi et al. 2014; Pardo & Jones 2017; Diebold et al 2019). There may be subtle differences between fingolimod and the other sphingosine-1-phosphate receptor modulators in terms of infections and adverse effects, however it has a relatively long-half-life compared to other agents, which may be relevant if one wants to stop treatment (Subei et al. 2015; Swallow et al. 2020). A small scale trial of fingolimod has been reported for severe COVID-19 (NCT04280588). Sphingosine-1-phosphate is involved with maintaining the germinal centre and B cell niche (Cinamon et al. 2008) and there may be reduced serum immunoglobulin level following fingolimod treatment (Zoehner et al. 2019) as such vaccine responses, whilst present are slightly reduced compared to the interferons (Olberg et al. 2018; Signoriello et al. 2020) as occurs with natalizumab (Olberg et al. 2018).

Natalizumab as the preferred high-efficacy agent. Currently natalizumab is perceived to be the high-efficacy treatment of choice (Coles et al. 2020. Table 1). Natalizumab, unlike depleting highly-active DMT, is potentially more rapidly reversible using plasma exchange and is not likely to inhibit migration of immune cells into lymphoid tissues and prevent novel immune responses, and as such has no or limited influence on vaccine antibody responses (Vågberg et al. 2012; Kaufman et al. 2014; Olber et al. 2018). The value of the use of natalizumab may also be enhanced because it is perceived to simply inhibit T cell migration into the central nervous system (Yednock et al.199; Schwab et al. 2015). However, both B cells and importantly monocytes express alpha 4 integrin (CD49d) and thus the antibody directed to CD49d inhibits monocyte binding to vascular cell adhesion molecule one (VCAM-1) (Yednock et al. 1992; Hyduk et al. 2009). Importantly, although natalizumab is used to block migration into the inflamed central nervous system and gut (Schwab et al. 2015), VCAM-1 is expressed in virally-inflamed lungs (Brodie et al. 1999). Therefore, alpha 4 integrin is likely to be involved in mononuclear cell diapedesis into the inflamed lung during SARS-CoV-2 infection (Brodie et al. 1999; Yen et al. 2006). This potential activity is perhaps consistent with increased lung infections in MS following treatment with natalizumab (Polman et al. 2006). Furthermore, that SARS-CoV-2 is neutrotrophic, (Baig et al. 2020; Moriguchi et al. 2020, Helms et al 2020) suggests that a potential risk of natalizumab treatment is that it blocks viral immunosurveillance of the central nervous system (Hoepner et al. 2014), however this issue is perhaps limited by the extended interval dosing that has been suggested to limit MS activation, reduce the risk of progressive multifocal leukoencephalopathy infection (Ryerson et al. 2019; Clerico et al. 2020). Thus, perhaps whilst natalizumab use could potentially be a risk factor for severe COVID-19, it is likely to limit monocyte and T cell damage to the lung, hopefully allowing recovery by other immune mechanisms and avoiding severe complications.

High-efficacy depleting agents are not the same and have distinct COVID-19 risks. Based on initial suggestions, immune reconstitution therapies (IRT) were not recommended to be started and ongoing treatment, i.e. additional courses, should be delayed (Table 1. Coles et al. 2020). Autologous HSCT is seen as a high risk strategy to initiate during the mass-infection stage of COVID-19 pandemic (Table 1) and will probably remain so until herd immunity (Kwok et al. 2020) develops to protect vulnerable individuals. Myeloablative HSCT removes both the adaptive and notably the innate immune systems and it is already well recognised that loss of the neutrophils, monocytes and other elements of the innate immune system puts people at risk of mortality from infection and until the innate and adaptive immune response reconstitutes people will be at risk for some time (Storek et al. 2008; Ge et al. 2019; Rush et al. 2019). However, once reconstituted the capacity to generate new immune responses occurs as seen following vaccination against childhood infections, to replace the lost immunity due to the HSCT procedure (Brinkmann et al. 2007, Rush et al. 2019). Therefore, there are clear risks from viral infections until the immune system reconstitutes. It is suggested that current licenced IRT, which both deplete T and B cells (Baker et al. 2017b; Baker et al. 2017c) carry similar risk (Coles et al. 2020). However, this does not seem to accommodate the actual biologies and as such, oral cladribine is dissimilar to alemtuzumab, in terms of its risk for SARS-CoV-2 infection and appears more similar to ocrelizumab in its immunodepletion profile (Table 2).

Table 2: High efficacy agents are not the same and oral cladribine is more similar to ocrelizumab than alemtuzumab 

Different characteristics of alemtuzumab, cladribine and ocrelizumab, relevant to efficacy and side-effect potential and their capacity to control MS and exhibit an effective anti-viral immune response. CRS cytokine release syndrome. NK natural killer. 1.Lemtrada® 2019. 2. Thomas et al. 2016, 3. Baker et al. 2017d, 4. Gross et al. 2016, 5. Baker et al. 2017b, 6. Baker et al. 2020b, 7. McCarthy et al. 2013, 8. Mavenclad® 2018, 9. Baker et al. 2017c, 10 Ceroni et al. 2018, 11. Baker et al. 2019, 12. Ocrevus® 2018; 13. Baker et al. 2020a, 14. Fernandez-Verlasco et al. 2019, 15. Stokmaier et al. 2018.

Alemtuzumab. This is a CD52-depleting antibody that induces rapid, long-lasting and 80-90% depletion of CD4, CD8 T cells and memory B cells (Table 2. Baker et al. 2017; Akgün et al. 2020). Alemtuzumab induces long-term disease remission if treated sufficiently early after symptom onset (Cohen et al. 2012. Havrdova et al. 2017, He et al. 2020b). Two short cycles of treatment give long term disease remission. Alemtuzumab treatment cycles are generally given at least 12 months apart, but this interval may be extended, even up to 18 months, which supports the important activity of memory B cells as they, and CD4 T cells, can be depleted for at least this time (Tuohy et al. 2015, Havrdova et al. 2017, Akgün et al. 2020). However, alemtuzumab induces transient monocyte depletion and can induce very long-term CD4 and CD8 T cell depletion (Kousin-Ezewu et al. 2014; Thomas et al. 2016, Baker et al. 2017b; Akgün et al. 2020). This could and does influence response to viral and other infections (Cohen et al. 2012; Wray et al. 2019) and could thus impact on SARS-CoV-2 outcome. Severe lymphopenia increases the risk of infections and pneumonia (Warny et al. 2018). Neutropenia can be marked and significant, but is unusual (Baker et al. 2017d). Infection risk is notable following infusion and then decreases with time as cellular repopulation occurs (Buonomo et al 2018; Wray et al. 2019). Alemtuzumab has a relatively short half-life and is cleared from the circulation within about a month (Li et al. 2018). Therefore, surviving cells can repopulate in response to infection and given the relatively low dose and delivery over a single week, allows cells escaping elimination to recover. Transitional/immature B cells rapidly repopulate in the relative absence of T cell regulation, possibly related to limited purging of the bone marrow, and can generate anti-drug responses within a month of treatment in 60-83% of people (Baker et al. 2017b). Therefore, perhaps it may be possible to generate anti-viral responses. As such childhood vaccine responses persist and novel vaccine responses are not notably inhibited with alemtuzumab within 6 months of treatment (McCarthy et al 2013). Thus with time people with MS are likely to be able to generate a SARS-CoV-2 response and respond to vaccination. Although the treatment protocol means that few infusion visits are required (Cohen et al. 2012; Havrdora et al. 2017), the adverse events, notably the secondary autoimmunities that develop in many people with MS (Tuohy et al. 2015; Havrdora et al. 2017) means that intensive monitoring is required, compared to ocrelizumab that required essentially no inter-infusion monitoring (Pardo & Jones 2017).

Ocrelizumab is a CD20-depleting antibody used to treat relapsing and active primary progressive MS (Hauser et al. 2017; Montalban et al. 2017). This depletes peripheral B cells including memory B cells (Fernandez Velasco et al. 2019). Based on a common mechanism of action (Baker et al. 2017a), there is an unanswered question of whether ocrelizumab will behave like alemtuzumab and cladribine and provide long-term disease inhibition from a short term treatment cycle (Table 2). Even if it does not behave as an IRT, based on memory B cell depletion and slow repopulation characteristics (Palanichamy et al. 2014; Baker et al. 2018), it may provide some comfort to suggest that delays of 6-12 months may be feasible without MS disease activity reoccurring. The latter is based on information from off-label and phase I/II studies with rituximab in MS (Bar-Or et al. 2008; Juto et al. 2020) and phase II extension trial data of ocrelizumab (Kappos et al. 2012; Baker et al. 2020a). As such looking at retreatment to maintain remission based on repopulation of CD27+ memory B cell population, after 3-4 cycles it seems that doses, at least with rituximab, can be extended to less than once a year (Novi et al. 2019; Novi et al. 2020). Given that ocrelizumab exhibits depletion for a longer duration than rituximab suggests similar or better results can be obtained with rituximab (Baker et al. 2020a). Although ocrelizumab can deplete CD8 T cells, this is only a relatively mild steady state depletion of only 6-8% depletion of CD8 cells and 1-2% of CD4 T cells and has a minor impact on monocytes (Gingele et al. 2018; Baker et al. 2020a). Although infections are generally mild following ocrelizumab treatment (Hauser et al. 2017), some viral infections do occur and can be serious and very rarely life threatening (Hauser et al. 2017; Nicolni et al. 2019). Importantly, this may become a problem with persistent B cell depletion as that which occurs with ocrelizumab (Hauser et al. 2017). In time this can lead to IgM, IgA and IgG hypogammaglobulinemia that will increase infection risk (Tallantrye et al. 2018; Vollmer et al. 2020). However, a delay in repeated cycles may allow immature cells that provide immunity to new infections to partially regenerate, although this process is slow with ocrelizumab (Kappos et al. 2012; Baker et al. 2020a), and improve the vaccination response. Consistent with marked B cell depletion, it is apparent that vaccination responses are blunted when initiated 3 months after infusion however, they are not absent (Stokmaier et al. 2018). As plasma cells do not express CD20, once formed they will not be directly targeted by ocrelizumab (Sabitino et al. 2019a). Ofatumumab is a novel subcutaneous CD20-depleting antibody awaiting licencing following a successful phase III programme (Hauser el al 2019). Ofatumumab dosing shows relatively rapid repopulation of immature B cells compared with slower repopulation with ocrelizumab (Savelieva et al. 2017; Baker et al. 2020a) and thus it remains to be established if the advantage of home injection and reversibility changes the use of anti-CD20 therapies compared to infusions with rituximab and ocrelizumab (Hauser el al. 2017, Hauser et al. 2019). Likewise, the real-life extended dosing experiment with ocrelizumab is probably now ongoing (Table 1). If data being captured by registries shows efficacy it is likely that the dosing schedule of ocrelizumab will eventually change on grounds of conveniences, safety and cost-effectiveness although this will need formal testing (Novi et a. 2019; Baker et al. 2020a).

Cladribine. This is an oral small molecule that behaves as an IRT that gives long term-term benefit from short treatment cycles (Giovannoni et al. 2010; Giovannoni et al. 2018). This is a 

B and T cell depletion agent that is eliminated within one day of treatment (Table 2) (Baker et al. 2017c; Baker et al. 2019; Hermann et al. 2019). Treatment induces depletion via apoptosis rather than cell lysis and thus avoids the need for steroids to manage infusion reactions associated with alemtuzumab and ocrelizumab (Cohen et al. 2012; Hauser et al. 2017). Cladribine can induce comparable long-term memory B cell depletion similar to that which is observed with alemtuzumab, but without the innate cell and the severe lymphopenia associated with alemtuzumab (Ceronie et al. 2018; Ruggieri et al. 2019). Indeed, the T cell depletion is more modest and CD4 cells are depleted by about 40-50% and CD8 T cells are depleted by 30-40% compared to baseline. In comparison, alemtuzumab results in B and T cell depletion of 80-90% (Baker et al 2017c). As such the T cells generally remain within the lower limit of the normal range as do natural killer cells that show modest depletion (Baker et al. 2017c; Comi et al. 2019b). The CD19 B cells recover perhaps slower than post-alemtuzumab, as cladribine probably penetrates and acts more in lymphoid tissues, and the dosing schedule of doses being given a month apart targets any rapidly emerging cells (Baker et al. 2017c, Baker et al. 2019). However, B cells probably emerge faster after cladribine compared to ocrelizumab as depleting titres of ocrelizumab remain high for months after infusion (Genovese et al. 2008; Baker et al. 2017c, Baker et al. 2020a). Unfortunately, there is no information available concerning the influence of vaccination responses of oral cladribine. Although there is an increased risk of viral infections (Giovannoni et al. 2010), these are notably less severe than with alemtuzumab (Pardo & Jones 2017) associated with the milder immunosuppression induced by cladribine. Thus, oral cladribine, behaves like a chemical CD19/CD20 depleter with some additional T cell activity and is perhaps functionally closer to CD20-depleting antibodies than CD52 depleting antibody and has the advantage that treatment is not continuous. During the time of self-isolation and shielding agents such as cladribine may have some merit as it is a high efficacy IRT that can be administered at home, with minimal post-dosing monitoring requirements (Table 2). 

Preliminary Experience and Personal View of Treatment. As analysis of the mechanisms of action of the different DMT coupled with emerging knowledge of the anti-viral and pathogenic mechanisms in COVID-19, suggest that initial fears relating to immunosuppression in MS, have yet to be realised, supporting that found in the SARS epidemics (D’Antiga 2020; Giovannoni 2020). The pragmatic approach of examining an individual patient’s circumstances, their prognostic profile and level of MS disease activity may help guide treatment approaches (Giovannoni et al. 2020; Giovannoni 2020). Although these are early days in the initial infection wave of COVID-19, already a number of PwMS have been infected with SAR-CoV-2 with the majority surviving based on early social media and registry data. Although a few people with MS have died they have tended to be older, with more advanced disease and multiple comorbidities. There are now over 360 people with MS and COVID-19 within Italian COVID MS registry with only 5 reported deaths, with only 2 people being treated with DMT and all having comorbidities associated with poor COVID-19 prognosis in the general population. Thus, there does not yet appear evidence that people with MS are at particular risk of severe COVID-19. As such we suggest that risks should be reviewed (Table 3) and advice regarding the risks associated with individual MS-DMT adjusted. Delays in treatment cycles may provide information on the biology of relapsing MS and, if successful may change prescribing habits in the future as there are risk/cost/benefit advantages of reduced dosing frequency. Thus, it will be interesting to determine whether one returns to the current status quo after the COVID-19 pandemic wanes or whether extended interval-dosing remains. Likewise, it will be intriguing to determine if real-life data shows that ocrelizumab exhibits IRT-like characteristics whereby long-term benefit can be seen with only short-term treatment cycle as seen with alemtuzumab and oral cladribine. The positive aspect of this unfortunate human experiment created by the SARS-CoV-2 epidemic, is that it will teach us more about the biology of MS and help inform how best to treat this disease and as safely as possible.

Table 3. Our opinion of altered risks of different MS DMT for COVID-19.

  This opinion was formed 18 April 2020 

Funding: This study received no funding

Disclosures: No company was involved in the decision to write or was involved in the content of this paper. Therefore, disclosures are not considered relevant, however within the past 5 years: DB received consultancy/speaker fees from: Canbex therapeutics, Inmunebio, Lundbeck, Merck, Novartis, Sanofi Genzyme. SA has received consultancy from Novartis. SA is section editor of multiple sclerosis and related disorders and associative editor at Clinical and Experimental Immunology. ASK has nothing relevant to declare. KS has received consultancy, speaker fees from: Biogen, Lipomed, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. GG has received received consultancy, speaker fees or research support from: Abbvie, Actelion, Atara, Biogen, Canbex therapeutics, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda, Teva. GG has received consultancy, speaker fees or research support from: Abbvie, Actelion, Atara, Biogen, Canbex therapeutics, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda, Teva. Editor of multiple sclerosis and related disorders.


Akgün K, Blankenburg J, Marggraf M, Haase R, Ziemssen T Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis.Front Immunol. 2020; 11:56.

Amanat F, Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity. 2020 Apr 3. pii: S1074-7613(20)30120-

Angerer IC, Hecker M, Koczan D, Roch L, Friess J, Rüge A, Fitzner B, Boxberger N, Schröder I, Flechtner K, Thiesen HJ, Winkelmann A, Meister S, Zettl UK.Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine-1-phosphate receptor modulator.CNS Neurosci Ther. 2018; 24:193-201

Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020; 11:995-998.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017a; 16:41-50.

Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K.Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017b; 74:961-969.

Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K. Both cladribine and alemtuzumab may effect MS via B-cell depletion.Neurol Neuroimmunol Neuroinflamm. 2017c; 4(4):e360

Baker D, Giovannoni G, Schmierer K. Marked neutropenia: Significant but rare in people with multiple sclerosis after alemtuzumab treatment. Mult Scler Relat Disord. 2017d; 18:181-183.

Baker D, Pryce G, Amor S, Giovannoni G, Schmierer K. Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis. Brain. 2018; 141:2834-2847.

Baker D, Pryce G, Herrod SS, Schmierer K. Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord. 2019; 30:176-186.

Baker D, Pryce G, James LK, Marta M, Schmierer K. The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis. bioRχiv. 2020a. doi:

Baker D, Ali L, Saxena G, Pryce G, Jones M, Schmierer K, Giovannoni G, Gnanapavan S, Munger KC, Samkoff L, Goodman A, Kang AS. The irony of humanization: alemtuzumab, the first, but one of the most immunogenic, humanized monoclonal antibodies. Front Immunol. 2020b; 11:124

Bar-Or A, Calabresi PA, Arnold D, Markowitz C, Shafer S, Kasper LH, Waubant E, Gazda S, Fox RJ, Panzara M, Sarkar N, Agarwal S, Smith CH. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol. 2008; 63:395-400.

Bilger A, Plowshay J, Ma S, Nawandar D, Barlow EA, Romero-Masters JC, Bristol JA, Li Z, Tsai MH, Delecluse HJ, Kenney SC.Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication.Oncotarget. 2017; 8:44266-44280.

Bao L, Deng W, Gao H, Xiao C, Liu J, Xue J, Lv Q, Liu J, Yu P, Xu Y, Qi F, Qu Y, Li F, Xiang Z, Yu H, Gong S, Liu M, Wang G, Wang S, Song Z, Zhao W, Han Y, Zhao L, Liu X, Wei Q, Qin C. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. BioRχiv 2020.03.13.990226; doi:

Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, van Buskirk C, Grossman BJ, Joyner M, Henderson JP, Pekosz A, Lau B, Wesolowski A, Katz L, Shan H, Auwaerter PG, Thomas D, Sullivan DJ, Paneth N, Gehrie E, Spitalnik S, Hod E, Pollack L, Nicholson WT, Pirofski LA, Bailey JA, Tobian AA. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020. pii: 138745. doi: 10.1172/JCI138745. [Epub].

Boffa G, Bruschi N, Cellerino M, Lapucci C, Novi G, Sbragia E, Capello E, Uccelli A, Inglese M.Fingolimod and Dimethyl-Fumarate-Derived Lymphopenia is not Associated with Short-Term Treatment Response and Risk of Infections in a Real-Life MS Population. CNS Drugs. 2020; 34:425-432.

Brinkman DM1, Jol-van der Zijde CM, ten Dam MM, te Boekhorst PA, ten Cate R, Wulffraat NM, Hintzen RQ, Vossen JM, van Tol MJ.Resetting the adaptive immune system after autologous stem cell transplantation: lessons from responses to vaccines.J Clin Immunol. 2007; 27:647-58.

Brodie SJ, de la Rosa C, Howe JG, Crouch J, Travis WD, Diem K.Pediatric AIDS-associated lymphocytic interstitial pneumonia and pulmonary arterio-occlusive disease: role of VCAM-1/VLA-4 adhesion pathway and human herpesviruses. Am J Pathol. 1999; 154:1453-1464.

Brownlee W, Bourdette D, Broadley S, Killestein J, Ciccarelli O. Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic. Neurology. 2020 Apr 2. pii: 10.1212/WNL.0000000000009507. doi:10.1212/WNL.0000000000009507. [Epub].

Buonomo AR, Zappulo E, Viceconte G, Scotto R, Borgia G, Gentile I. Risk of opportunistic infections in patients treated with alemtuzumab for multiple sclerosis. Expert Opin Drug Saf. 2018; 17:709-717

Cai Y, Hao Z, Gao Y, Ping W, Wang Q, Peng S, Zhao B, Sun W, Zhu M, Li K, Han Y, Kuang D, Chu Q, Fu X, Zhang N.COVID-19 in the perioperative period of lung resection: a brief report from a single thoracic surgery department in Wuhan, China.J Thorac Oncol. 2020. pii: S1556-0864(20)30298-7. doi: 10.1016/j.jtho.2020.04.003. [Epub].

Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD.Lancet Neurol. 2014 Jun;13(6):545-56. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545-56.

Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, Lock H, Longhurst HJ, Giovannoni G, Schmierer K. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J Neurol. 2018;265:1199-1209

Channappanavar RFett CZhao JMeyerholz DKPerlman S.Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection.J Virol. 2014; 88:11034-44

Chen Z, Mi L, Xu J, Yu J, Wang X, Jiang J, Xing J, Shang P, Qian A, Li Y, Shaw PX, Wang J, Duan S, Ding J, Fan C, Zhang Y, Yang Y, Yu X, Feng Q, Li B, Yao X, Zhang Z, Li L, Xue X, Zhu P. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J Infect Dis. 2005; 191:755-760.

Chen D, Xu W, Lei Z, Huang Z, Liu J, Gao Z, Peng L. Recurrence of positive SARS-CoV-2 RNA in COVID-19: A case report. Int J Infect Dis. 2020c Mar 5;93:297-299. doi: 10.1016/j.ijid.2020.03.003. [Epub ahead of print]

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020e. pii: 137244. doi: 10.1172/JCI137244. [Epub].

Chen Y, Chen L, Deng Q, Zhang G, Wu K, Ni L, Yang Y, Liu B, Wang W, Wei C, Yang J, Ye G, Cheng Z.The Presence of SARS-CoV-2 RNA in Feces of COVID-19 Patients. J Med Virol. 2020d. doi: 10.1002/jmv.25825. [Epub].

Chen Y, Feng Z, Diao B, Wang R, Wang G, Wang C, Tan Y, Liu L, Wang C, Liu L, Liu Y, Yuan Z, Ren L, Wu Y. The novel severe acute respiratory syndrome coronavirus 2 (sars-cov-2) directly decimates human spleens and lymph nodes medRχiv. 2020f. doi:

Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020b; 92:418-423.

Chen W, Lan Y, Yuan X, Deng X, Li Y, Cai X, Li L, He R, Tan Y, Deng X, Gao M, Tang G, Zhao L, Wang J, Fan Q, Wen C, Tong Y, Tang Y, Hu F, Li F, Tang X. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity. Emerg Microbes Infect. 2020a; 9:469-473.

Chen WH, Strych U, Hotez PJ, Bottazzi ME. The SARS-CoV-2 Vaccine Pipeline: an Overview. Curr Trop Med Rep. 2020g. Mar 3:1-4

Chu H, Chan JF, Wang Y, Yuen TT, Chai Y, Hou Y, Shuai H, Yang D, Hu B, Huang X, Zhang X, Cai JP, Zhou J, Yuan S, Kok KH, To KK, Chan IH, Zhang AJ, Sit KY, Au WK, Yuen KY.Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19.Clin Infect Dis. 2020. pii: ciaa410. doi: 10.1093/cid/ciaa410. [Epub]

Cinamon G, Zachariah MA, Lam OM, Foss FW Jr, Cyster JG. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol. 2008;9:54-62.

Clerico M, De Mercanti SF, Signori A, Iudicello M, Cordioli C, Signoriello E, Lus G, Bonavita S, Lavorgna L, Maniscalco GT, Curti E, Lorefice L, Cocco E, Nociti V, Mirabella M, Baroncini D, Mataluni G, Landi D, Petruzzo M, Lanzillo R, Gandoglia I, Laroni A, Frangiamore R, Sartori A, Cavalla P, Costantini G, Sormani MP, Capra R.Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved? Neurotherapeutics. 2020; 17:200-207.

Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; CARE-MS I investigators.Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.Lancet. 2012; 380:1819-28.

Coles A, Lim M, GiovannoniG, Anderson P, Dorsey-Campbell, Qualie M.ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic. 2020 2 Apr ( /collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_ DMTs _ for_MS_and_COVID19_VERSION_4_April_2nd.pdf

Comi G, Cook S, Giovannoni G, Rieckmann P, Sørensen PS, Vermersch P, Galazka A, Nolting A, Hicking C, Dangond F. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis.Mult Scler Relat Disord. 2019b;29:168-174

Comi G, Miller AE, Benamor M, Truffinet P, Poole EM, Freedman MS. Characterizing lymphocyte counts and infection rates with long-term teriflunomide treatment: Pooled analysis of clinical trials.Mult Scler. 2019a. doi: 10.1177/1352458519851981. [Epub].

Compston A, Coles A. Multiple sclerosis. Lancet. 2008; 372:1502-1517.

Cossarizza A, De Biasi S, Guaraldi G, Girardis M, Mussini C; Modena Covid-19 Working Group (MoCo19)#. SARS-CoV-2, the Virus that Causes COVID-19: Cytometry and the New Challenge for Global Health.Cytometry A. 2020; 97:340-343. 

D’Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transpl. 2020. doi: 10.1002/lt.25756. [Epub]

Dahl H, Linde A, Strannegård O. In vitro inhibition of SARS virus replication by human interferons.Scand J Infect Dis. 2004; 36:829-31

Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ. 2020 Apr 2;369:m1375. doi: 10.1136/bmj.m1375.

de Assis RR, Jain A, Nakajima R, Jasinskas A, Felgner J, Miago Obiero R, Oladapo Adenaiye 0, Tai S, Hong FH, Norris P, Stone M, Simmons G, Bagri A, Schreiber M, Buser A, Holbro A, Battegay M, Milton Dk, Prometheus Study Group, Davies H, Corash LM, Busch MP, Felgner PL, Khan S. Analysis of SARS-CoV-2 Antibodies in COVID-19 Convalescent Plasma using a Coronavirus Antigen Microarray. BioRχiv doi:

Diebold M, Sievers C, Bantug G, Sanderson N, Kappos L, Kuhle J, Lindberg RLP, Derfuss T. Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.J Autoimmun. 2018; 86:39-50.

Diebold M, Fischer-Barnicol B, Tsagkas C, Kuhle J, Kappos L, Derfuss T, Décard BF. Hepatitis E virus infections in patients with MS on oral disease-modifying treatment. Neurol Neuroimmunol Neuroinflamm. 2019; 6(5). pii e594..

Du RH, Liang LR, Yang CQ, Wang W, Cao TZ, Li M, Guo GY, Du J, Zheng CL, Zhu Q, Hu M, Li XY, Peng P, Shi HZ. Predictors of Mortality for Patients with COVID-19 Pneumonia Caused by SARS-CoV-2: A Prospective Cohort Study.Eur Respir J. 2020  pii: 2000524. doi: 10.1183/13993003.00524-2020. [Epub]

Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020. pii: 202004168. doi: 10.1073/pnas.2004168117. [Epub]

Fernández Ó, Giovannoni G, Fox RJ, Gold R, Phillips JT, Potts J, Okwuokenye M, Marantz JL.Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM.Clin Ther. 2017; 39:1671-1679.

Fernandez Velasco JI, Villarrubia Migallon N, Monreal E, Sainz de la Maza S, Meca Lallana V, Meca Lallana J, Sanchez P, Carreon Guarnizo E, Izquierdo G, Tejeda Velarde A, Rodriguez Martin E, Roldan Santiago E, Gascon F, Aladro Y, Brieva L, Saiz A, Iñiguez C, Gonzalez Suarez I, Masjuan J, Costa-Frossard L, Villar LM. Effects of ocrelizumab treatment in peripheral blood leukocyte subsets of primary progressive multiple sclerosis patients. P686. 2019:25(S2):341-342

Forster P, Forster L, Renfrew C, Forster M. Phylogenetic network analysis of SARS-CoV-2 genomes.Proc Natl Acad Sci U S A. 2020 Apr 8. pii: 202004999.

Fox, SE, Akmatbekov A, Harbert JL, Li G, Brown JQ, Vander Heide RS. Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans. MedRxiv. 2020.

Gabutti G, d’Anchera E, Sandri F, Savio M, Stefanati A.Coronavirus: Update Related to the Current Outbreak of COVID-19.Infect Dis Ther. 2020. doi: 10.1007/s40121-020-00295-5. [Epub] 

Ge F, Lin H, Li Z, Chang T. Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis.Neurol Sci. 2019; 40:479-487.

Genovese MC, Kaine JL, Lowenstein MB, Del Giudice J, Baldassare A, Schechtman J, Fudman E, Kohen M, Gujrathi S, Trapp RG, Sweiss NJ, Spaniolo G, Dummer W; ACTION Study Group.Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study.Arthritis Rheum. 2008;58:2652-2661.

Guo L, Ren L, Yang S, Xiao M, Chang, Yang F, Dela Cruz CS, Wang Y, Wu C, Xiao Y, Zhang L, Han L, Dang S, Xu Y, Yang Q, Xu S, Zhu H, Xu Y, Jin Q, Sharma L, Wang L, Wang J. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis. 2020 Mar 21. pii: ciaa310. doi: 10.1093/cid/ciaa310

Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ; CLARITY Study Group.A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.N Engl J Med. 2010;362:416-426

Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, Rieckmann P, Comi G, Dangond F, Adeniji AK, Vermersch P. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.Mult Scler. 2018; 24:1594-1604

Giovannoni G, Hawkes C, Lechner-Scott J, Levy M, Waubant E, Gold J The COVID-19 pandemic and the use of MS disease-modifying therapies. Mult Scler Rel Disord. 2020. DOI: /j.msard.2020.102073.

Giovannoni G. Anti-CD20 immunosuppressive disease-modifying therapies and COVID-19. Mult Scler Rel Disord. 2020. DOI:  [Epub]

Gingele S, Jacobus TL, Konen FF, Hümmert MW, Sühs KW, Schwenkenbecher P, Ahlbrecht J, Möhn N, Müschen LH, Bönig L, Alvermann S, Schmidt RE, Stangel M, Jacobs R, Skripuletz T. Ocrelizumab Depletes CD20⁺ T Cells in Multiple Sclerosis Patients. Cells. 2018 Dec 28;8(1). pii: E12. doi: 10.3390/cells8010012.

Gramberg THofmann HMöller PLalor PFMarzi AGeier MKrumbiegel MWinkler TKirchhoff FAdams DHBecker SMünch JPöhlmann S. LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus, Virology. 2005; 340: 224e236. 

Gross CC, Ahmetspahic D, Ruck T, Schulte-Mecklenbeck A, Schwarte K, Jörgens S, Scheu S, Windhagen S, Graefe B, Melzer N, Klotz L, Arolt V, Wiendl H, Meuth SG, Alferink J. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016: 3(6):e289.

Hammarlund E, Thomas A, Amanna IJ, Holden LA, Slayden OD, Park B, Gao L, Slifka MK.Plasma cell survival in the absence of B cell memory. Nat Commun 2017; 8:1781.

Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.J Pathol. 2004;203:631.

Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis N Engl J Med. 2017; 376:221-234.

Hauser SL, Bar-Or A, Cohen J, Comi G, Correale J, Coyle PK, Cross AH, de Seze J, Montalban X, Selmaj K, Wiendl H, Goodyear A, Haring DA, Kerloeguen C, Tomic D, Willi R, Ramanathan K, Merschhemke M, Kappos L.Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. 336. Mult scler 2019 25(S2):890-891.

Havrdova E, Arnold DL, Cohen JA, Hartung HP, Fox EJ, Giovannoni G, Schippling S, Selmaj KW, Traboulsee A, Compston DAS, Margolin DH, Thangavelu K, Rodriguez CE, Jody D, Hogan RJ, Xenopoulos P, Panzara MA, Coles AJ; CARE-MS I and CAMMS03409 Investigators. Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy. Neurology. 2017;89:1107-1116.

Haveri A, Smura T, Kuivanen S, Österlund P, Hepojoki J, Ikonen N, Pitkäpaasi M, Blomqvist S, Rönkkö E, Kantele A, Strandin T, Kallio-Kokko H, Mannonen L, Lappalainen M, Broas M, Jiang M, Siira L, Salminen M, Puumalainen T, Sane J, Melin M, Vapalahti O, Savolainen-Kopra C.

Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020. Euro Surveill. 2020; 25(11). doi: 10.2807/1560-7917.ES.2020.25.11.2000266.

He, X., Lau, E.H.Y., Wu, P. et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: a prospective contact-tracing study.Nat Med. 2020a.

He A, Merkel B, Brown JWL, Zhovits Ryerson L, Kister I, Malpas CB, Sharmin S, Horakova D, Kubala Havrdova E, Spelman T, Izquierdo G, Eichau S, Trojano M, Lugaresi A, Hupperts R, Sola P, Ferraro D, Lycke J, Grand’Maison F, Prat A, Girard M, Duquette P, Larochelle C, Svenningsson A, Petersen T, Grammond P, Granella F, Van Pesch V, Bergamaschi R, McGuigan C, Coles A, Hillert J, Piehl F, Butzkueven H, Kalincik T; MSBase study group.Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.Lancet Neurol. 2020b; 19:307-316

Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana M, Anheim M, Meziani F. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020. doi: 10.1056/NEJMc2008597. [Epub]

Hensley LE, Fritz LE, Jahrling PB, Karp CL, Huggins JW, Geisbert TW. Interferon-beta 1a and SARS coronavirus replication. Emerg Infect Dis. 2004; 10:317-319.

Hermann R, Karlsson MO, Novakovic AM, Terranova N, Fluck M, Munafo A. The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin Pharmacokinet. 2019; 58:283-297.

Herold T, Jurinovic V, Arnreich C, Hellmuth JC, von Bergwelt-Baildon M, Klien M, einberger T.

Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients medRxiv 2020.04.01.20047381; doi:

Hjorth M, Dandu N, Mellergård J. Treatment effects of fingolimod in multiple sclerosis: Selective changes in peripheral blood lymphocyte subsets. PLoS ONE. 2020; 15(2):e0228380.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 pii: S0092-8674(20)30229-4. [Epub]

Hoepner R, Faissner S, Salmen A, Gold R, Chan A. Efficacy and side effects of natalizumab therapy in patients with multiple sclerosis.J Cent Nerv Syst Dis. 2014; 6:41-9.

Huang L, Zhang X, Zhang X, Wei Z, Zhang L, Xu J, Liang P, Xu PY, Zhang C, Xu PA. Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: a prospective contact-tracing study.J Infect. 2020 Apr 10. pii: S0163-4453(20)30117-1. doi: 10.1016/j.jinf.2020.03.006. [Epub]

Hyduk SJ, Cybulsky MI. Role of alpha4beta1 integrins in chemokine-induced monocyte arrest under conditions of shear stress. Microcirculation. 2009;16:17-30.

Iwasaki, A, Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev Immunol. 2020.

Juto A, Fink K, Al Nimer F, Piehl F. Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity. Mult Scler Relat Disord. 2020;37:101468.

Kalincik T, Kubala Havrdova E, Horakova D, Izquierdo G, Prat A, Girard M, Duquette P, Grammond P, Onofrj M, Lugaresi A, Ozakbas S, Kappos L, Kuhle J, Terzi M, Lechner-Scott J, Boz C, Grand Maison F, Prevost J, Sola P, Ferraro D, Granella F, Trojano M, Bergamaschi R, Pucci E, Turkoglu R, McCombe PA, Pesch VV, Van Wijmeersch B, Solaro C, Ramo-Tello C, Slee M, Alroughani R, Yamout B, Shaygannejad V, Spitaleri D, Sánchez-Menoyo JL, Ampapa R, Hodgkinson S, Karabudak R, Butler E, Vucic S, Jokubaitis V, Spelman T, Butzkueven H. Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis.J Neurol Neurosurg Psychiatry. 2019;90(4):458-468.

Kappos L, Li D, Calabresi P, O’Connor P et al. Long-term safety and efficacy of ocrelizumab in patients with relapsing–remitting multiple sclerosis: week 144 results of a Phase II, randomised, multicentre trial. Mult Scler J 2012;18 (Suppl. 4): 140–141.

Kaufman M, Pardo G, Rossman H, Sweetser MT, Forrestal F, Duda P. Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis. J Neurol Sci. 2014; 341:22-7

Khodadadi L, Cheng Q, Radbruch A, Hiepe F. The Maintenance of Memory Plasma Cells. Front Immunol. 2019;10:721.

Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH.Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine.Am J Epidemiol. 1969;89(4):422-34.

Kimball A, Hatfield KM, Arons M, James A, Taylor J, Spicer K, Bardossy AC, Oakley LP, Tanwar S, Chisty Z, Bell JM, Methner M, Harney J, Jacobs JR, Carlson CM, McLaughlin HP, Stone N, Clark S, Brostrom-Smith C, Page LC, Kay M, Lewis J, Russell D, Hiatt B, Gant J, Duchin JS, Clark TA, Honein MA, Reddy SC, Jernigan JA; Public Health – Seattle & King County; CDC COVID-19 Investigation Team. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility – King County, Washington, March 2020.MMWR Morb Mortal Wkly Rep. 2020; 69:377-381.

Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, Jones J.Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.Neurology. 2014; 82:2158-64.

Kowarik MC, Pellkofer HL, Cepok S, Korn T, Kümpfel T, Buck D, Hohlfeld R, Berthele A, Hemmer B.Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.Neurology. 2011; 76:1214-21.

Kunkl M, Frascolla S, Amormino C, Volpe E, Tuosto L. T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis. Cells. 2020; 9(2). pii: E482. doi: 10.3390/cells9020482

Kwok KO, Lai F, Wei WI, Wong SYS, Tang JWT. Herd immunity – estimating the level required to halt the COVID-19 epidemics in affected countries.J Infect. 2020 Mar 21. pii: S0163-4453(20)30154-7.

Lai CC, Liu YH, Wang CY, Wang YH, Hsueh SC, Yen MY, Ko WC, Hsueh PR. Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths. J Microbiol Immunol Infect. 2020. pii: S1684-1182(20)30040-2 . [Epub].

Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J.The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020 Mar 10. doi: 10.7326/M20-0504. [Epub]

Lemtrada® EU Summary of Product Characteristics. Nov 2019.

Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020; 5:562-569.

Leung DT, Tam FC, Ma CH, Chan PK, Cheung JL, Niu H, Tam JS, Lim PL. Antibody response of patients with severe acute respiratory syndrome (SARS) targets the viral nucleocapsid. J, Infect Dis. 2004: 190: 379-386.

Li Y, Chen M, Cao H, Zhu Y, Zheng J, Zhou H. Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response. Microbes Infect. 2013; 15:88-95.

Li Z, Richards S, Surks HK, Jacobs A, Panzara MA. Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis. Clin Exp Immunol. 2018;194:295-314.

Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, Zhang HY, Sun W, Wang Y. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020. doi: 10.1002/jmv.25757

Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, et al. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019; 4: e123158.

Liu Y, Liao W, Wan L, Xiang T, Zhang W. Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19. Viral Immunol. 2020a. doi: 10.1089/vim.2020.0062. [Epub]

Liu Y, Liao W, Wan L, Xiang T, Zhang W. Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19. Viral Immunol. 2020c. doi: 10.1089/vim.2020.0062. [Epub]

Liu Z, Long W, Tu M, Chen S, Huang Y, Wang S, Zhou W, Chen D, Zhou L, Wang M, Wu M, Huang Q, Xu H, Zeng W, Guo L. Lymphocyte subset (CD4+, CD8+) counts reflect the severity of infection and predict the clinical outcomes in patients with COVID-19.J Infect. 2020b. pii: S0163-4453(20)30182-1.

Lippi G, Mattiuzzi C, Sanchis-Gomar F, Henry BM. Clinical and demographic characteristics of patients dying from COVID-19 in Italy versus China. J Med Virol. 2020 Apr 10. doi: 10.1002/jmv.25860. [Epub ahead of print]

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-574.

Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, Winter H, Meister M, Veith C, Boots AW, Hennig BP, Kreuter M, Conrad C, Eils R.SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J. 2020:e105114. doi: 10.15252/embj.20105114. [Epub]

Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol. 2020 Apr 6. doi: 10.1002/jmv.25801. [Epub ahead of print]

Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, Laurence J. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020. pii: S1931-5244(20)30070-0. doi: 10.1016/j.trsl.2020.04.007. [Epub]

Marzi A. Gramberg TSimmons GMöller PRennekamp AJKrumbiegel MGeier MEisemann JTurza NSaunier BSteinkasserer ABecker SBates PHofmann HPöhlmann S. DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus, J. Virol. 2004: 78: 12090e12095.

Mavenclad® EU Summary of Product Characteristics. Jul 2018;

McCarthy CL, Tuohy O, Compston DA, Kumararatne DS, Coles AJ, Jones JL. Immune competence after alemtuzumab treatment of multiple sclerosis. Neurology. 2013; 81:872-876.

Mehta D, Miller C, Arnold DL, Bame E, Bar-Or A, Gold R, Hanna J, Kappos L, Liu S, Matta A, Phillips JT, Robertson D, von Hehn CA, Campbell J, Spach K, Yang L, Fox RJ.Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice.Neurology. 2019; 92:e1724-e1738

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIOOcrelizumab versus placebo in primary progressive multiple sclerosis. Clinical Investigators. N Engl J Med. 2017 ;376:209-220.

Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, Sakata H, Kondo K, Myose N, Nakao A, Takeda M, Haro H, Inoue O, Suzuki-Inoue K, Kubokawa K, Ogihara S, Sasaki T, Kinouchi H, Kojin H, Ito M, Onishi H, Shimizu T, Sasaki Y, Enomoto N, Ishihara H, Furuya S, Yamamoto T, Shimada S. A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 2020. pii: S1201-9712(20)30195-8.

Naismith RT, Wolinsky JS, Wundes A, LaGanke C, Arnold DL, Obradovic D, Freedman MS, Gudesblatt M, Ziemssen T, Kandinov B, Bidollari I, Lopez-Bresnahan M, Nangia N, Rezendes D, Yang L, Chen H, Liu S, Hanna J, Miller C, Leigh-Pemberton R. Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study. Mult Scler. 2019 Nov 4:1352458519881761 [Epub]

Nicolini LA, Canepa P, Caligiuri P Mikulska M, Novi G, Viscolli C, Uccelli A. Fulminant hepatitis associated with echovirus 25 during treatment with ocrelizumab for multiple sclerosis. JAMA Neurol. 2019 76:866-867.

Novi G, Fabbri S, Bovis F, et al. Tailoring B-cells depleting therapy in MS according to memory B-cells monitoring: a pilot study. P971. Mult Scler.  2019; 25: (S2) 509-510

Novi G, Fabbri S, Bovis F, Sbragi E, Gazzola P, Maietta I, Giacomo B, Cellerino M, Lapucci C, Brushi N, Capello E, Laroni A, Mancardi GL, Sormani MP, Inglese M, Uccelli A.  Tailoring B-cells depleting therapy in MS according to memory B-cells monitoring: a pilot study. Neurol 2020; P15.012

O’Brien TR, Thomas DL, Jackson SS, Prokunina-Olsson L, Donnelly RP, Hartmann R. Weak induction of interferon expression by sars-cov-2 supports clinical trials of interferon lambda to treat early covid-19. Clin Infect Dis  2020. ciaa453, [Epub]

Okba NMA, Müller MA, Li W, Wang C, GeurtsvanKessel CH, Corman VM, Lamers MM, Sikkema RS, de Bruin E, Chandler FD, Yazdanpanah Y, Le Hingrat Q, Descamps D, Houhou-Fidouh N, Reusken CBEM, Bosch BJ, Drosten C, Koopmans MPG, Haagmans BL. Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease 2019 Patients.Emerg Infect Dis. 2020;26(7). doi: 10.3201/eid2607.200841. [Epub]

Olberg HK, Eide GE, Cox RJ, Jul-Larsen Å, Lartey SL, Veeler CA, Myhr KM Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory. Eur J Neurol. 2018;25:527-534

Ocrevus® EU Summary Product Characterisitics, Sep 2018;

Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020; 11:1620

Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von Büdingen HC. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014; 193:580-586.

Pardo G, Jones DE. The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.J Neurol. 2017; 264:2351-2374.

Pei S, Yuan X, Zhang Z, Yao RR, Xie Y, Shen M, Li B, Chen X, Yin M. Convalescent plasma to treat covid-19: Chinese strategy and experiences. MedRχiv. 2020. doi:

Perini P, Rinaldi F, Puthenparampil M, Marcon M, Perini F, Gallo P.Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient.Mult Scler Relat Disord. 2018; 26:68-70

Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med. 2006; 354:899-910.

Prompetchara E, Ketloy C, Palaga T.Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38: 1-9.

Pung R, Chiew CJ, Young BE, Chin S, Chen MI, Clapham HE, Cook AR, Maurer-Stroh S, Toh MPHS, Poh C, Low M, Lum J, Koh VTJ, Mak TM, Cui L, Lin RVTP, Heng D, Leo YS, Lye DC, Lee VJM; Singapore 2019 Novel Coronavirus Outbreak Research Team. Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures. Lancet. 2020; 395(10229):1039-1046.

Rokni MGhasemi VTavakoli Z.Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS.Rev Med Virol. 2020 Apr 8. doi: 10.1002/rmv.2107. [Epub]

Ruggieri M, Gargano C, Iaffaldano A, Manni A, Iaffaldano P, Paolicelli D, Trojano M. Changes in lymphocyte subpopulations in highly active multiple sclerosis patients during cladribine treatment. Eur J Neurol 2019; 26(Suppl 1):491

Rush CA, Atkins HL, Freedman MS.Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis.Cold Spring Harb Perspect Med. 2019;9(3). pii: a029082.

Ryerson LZ, Foley J, Chang I, Kister I, Cutter G, Metzger RR, Goldberg JD, Li X, Riddle E, Smirnakis K, Kasliwal R, Ren Z, Hotermans C, Ho PR, Campbell N. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology. 2019;93:e1452-e1462

Sabatino JJ Jr, Zamvil SS, Hauser SL. B-Cell Therapies in Multiple Sclerosis.Cold Spring Harb Perspect Med. 2019a;9. pii: a032037.

Sabatino JJ Jr, Wilson MR, Calabresi PA, Hauser SL, Schneck JP, Zamvil SS. Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis. Proc Natl Acad Sci U S A. 2019b; 116:25800-25807.

Sarzi-Puttini PGiorgi VSirotti SMarotto DArdizzone SRizzardini GAntinori SGalli M. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol. 2020;38:337-342.

Savelieva M, Kahn J, Bagger M, Meier DP, Tomic D, Leppert D, Wallström E. Comparison of the B-cell recovery time following discontinuation of anti-CD20 therapies. EP1624. Mult scler. 2017; 23 (S3):852-853

Schwab N, Schneider-Hohendorf T, Wiendl H. Therapeutic uses of anti-α4-integrin (anti-VLA-4) antibodies in multiple sclerosis. Int Immunol. 2015;27(1):47-53.

Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Mar 27. doi: 10.1001/jama.2020.4783. [Epub].

Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Liu R, He X, Shuai L, Sun Z, Zhao Y, Liu P, Liang L, Cui P, Wang J, Zhang X, Guan Y, Tan W, Wu G, Chen H, Bu Z.Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science. 2020. pii: eabb7015. doi: 10.1126/science.abb7015. [Epub]

Signoriello E, Bonavita S, Sinisi L, Russo CV, Maniscalco GT, Casertano S, Saccà F, Lanzillo R, Morra VB, Lus G. Is antibody titer useful to verify the immunization after VZV Vaccine in MS patients treated with Fingolimod? A case series. Mult Scler Relat Disord. 2020; 40:101963.

Stein RA COVID-19 and rationally layered social distancing. Int J Clin Pract. 2020 Mar 14:e13501. doi: 10.1111/ijcp.13501. [Epub]

Stokmaier D, Winthrop K, Chognot C, et al. Effect of ocrelizumab on vaccine responses in pateinets with multiple sclerosis (S36.002). Neurology; 2018; 90 (15 Suppl): S36.002

Storek J, Geddes M, Khan F, Huard B, Helg C, Chalandon Y, Passweg J, Roosnek E.Reconstitution of the immune system after hematopoietic stem cell transplantation in humans.Semin Immunopathol. 2008;30(4):425-37

Subei AM, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis.CNS Drugs. 2015; 29(7):565-75.

Swallow E, Patterson-Lomba O, Yin L, Mehta R, Pelletier C, Kao D, Sheffield JK, Stonehouse T, Signorovitch J.Comparative safety and efficacy of ozanimod versus fingolimod for relapsing multiple sclerosis.J Comp Eff Res. 2020; 9(4):275-285.

Tallantrye EC, Whittam DH, Jolles S, Pailing D, Constantinesecu, Robertson NP, Jacob A. Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation. J. Neurol. 2018; 265:1115-1122

Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, Zhou Y, Du L. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020. doi: 10.1038/s41423-020-0400-4. [Epub]

Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer. J Thorac Oncol. 2020a 28. pii: S1556-0864(20)30132-5. 

Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, Lu L, Jiang S, Yang Z, Wu Y, Ying T. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect. 2020b;9(1):382-385

To KK, Tsang OT, Leung WS, Tam AR, Wu TC, Lung DC, Yip CC, Cai JP, Chan JM, Chik TS, Lau DP, Choi CY, Chen LL, Chan WM, Chan KH, Ip JD, Ng AC, Poon RW, Luo CT, Cheng VC, Chan JF, Hung IF, Chen Z, Chen H, Yuen KY.Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.Lancet Infect Dis. 2020. pii: S1473-3099(20)30196-1 [Epub]

Thevarajan I, Nguyen THO, Koutsakos M, Druce J, Caly L, van de Sandt CE, Jia X, Nicholson S, Catton M, Cowie B, Tong SYC, Lewin SR, Kedzierska K. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med. 2020;26(4):453-455

Thomas K, Eisele J, Rodriguez-Leal FA, Hainke U, Ziemssen T.Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS.Neurol Neuroimmunol Neuroinflamm. 2016; 3(3):e228

Thomas K, Sehr T, Proschmann U, Rodriguez-Leal FA, Haase R, Ziemssen T. Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculation. J Neuroinflammation. 2017;14(1):41.

Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, May K, Button T, Azzopardi L, Kousin-Ezewu O, Fahey MT, Jones J, Compston DA, Coles A. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015; 86:208-15.

Vågberg M, Kumlin U, Svenningsson A. Humoral immune response to influenza vaccine in natalizumab-treated MS patients. Neurol Res. 2012;34(7):730-3

Vollmer B, Vollmer T, Corboy J, Alvarez E. Evaluation of risk factors in developing lymphopenia and hypogammaglobulinemia in anti-CD20 treated multiple sclerosis patients. Neurology 2020. S29.002.

von Hehn C, Howard J, Liu S, Meka V, Pultz J, Mehta D, Prada C, Ray S, Edwards MR, Sheikh SI.Immune response to vaccines is maintained in patients treated with dimethyl fumarate.Neurol Neuroimmunol Neuroinflamm. 2017;5(1):e409. doi: 10.1212/NXI.0000000000000409. eCollection 2018 Jan.

Wang, D., B. Hu, C. Hu, F. Zhu, X. Liu, J. Zhang, B. Wang, H. Xiang, Z. Cheng, Y. Xiong, et al. 2020. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020b 323:1061.

Wang K, Chen W, Yu-Sen Zhou, Jian Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, Bin Wang, Xiu-Xuan Sun, Chun-Fu Wang, Xu Yang, Peng Lin, Yong-Qiang Deng, Ding Wei, Xiang-Min Yang, Yu-Meng Zhu, Kui Zhang, Zhao-Hui Zheng, Jin-Lin Miao, Ting Guo, Ying Shi, Jun Zhang, Ling Fu, Qing-Yi Wang, Huijie Bian, Ping Zhu, Zhi-Nan Chen SARS-CoV-2 invades host cells via a novel route: CD147-spike protein 2020a doi:

Wang X, Xu W, Hu G, Xia S, Sun Z, Liu Z, Xie Y, Zhang R, Jiang S, Lu L. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell Mol Immunol. 2020c. doi: 10.1038/s41423-020-0424-9. [Epub ahead of print

Warny M, Helby J, Nordestgaard BG, Birgens H, Bojesen SE. Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study. PLoS Med. 2018;15(11):e1002685.

Weiss PMurdoch DR. Clinical course and mortality risk of severe COVID-19.Lancet. 2020 Mar;395(10229):1014-1015

Wen W, Su W, Tang H, Le W, Zhang X, Zheng Y, Liu X, Xie L, Li J, Ye J, Cui X, Miao Y, Wang D, Dong J, Xiao CL, Chen W, Wang H.Immune Cell Profiling of COVID-19 Patients in the Recovery Stage by Single-Cell Sequencing. medRxiv 2020.03.23.20039362; 


Willis MD, Robertson NP. Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2.J Neurol. 2020 Apr 17. doi: 10.1007/s00415-020-09822-3. [Epub].

Wijnands JMA, Zhu F, Kingwell E, Fisk JD, Evans C, Marrie RA, Zhao Y, Tremlett H. Disease-modifying drugs for multiple sclerosis and infection risk: a cohort studyJ Neurol Neurosurg Psychiatry. 2018; 89(10):1050-1056.

Wray S, Havrdova E, Snydman DR, Arnold DL, Cohen JA, Coles AJ, Hartung HP, Selmaj KW, Weiner HL, Daizadeh N, Margolin DH, Chirieac MC, Compston DAS. Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study. Mult Scler. 2019;25(12):1605-1617.

Xiang F, Wang X, He X, Peng Z, Yang B, Zhang J, Zhou Q, Ye H, Ma Y, Li H, Wei X, Cai P, Ma WL. Antibody Detection and Dynamic Characteristics in Patients with COVID-19. Clin Infect Dis. 2020. pii: ciaa461. doi: 10.1093/cid/ciaa461. [Epub ahead of print]

Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, Guo Q, Sun X, Zhao D, Shen J, Zhang H, Liu H, Xia H, Tang J, Zhang K, Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Gong S. Nat Med. 2020a; 26:502-505

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020b;8:420-422

Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, Mou HM, Wang LH, Zhang HR, Fu WJ, Luo T, Liu F, Chen C, Xiao HL, Guo HT, Lin S, Xiang DF, Shi Y, Li QR, Huang X, Cui Y, Li XZ, Tang W, Pan PF, Huang XQ, Ding YQ, Bian XW.[A pathological report of three COVID-19 cases by minimally invasive autopsies]. Zhonghua Bing Li Xue Za Zhi. 2020;49(0):E009.

Yang ZYHuang YGanesh LLeung KKong WPSchwartz OSubbarao KNabel GJ. pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN, J. Virol. 2004; 78 (11): 5642e5650. 

Yang Y, Zeyu Xiong, Sheng Zhang, Yan Yan, Justin Nguyen, Bernard Ng, Huifang Lu, John Brendese, Fan Yang, Hong Wang, Xiao-Feng Yang Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors Biochem J. 2005; 392: 135–143.

Ye G, Pan Z, Pan Y, Deng Q, Chen L, Li J, Li Y, Wang X. Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation. J Infect. 2020a . pii: S0163-4453(20)30114-6. doi: 10.1016/j.jinf.2020.03.001.

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.

J Infect. 2020b Apr 10. pii: S0163-4453(20)30165-1.

Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992; 356:63-6

Yen YT, Liao F, Hsiao CH, Kao CL, Chen YC, Wu-Hsieh Modelling the early events of severe acute respiratory syndrome coronavirus infection in vitro. BA. J Virol. 2006;80:2684-2693

Yao H, Lu X, Chen Q, Xu K, Chen Y, Cheng L, Liu F, Wu Z, Wi H, Jin C, Zheng M, Wu N, Jiang C, Li L. Patient-derived mutations impact pathogenicity of SARS-CoV2. medRχiv. 2020.04.14.20060160; doi:

Zhang Y, Gao Y, Qiao L, Wang W, Chen D. Inflammatory response cells during acute respiratory distress syndrome in patients with coronavirus disease 2019 (COVID-19). Ann Intern Med. 2020a; doi:

Zhang T, Sun LX, Feng RE.Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019].Zhonghua Jie He He Hu Xi Za Zhi. 2020b Apr 3;43(0): . doi: 10.3760/cma.j.cn112147-20200311-00312. [Epub ahead of print]

Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, Wang X, Yuan J, Li T, Li J, Qian S, Hong C, Wang F, Liu Y, Wang Z, He Q, Li Z, He B, Zhang T, Fu Y, Ge S, Liu L, Zhang J, Xia N, Zhang Z. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020. pii: ciaa344. doi: 10.1093/cid/ciaa344. [Epub]

Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, Xu Y, Tian Z.  Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020.

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579:270-273.

Zhu J, Ji P, Pang J, Zhong Z, Li H, He C, Zhang J, Zhao C. Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis.J Med Virol. 2020b Apr. doi: 10.1002/jmv.25884. [Epub].

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020a; 382:727-733

Zoehner G, Miclea A, Salmen A, Kamber N, Diem L, Friedli C, Bagnoud M, Ahmadi F, Briner M, Sédille-Mostafaie N, Kilidireas C, Stefanis L, Chan A, Hoepner R, Evangelopoulos ME.Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course.Ther Adv Neurol Disord. 2019; 12:1756286419878340.

About the author



  • I am getting more confused by the day about Ocrelizumab. The main body of text makes it sound high risk. The table says low risk.
    I think I’ve understood I don’t need to be shielded as otherwise young and no co-morbidities, but as a HCW does ocrelizumab alone mean that I cannot work?

    • The risks are relative…but I would re-read, it suggests that ocrelizumab does not target the main elements involved in protecting you from SARS-Cov-2 infection, therefore it would be lower risk….The caveat comes, do you get a protective antibody response. The answer is probably to some extent, but it is likely to be blunted. These risks are all theorhectical risks. If you read ProfGs post it rather supports the views

  • I am still trying to understand the following regarding natalizumab: if a patient is on a 28-day SID regimen, with the last does administered on the first of March (by way of example).
    Patient transitioned to EID and next does is in mid-April.
    Is the patient considered derisked from the 1st of April?
    Or will it take [3] months to wash out SID and fully convert to EID, sort of speak?

    The above question is crucial for many if the government ends up relaxing the lockdown on the 11th of May.

    • In terms of viral encephalitis yes the de-risking would come from 1 april as far as I would understand, however ProfG or Biogen can correct me. The antibody falls away and allows your CD4 cells to enter brain and this provides the stimulous for the anti-viral response….however it makes the assumption of what targets JC virus and Coronavirus is the same.

  • Spotted a couple of typos that might need clearing before you submit.
    I’m not a physician but I “know a man who is”.
    I have a relative on the review board for a pharmacovigilance journal who has more-than a passing interest in MS, shall I ask if he’ll cast an eye over it?

    • Thanks, I have spotted a few typos too I submitted the paper, but have already shortened it and added more stuff.

  • Thanks for the review!
    The question is how to deal with continuing natalizumab infusion (EID) in a COVID+ patient under the “quarantine” time

By MouseDoctor



Recent Posts

Recent Comments