ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic is concerning for patients with neuroimmunological diseases who are receiving immunotherapy. Uncertainty remains about whether

immunotherapies increase the risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or increase the risk of severe disease and death upon infection. National and

international societies have developed guidelines and statements, but consensus does not exist in several areas. In this Review, we attempt to clarify where consensus exists and where

uncertainty remains to inform management approaches based on the first principles of neuroimmunology. We identified key questions that have been addressed in the literature and collated the

neuroimmunology in particular because, although the risk of viral infection has become more relevant, most of the considerations apply to the general management of neurological

immunotherapy. We also give special consideration to immunosuppressive treatment and cell-depleting therapies that might increase susceptibility to SARS-CoV-2 infection but reduce the risk

of severe COVID-19. KEY POINTS * The risk that the coronavirus disease 2019 (COVID-19) pandemic poses for people who are receiving immunotherapy for neuroimmunological disease remains

unclear. * Guidelines and statements have been published by societies and individuals, but the level of consensus differs for different aspects; we use a Delphi-like process to clarify where

consensus exists. * Without evidence, management of neuroimmunological diseases in the context of COVID-19 requires application of the first principles of immunotherapy, taking into account

disease-related, patient-related, physician-related, environment-related and COVID-19-related factors. * In general, corticosteroids, intravenous immunoglobulin and/or plasma exchange for

the treatment of acute neuroimmunological deteriorations can be administered with low risk in the COVID-19 pandemic. * In general, ongoing immunotherapy should not be stopped because of the

COVID-19 pandemic; treatment initiation and optimization are also recommended. * For some aspects of immunotherapy in the context of COVID-19, consensus in the literature is low, and

collection of data in patient registries is important for resolving these uncertainties. SIMILAR CONTENT BEING VIEWED BY OTHERS LIFTING THE MASK ON NEUROLOGICAL MANIFESTATIONS OF COVID-19

Article 24 August 2020 COVID-19: IMMUNOPATHOGENESIS AND IMMUNOTHERAPEUTICS Article Open access 25 July 2020 RECOMMENDATIONS FOR THE MANAGEMENT OF COVID-19 IN PATIENTS WITH HAEMATOLOGICAL

MALIGNANCIES OR HAEMATOPOIETIC CELL TRANSPLANTATION, FROM THE 2021 EUROPEAN CONFERENCE ON INFECTIONS IN LEUKAEMIA (ECIL 9) Article 29 April 2022 INTRODUCTION Coronavirus disease 2019

(COVID-19) is a novel illness caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2. The first infections were reported in China in late 2019, and the WHO

declared a global pandemic on 11 March 2020. The disease course is highly heterogeneous, ranging from infectious but asymptomatic to severe disease and death, often due to respiratory

failure3. The host reaction to the virus can include antibody-mediated inflammation4 and a cytokine storm5 that are thought to have a major impact on outcome. Most people recover with only

supportive care, indicating that the infection induces short-term immunity, but whether long-term immunity develops or recurrent circulation of SARS-CoV-2 can be expected — as seen with

other coronaviruses — is unknown6. The COVID-19 pandemic raises important questions about the risk to patients with neuroimmunological diseases who are treated with immunotherapies. These

diseases — a key example of which is multiple sclerosis (MS) — are thought to result from immune tolerance dysfunction that affects immune regulatory networks7 and often necessitates

continuous immunosuppressive or immunomodulatory therapy. Immunosuppressive therapies can limit immune competence, whereas immunomodulatory therapies adjust the immune system without

affecting immune competence8. Immunotherapies can affect the risk of infections9 and some therapies are associated with an increased risk from particular types of pathogens10. Several

elements of the risk of COVID-19 in patients with neuroimmunological disease are unclear; for example, whether these patients have an increased risk of being infected by SARS-CoV-2 after

exposure, whether they have an increased risk of developing a clinical rather than asymptomatic infection, and whether they have an increased risk of a clinical infection becoming severe

enough to require intensive care or to lead to persistent disability or death. We refer to the sum of these risks as an ‘increased risk of severe COVID-19’. A further complication is that

there is a rationale for immunotherapy being beneficial in COVID-19, especially in the management of complications such as acute respiratory distress syndrome (ARDS)11,12, though caution is

needed given the negative history of immunotherapy for infection, including negative trials of corticosteroids for ARDS13. Initial reports of patients with immunosuppression and COVID-19 are

complicated but suggest no general deleterious effect14 and a potentially helpful role of immunosuppression, especially in patients who are at risk of serious complications in the second

phase of the disease15,16. Several national and international guidelines, recommendations and statements and individual opinion pieces have addressed the management of patients with

neuroimmunological disease, especially MS, during the COVID-19 pandemic. However, these publications are heterogeneous in their level of detail and their findings. In this Review, we bring

together the existing information and develop an overview of the current consensus in the literature based on a ‘Delphi-like’ process17 (Box 1). We searched the available literature,

including publications of national and international societies and statements related to COVID-19 and neurology (Supplementary Table 1). We identified key questions addressed within these

publications and compiled the answers, indicating the level of consensus in the literature (Table 1). On this basis, we propose an algorithm that encompasses the factors that influence

decision-making for patients with neuroimmunological diseases in the COVID-19 era. BOX 1 DEVELOPMENT OF A DELPHI-LIKE PROCESS The homepages of national and international neurological

societies and patient organizations were screened for relevant recommendations, statements and agreements (Supplementary Table 1). The formats and content of the search results were

heterogeneous, ranging from short, general advice to very detailed disease-specific and, in some instances, product-specific recommendations. On the basis of the frequency with which topics

were addressed in the relevant literature — probably a reflection of the most urgent real-world needs — key questions were developed. Answers to these questions were drawn out of the

literature and an approval rate was calculated (see the figure). A summary of each question, the relevant answer/recommendation and level of consensus are presented in Table 1. THE

CHALLENGES OF COVID-19 In the modern medical era of randomized controlled trials, Cochrane analyses and, at the very least, detailed series, we are habituated to making decisions supported

by an evidence base. In the unusual situation of the COVID-19 pandemic, a potentially lethal novel construct has been superimposed on the existing complexities of our patients and their

management, and little specific evidence is available, making management decisions difficult and complex. In multiple series published to date, a total of several hundreds of patients

receiving immunosuppressive therapy for various diseases have recovered from COVID-19, thereby reassuring us that the infection is not necessarily catastrophic. Nevertheless, we must keep in

mind that very large numbers of patients must be studied before small effects can be excluded. For example, in a trial in which population X receives intervention Y that increases the

likelihood of outcome Z from 2% to 4%, a sample size of 1,141 per group is needed for an α of 0.05, a β of 0.2 and a power of 0.8. In this scenario, X represents patients with

neuroimmunological disease, Y represents the patients’ immunotherapy and Z is the likelihood of requiring intensive care or of death if the drug doubles the risk of catastrophic COVID-19. We

simply do not have that amount of data yet — until we do, we should work from first principles. In this scenario an explicit reiteration of the first principles of medicine is warranted in

balancing neuroimmune treatments with the risk of COVID-19 (Box 2), including pertinent factors that influence decision making in addition to the recommendations (Box 3; Table 1). The

following points and factors are critical for making decisions about the initiation, continuation and optimization of a patient’s neuroimmunological treatment: * First, do no harm —

inactivity that leads to permanent damage is a form of harm by neglect, but caution should be exercised if the situation allows (for example, if the patients have highly relevant

comorbidities, or if the burden of the underlying disease is low). * In general, immunosuppressive strategies produce a substantial benefit in relation to the disease being treated, but the

trade-off is often a modest increase in the risk of infection that is dependent on dose, duration and intensity of therapy. * Disease-related factors; for example, how serious and reversible

the patient’s disease is (for example, myasthenia is reversible, so undertreatment is more acceptable than for aquaporin 4-related neuromyelitis optica, which is not), the individual’s

clinical course and the current disease activity. * Patient-related factors; for example, the factors that influence the patient’s risk of serious or lethal COVID-19 (including age, sex,

comorbidities and perception of the situation, such as risk aversion). * The patient should be asked whether the disease they have or the one they could get matters more to them — the

doctor’s risk prioritization does not always match the patient’s. * Physician-related factors, such as experience, understanding of the disease and its treatment, treatments available and

monitoring capabilities. * Environmental factors; for example, the local likelihood of exposure to COVID-19 now and in the future, and local logistical issues, such as limitations in patient

support, infusion units or intensive care units. * Treatment-related factors, such as the extent to which treatment could affect the response to COVID-19, whether the treatment is

reversible and whether the dose can be reduced or deferred. BOX 2 FACTORS IN TREATMENT DECISIONS FOR NEUROIMMUNOLOGICAL DISEASES FIRST DIMENSION — GENERAL FACTORS * Patient-related factors

(including age, comorbidities, gender, personal perspective) * Disease-related factors (including diagnosis, prognosis, disease activity, reversibility) * Physician-related factors

(including experience, personal evaluation) * Treatment-associated factors (including immunosuppressive effects, cell depletion, reversibility) SECOND DIMENSION — PHASE OF TREATMENT * Acute

deterioration (corticosteroids, plasma exchange or intravenous immunoglobulin) * Treatment initiation (time point of start, mode of action) * Treatment continuation (dosage, possibility of

delaying, safety controls, cessation) * Treatment optimization (dosage, time point, mode of action, reversibility) THIRD DIMENSION — SARS-COV-2-ASSOCIATED FACTORS * No infection * Acute mild

infection * Acute severe infection * Recovered from infection or COVID-19 * Local infection rate * Local strategy for pandemic management COVID-19, coronavirus disease 2019; SARS-CoV-2,

severe acute respiratory syndrome coronavirus 2. BOX 3 SUMMARY OF THE MAIN RESULTS OF THE DELPHI-LIKE PROCESS ASPECTS FOR WHICH CONSENSUS IS STRONG * Patients without infection should not

stop ongoing immunotherapy. * In acute deterioration of neuroimmunological conditions, corticosteroids, intravenous immunoglobulin or plasma exchange can be administered. * In MS, glatiramer

acetate and IFNβ do not have a negative effect in relation to SARS-CoV-2 infection or the course of COVID-19. * In active MS, natalizumab is considered to be associated with a lower risk of

COVID-19 than other high-efficacy disease-modifying therapies. * In MS, sphingosine 1-phosphate receptor modulators and cell-depleting therapies increase the risk of SARS-CoV-2 infection. *

In MS, postponement of cell-depleting therapy can be considered in patients continuing on therapy. ASPECTS FOR WHICH CONSENSUS IS LOW * Whether teriflunomide and dimethyl fumarate increase

the risk of SARS-CoV-2 infection * Whether patients with mild or asymptomatic COVID-19 and those with a high risk of exposure to SARS-CoV-2 should stop immunotherapy during the COVID-19

pandemic * How disease-modifying therapies influence the course of severe COVID-19 in which overwhelming inflammation occurs COVID-19, coronavirus disease 2019; MS, multiple sclerosis;

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. TREATMENT OF ACUTE DETERIORATIONS Acute deteriorations or relapses of neuroimmunological diseases are usually treated with

corticosteroid pulse therapy, plasma exchange or intravenous immunoglobulin (IVIg) before initiation of or changes to long-term disease-modifying therapies (DMTs). In this section, we

discuss the use of these acute treatments in the context of COVID-19. CORTICOSTEROIDS Corticosteroids dampen cytokine responses and the recruitment of leukocytes, and suppress T cell

activation and differentiation18; for these reasons, they can increase the risk of infection as a result of short-term lymphopenia19. However, short-term therapy is not usually associated

with a marked increase in the risk of infection20. Chronic, high doses of steroids increase the rate of infections and are associated with other long-term adverse effects, such as

hypertension, osteoporosis and muscle weakness. The question of short-term corticosteroid therapy for acute relapses of neuroimmunological diseases in the COVID-19 era was not addressed in

all sources included in our Delphi-like analysis. Where this question was addressed, it related to MS, and we identified agreement that steroid pulse therapy should be administered for a

relapse with a relevant neurological deficit (Table 1, Question 2). For relapses with very minor symptoms (for example, dysaesthesias) or where no evidence indicates a benefit of treatment

(for example, repetitive pulses in progressive disease), corticosteroids should currently be avoided. Steroid tapering — which is sometimes done to prolong and consolidate the pulse effect

when pulse treatment has not produced substantial clinical improvement — is not recommended. Overall, short-term treatment with corticosteroids carries a low risk in relation to COVID-19 and

should be administered whenever necessary. Corticosteroid therapy has been used in the treatment of SARS-associated and Middle East respiratory syndrome (MERS)-associated pneumonia21, but

analysis has revealed no beneficial effects and, in some cases, harmful effects22. Evidence in relation to the use of corticosteroids for the treatment of COVID-19 is lacking and expert

opinions are contradictory — their use has been recommended for severe COVID-19 when the criteria for ARDS is fulfilled, but not for severe COVID-19 without ARDS23. Preliminary results of an

ongoing trial suggest a survival benefit of low dose dexamethasone in patients requiring at least oxygen treatment24. Ongoing clinical trials of corticosteroids in COVID-19 might provide

further insights. PLASMA EXCHANGE AND IVIG Plasma exchange or IVIg are used for acute therapy in many neuroimmunological diseases. In some diseases, such as chronic inflammatory

demyelinating polyneuropathy (CIDP) and myasthenia gravis, these therapies are used repeatedly with or without other DMTs. Plasma exchange usually requires the patient to attend hospital,

sometimes requires a central venous catheter with an associated risk of infection and reduces levels of the patient’s own immunoglobulins and complement factors for several weeks, which

could affect COVID-19 response and outcome. IVIg usually requires the patient to attend hospital or an infusion unit, although home administration is possible in some cases (depending also

on the regulatory environment). This treatment does not lower immunoglobulin levels and arguably has no compromising effects related to COVID-19. Discussion in the literature about the use

of plasma exchange and IVIg in the context of COVID-19 is limited, but overall, the risk of increasing the likelihood of infection or of severe disease is considered mild (Table 1, Question

14) and is likely to offset risks associated with the neuroimmunological disease. Use of plasma exchange or IVIg can reduce the need for concurrent corticosteroid use and accelerate recovery

and discharge from hospital, thereby reducing time in hospital and the related risks. Subcutaneous immunoglobulin can be used for CIDP and enables home administration that avoids the risk

of additional exposure to SARS-CoV-2. Beneficial effects of IVIg in COVID-19 are highly unlikely if standard, SARS-CoV-2-naive immunoglobulin preparations are used, although the

immunomodulatory effects and a consequent reduction in antibody-dependent hyperinflammation have the potential to be beneficial25,26. By contrast, some evidence suggests that IVIg might

increase the risk of thrombosis and substantial thrombotic complications, including multifocal stroke, in COVID-19 (ref.27). SERIOUS EXACERBATIONS In neuromyelitis optica spectrum disorders

(NMOSD), disability is generally relapse-related28 and early treatment of relapses improves outcomes29. Consequently, any risk of COVID-19 that is associated with corticosteroid pulse

therapy or plasma exchange is likely to be outweighed by the risk of long-term disability if not treated30. In myasthenia gravis, acute deterioration can require plasma exchange or IVIg31

and the first reports on myasthenic crisis as a complication of COVID-19 and on the course of COVID-19 in patients with myasthenia gravis are heterogeneous32,33. Dysphagia or respiratory

insufficiency can be life threatening, so IVIg or plasma exchange should be administered to patients with these symptoms34. Results are currently collected in various registries, with

increasing numbers providing a better repository for evaluations; these registries include: Coronavirus and MS reporting database (COVIMS), Lean European Open Survey on SARS-CoV-2 Infected

Patients (LEOSS) and COVID-19 Associated Risks and Effects in Myasthenia Gravis (CARE-MG). GENERAL CHRONIC IMMUNOSUPPRESSION Approved therapies are available for few neuroimmunological

diseases other than MS, so most are likely to be treated with general immunosuppressive medications, such as corticosteroids, azathioprine, mycophenolate, methotrexate and rituximab, with

adjunctive IVIg and plasma exchange. Exceptions include neurosarcoidosis, giant cell arteritis (GCA) and NMOSD, for which infliximab, tocilizumab and eculizumab, respectively, can be used.

In our opinion, these drugs should not substantially increase the risk of serious COVID-19, but data from registries are needed. Similarly, life-threatening conditions such as vasculitis and

autoimmune encephalitis can necessitate use of potent immunosuppression with cyclophosphamide, sometimes in combination with rituximab and other drugs. In these conditions, the severity and

potentially irreversible nature of the underlying diseases should take priority over probable increases in the risk of severe COVID-19. Long-term oral corticosteroid treatment for several

diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE) and GCA, clearly increases the risk of serious infections for which the patient requires hospitalization,

although data in most neuroimmunological diseases are less cohesive35,36,37. Higher doses, longer durations of therapy and older age are all additional risk factors for infection during

chronic treatment with corticosteroids20. In a study of patients with immune-mediated inflammatory diseases and COVID-19 in New York, USA, patients treated with chronic corticosteroids or

any small-molecule drug were more likely to require hospitalization for COVID-19 than patients who were not receiving corticosteroids (see the supplementary files in the original study)16,

even though the rate of hospitalization among patients with immune-mediated inflammatory disease was not higher than among the general population. In patients with newly diagnosed CIDP, IVIg

or plasma exchange are suggested in preference to corticosteroids38. The immunosuppressive drugs azathioprine, mycophenolate and methotrexate are clearly associated with occasional atypical

infections, such as progressive multifocal leukoencephalopathy (PML) and _Pneumocystis jirovecii_ pneumonia39. These infections can occur with these drugs when used alone but are more

common when the drugs are used as combined immunotherapies, such as after organ transplantation. These drugs are also associated with a small increase in the relative risk of all serious

infections in conditions such as SLE, but the risk is smaller than that with corticosteroids35. Whether azathioprine, mycophenolate and methotrexate should be stopped or their dose reduced

in the event of an active SARS-COV-2 infection or a high-risk exposure is disputed not only in the recommendations made so far (Table 1, Question 22) but even in the approved product

information documents40,41. Authors of opinion pieces have recommended that treatment decisions with these drugs in the context of COVID-19 are decided on the basis of the immunological

disease, latency of response to specific immune therapies, other patient risks and the strength of evidence that treatment will be beneficial26,38. Long-term corticosteroid treatment should

not be stopped abruptly and weaning should be done under physician supervision. In our opinion, minimizing the dosage of chronic corticosteroids is a reasonable way to reduce the risk of

infection without compromising immune competence. The available evidence supports steroid-sparing immunotherapy in general practice, meaning that the introduction of an immunosuppressive

agent such as mycophenolate should not be delayed if the alternative is continuation of high-dose corticosteroids, even in the context of COVID-19. If an individual who is receiving chronic

immunosuppressive therapy is diagnosed with COVID-19 or is considered to be at high risk of infection, a patient-focused individual decision should be made on whether to stop or reduce the

dosage of their immunosuppressive drug. This decision should take into account factors such as the severity of the two diseases, the patient’s age, the presence of risk factors for COVID-19,

the likelihood that short-term drug withdrawal will precipitate a relapse (negligible in myasthenia gravis but high for some drugs in MS), current and recent lymphocyte counts (which can

also be low in acute COVID-19), and the pharmacokinetics of the immunosuppressive drug. THERAPIES FOR MULTIPLE SCLEROSIS TREATMENT Most therapeutic approaches to MS involve long-term

immunotherapy. The general consensus among the available recommendations is that patients with MS should not stop their DMT during the COVID-19 pandemic without advice from their neurologist

(Table 1, Question 3). Discontinuation carries the risk of deterioration or relapse that could lead to an increase in disability and hospital admission. The risks of each therapy are

discussed in more detail below. IFNΒ1A AND IFNΒ1B IFNβ1a and IFNβ1b are recombinant cytokines that increase the cytotoxicity of natural killer cells, the phagocytic activity of macrophages

and the antibody-dependent cytotoxicity of leukocytes42. National and international neurological societies agree that treatment with IFNβ does not increase the risk for patients during the

COVID-19 pandemic. Interferons are not considered to be immunosuppressive and could therefore be a safe option for initiation of DMT in patients with mild-to-moderate MS disease activity

during the COVID-19 pandemic (Table 1, Questions 4 and 15). In general, interferons impair viral replication43 and previous evidence suggests that IFNβ is mildly effective in animal models

of MERS when used in combination with lopinavir and ritonavir44, so the potential for IFNβ in the treatment of COVID-19 could be worth investigating. GLATIRAMER ACETATE Glatiramer acetate is

a synthetic amino acid copolymer that contains the key amino acids from myelin basic protein45. Its mechanism of action includes attenuation and rebalancing of T cell responses (a shift

towards the type 2 T helper cell phenotype), cytokine secretion and B cell function46,47. Glatiramer acetate is not immunosuppressive and is not associated with increased risk of infection.

The consensus in the literature is that treatment with glatiramer acetate should not increase the risk of severe COVID-19 in patients with MS (Table 1, Question 4 and 10), so is another good

option for initiation of DMT in patients with mild-to-moderate disease during the COVID-19 pandemic. TERIFLUNOMIDE Teriflunomide selectively and reversibly inhibits dihydro-orotate

dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway48. By influencing mitochondrial metabolism, teriflunomide causes selective immune suppression by

inhibiting growth and division of rapidly dividing cells, including activated T cells and B cells49. Owing to the mechanism of action, mild decreases in lymphocyte counts have been observed

during teriflunomide treatment but rates of grade 2 lymphopenia and serious infections are low, even after long-term therapy50. Expert opinions on whether teriflunomide can increase the

risk of severe COVID-19 are heterogeneous, probably owing to the known risk of lymphopenia. Decreases in lymphocyte counts occur within 6 months of teriflunomide initiation but are mostly

mild when the dosing scheme approved for MS is used. On this basis, most, but not all, recommendations suggest that teriflunomide should not increase the risk of severe COVID-19 (Table 1,

Questions 20 and 10). Importantly, teriflunomide has a long half-life (~16 days in the plasma) and elimination takes time because the drug persists in the enterohepatic cycle, so health-care

providers and patients should keep these factors in mind if stopping teriflunomide is considered upon SARS-CoV-2 infection. Teriflunomide can inhibit replication of Epstein–Barr virus,

cytomegalovirus (CMV), herpes simplex virus (HSV) 1 and 2, and poliovirus51,52,53,54. These observations suggest that DHODH inhibition could be a therapeutic strategy for COVID-19 (ref.55).

DIMETHYL FUMARATE Dimethyl fumarate reduces the absolute lymphocyte count, although the mechanisms of action are not fully understood. Memory CD8+ T cells are most profoundly affected but

levels of pro-inflammatory CD4+ T cell subsets, and B cell subsets are also decreased, creating a bias towards an anti-inflammatory state56,57. Lymphocytes normally decrease within the first

6 months of treatment but moderate or severe prolonged lymphopenia has been observed in 2–9% of patients58. Lymphopenia is considered to be a risk factor for dimethyl fumarate-associated

PML (caused by JC virus)59, so dimethyl fumarate therapy must be stopped if lymphocyte counts are ≤500 cells/µl. In addition, in rare cases, low lymphocyte counts in patients receiving

dimethyl fumarate have been associated with HSV encephalitis60. Though the risk of lymphopenia after initiation of dimethyl fumarate treatment is a potential risk for COVID-19, most national

and international recommendations suggest that dimethyl fumarate treatment should not increase the risk of severe COVID-19 (Table 1, Question 21). NATALIZUMAB Natalizumab was the first

monoclonal antibody to be approved for the treatment of relapsing–remitting MS. The target of the antibody is integrin α4, which mediates immune cell adhesion and migration via interactions

with vascular cell adhesion molecule 1 and fibronectin61. In general, infection rates among patients receiving natalizumab are low10,62 besides a slight increase in the risk of HSV

infection. The initial trial of natalizumab did suggest an increased risk of pneumonia63 but this observation does not seem to have been replicated in real-world series62,64. The most

concerning adverse effect of natalizumab is a low risk of PML, which is influenced by the JC virus antibody index, the duration of therapy and prior exposure to immune-suppressive agents65.

Most, but not all, international and national recommendations suggest that natalizumab therapy should not increase the risk of severe COVID-19 (Table 1, Question 18). On this basis

natalizumab is a candidate for patients who need to start on a high-efficacy therapy during the COVID-19 pandemic, and natalizumab should be continued for all patients who are already

receiving the therapy (Table 1, Question 11). Indeed, cessation or interruption of natalizumab treatment carries a considerable risk of MS disease exacerbation or rebound activity in

patients with highly active MS66, the consequences of which are likely to outweigh the risk of COVID-19. Natalizumab has been suggested as a bridging therapy (a drug that can be used for an

immediate effect owing to its fast onset of activity and high efficacy but that is not necessarily considered a long-term option) during the COVID-19 pandemic, and the first reports of

SARS-CoV-2 infection in patients receiving natalizumab therapy have suggested no increase in risk67,68. Furthermore, extended dosing intervals can be used to limit infusions and,

consequently, limit the exposure of patients to hospitals69. Extended dosing intervals could also decrease the risk of COVID-19-related encephalitis by allowing some CNS immunosurveillance.

The CNS is not thought to be the primary site or a major site of SARS-CoV-2 infection, although CNS manifestations, including dizziness, headache, impaired consciousness, acute

cerebrovascular disease, ataxia and seizures, have been reported in patients with severe COVID-19 (refs70,71). Some evidence indicates that integrins have a role in host cell entry by

SARS-CoV-2 (refs72,73), suggesting that natalizumab could even have beneficial effects in cases where CNS infection does occur. FINGOLIMOD, SIPONIMOD AND OZANIMOD Fingolimod, siponimod and

ozanimod are sphingosine 1-phosphate receptor (S1PR) modulators that result in downregulation of S1PR, which prevents egress of lymphocytes from lymphoid tissue. All three drugs are known to

decrease blood lymphocyte counts, but importantly this effect does not reflect the death or loss of lymphocytes, especially not those in the bone marrow — it means that these cells might

still be recruitable and functional but entrapped. Fingolimod treatment has been associated with increased rates of varicella zoster virus (VZV) activation or reactivation74, and other viral

infections, such as PML, have been described in rare cases75,76,77. Siponimod and ozanimod are more selective for the S1PR than is fingolimod but they have similar effects on lymphocyte

counts and have been associated with similar infections78,79,80,81. The effects of these drugs are reversible and their half-lives are short but the effects of S1PR modulators on lymphocyte

count can persist for several weeks to months82. National and international experts foresee a mild-to-moderate increase in the risk of SARS-CoV-2 infection among patients who are treated

with fingolimod, siponimod or ozanimod (Table 1, Question 6). However, cessation or interruption of therapy with S1PR modulators can trigger a severe disease rebound with a high risk of

relapse, so patients who are already receiving fingolimod, siponimod or ozanimod should continue their therapy. For patients who need to switch therapy or start a new therapy, other

treatment options should be considered. Fingolimod also has the potential to be of benefit in COVID-19 on the basis that secondary invasion of alveoli by lymphocytes is thought to be harmful

in this disease83 and could be prevented by fingolimod. A clinical trial of this approach is currently recruiting patients84. The effect of S1PR modulation on the outcome of the second

phase of COVID-19 is the question under investigation. IMMUNE-DEPLETING AND REPOPULATING THERAPIES B CELL-DEPLETING THERAPIES Ocrelizumab, ofatumumab and rituximab are monoclonal CD20

antibodies that deplete CD20+ B cells and small populations of CD20+ T cells. Inebilizumab is a CD19 antibody that depletes B cells expressing CD19. Ocrelizumab is approved for the treatment

of relapsing–remitting and primary progressive MS, ofatumumab is expected to be approved soon, and rituximab is used off-label in several neuroimmunological diseases, including NMOSD,

myasthenia gravis, immune neuropathies and MS. Inebilizumab has recently been approved for the treatment of NMOSD. B cell depletion reduces humoral and cellular immunity. Immunoglobulin

levels can decrease as the duration of treatment increases, but broad cytopenia rarely occurs85. In phase III studies, ocrelizumab treatment was associated with a slight increase in the risk

of infections (generally mild to moderate and none unusual, such as opportunistic infections)86. Ofatumumab was not associated with an increased risk of infections in the phase II study

programme, but longer term observations are currently lacking87. Similarly, although serious infections were not associated with rituximab treatment in phase III studies, real-world use has

revealed some risks — long-term use of rituximab is associated with an increased risk of severe infection, and rituximab and ocrelizumab have been associated with reactivation of hepatitis B

and C viruses10,88,89. In addition, PML has been reported in several patients receiving rituximab for various diseases and PML was associated with ocrelizumab in one patient (as of April

2020), although multiple influencing factors have to be considered in this case90. The first reports on the impact of B cell-depleting therapy on COVID-19 have been published14,67,91. In 232

patients with MS and suspected or proven COVID-19, the severity of COVID-19 was classified as mild (no or mild pneumonia) in 222 (96%), severe (shortness of breath, respiratory rate ≥30

breaths/min, blood oxygen saturation ≤93%, PaO2:FiO2 <300 mmHg/%, and an increase in lung infiltrates of >50% within 24–48 h) in 4 (2%) and critical (respiratory failure, septic shock

and multiple organ dysfunction or failure) in 6 (3%). Of the 6 patients with critical illness, 1 recovered and 5 died. Of the 28 patients receiving a B cell-depleting therapy, 3 (10%)

developed a severe or critical disease course14. In addition, 100 patients with confirmed or suspected SARS-CoV-2 infection have been studied within pharmacovigilance reporting conditions by

Roche92; 26 of these patients were admitted to hospital and 13 remained in hospital at the time of writing. Five patients were classified as critically ill and needed intensive care. Among

the limited data currently available, outcomes of COVID-19 during B cell-depleting therapy range from mild disease to death but — although the number of patients is low — rates of critical

illness and death do not seem to be increased dramatically relative to the wider population93. This observation could be explained by the fact that, although B cell-depleting therapies are

thought to increase susceptibility to acute respiratory infections94, antibody-mediated inflammation and a cytokine storm are thought to mediate severe COVID-19 outcomes, so B cell depletion

might not necessarily be associated with more severe disease95. International and national recommendations suggest that B cell-depleting therapy is likely to increase the risk of severe

COVID-19 (Table 1, Question 12) but that the risk level depends on the duration of therapy and the time since the last dose because immunoglobulin deficiency occurs more frequently after 2–3

years of treatment and circulating drug levels are likely to decline during the treatment interval. Depletion of B cells in the peripheral circulation lasts for at least 5–6 months after

the last dose and full recovery of B cells after a course of treatment with ocrelizumab takes up to 72 weeks. On the basis of current knowledge, postponement of the next dose of B

cell-depleting therapy is advisable for some patients with MS (Table 1, Question 13), especially those with additional risk factors and progressive disease, or unsafe infusion environments.

However, the pandemic is ongoing and therapy cannot be delayed indefinitely — waiting until disease activity returns is not advisable. Levels of peripheral B cells and the recovery of these

levels is one possible indicator that can be monitored to assess the urgency of the next infusion. In principle, CD20 antibody therapy could be initiated during the COVID-19 pandemic in

suitable patients (for example, those with high disease activity, no comorbidities and a younger age), but the risk to benefit ratio should be taken into account, especially in older

patients and those with comorbidities. B cell depletion in older patients with progressive MS and in patients with mild MS and no activity should be viewed with particular caution because

these patients are least likely to benefit from anti-CD20 therapies. Another issue that must be considered with B cell-depleting therapy is the nature of the immune response to either a

primary infection with SARS-CoV-2 or a primary vaccination, should a vaccine be developed. Rituximab treatment is known to inhibit the primary antibody response to a neoantigen to a greater

extent than the secondary response to a known antigen96, whereas in one patient undergoing ocrelizumab therapy, B cell and T cell responses to primary VZV infection were not impaired97. In

68 patients receiving ocrelizumab, pre-existing humoral immunity was not affected by B cell depletion and even if the humoral response to a neoantigen or vaccine was attenuated, patients

were able to mount humoral responses98. However, the primary immune response and the associated class shifting of immunoglobulins to IgG and IgA might be affected more than the response to a

secondary immunization (contact with the antigen for a second time)98, which could result in a cohort of patients who have little immunity to SARS-CoV-2 infection despite vaccination.

ALEMTUZUMAB Alemtuzumab is a monoclonal antibody to CD52 that leads to depletion of T cells and B cells99,100. Treatment impairs cellular and humoral immunity; the extent of impairment

depends on the time since the last dose and the number of treatment cycles101,102. Alemtuzumab changes the immune system from a pro-inflammatory state to a regulatory state, and the effect

is long-lasting; low lymphocyte counts — specifically low CD4+ T cell counts — can last for months and neutropenia occurs in some patients103. In the first few months after dosing, the risk

of HSV re-activation is increased104. Frequent CMV infection and VZV activation have also been reported and immunity against intracellular bacteria (for example, listeria) seems to be

compromised during and shortly after infusion periods104. Analysis of long-term data has shown that the incidence of infections decreases substantially 2 years after the last dose of

alemtuzumab and that most infections after this time were mild104. Secondary autoimmunity after CD52 depletion can occur up to 4 years after the last infusion cycle but long-term extension

studies do not indicate altered immune competence or high infection rates. The consensus among national and international recommendations is that patients receiving alemtuzumab have an

increased risk of severe COVID-19 (moderate to high confidence) owing to the profound effects of the drug on the immune system (Table 1, Question 8). The absolute risk of infection clearly

depends on the time since the last dose — the highest risk is in the weeks that follow immune depletion102. Therefore, alemtuzumab should only be used with caution in the COVID-19 pandemic;

careful evaluation of the risks and benefits in a particular patient is needed. CLADRIBINE TABLETS Cladribine is a synthetic purine nucleoside analogue that inhibits DNA synthesis

selectively, mainly in circulating T cells and B cells. This action leads to an extended decrease in lymphocyte counts (depletion) with minimal effect on innate immunity, followed by gradual

repopulation of the lymphocytes105,106. Depletion of CD19+ B cells occurs earlier and to a greater extent than that of CD4+ and CD8+ T cells107,108. However, depletion is less profound than

that seen with alemtuzumab107,109,110,111, which might account for the fact that the rates and severity of infection are generally lower with cladribine and usually occur within the first

few months after dosing. Cladribine might affect immune competence against intracellular bacteria (for example, _Mycobacterium tuberculosis_)112. No data are yet available on the impact of

cladribine tablets on COVID-19 but consensus among national and international societies is that cladribine can increase the risk of severe COVID-19 (moderate to high confidence), depending

on the time since the last dose — a shorter time since the last dose is associated with a higher risk (Table 1, Question 9). Given that cladribine has long-lasting effects and the interval

between treatment cycles is 1 year, a second cycle of treatment can be delayed if the patient is stable, but this option depends on the local infection rate (Table 1, Question 12) — if the

local infection rate is high, delay should be considered. Cladribine tablets can be initiated in suitable patients (for example, patients with high disease activity, younger age and no

comorbidities) during the COVID-19 pandemic, but the risk-to-benefit ratio should be considered, especially for older patients and those with comorbidities. HAEMATOPOIETIC STEM CELL THERAPY

Haematopoietic stem cell therapy (HSCT) is an off-label treatment used for MS113 and, in rare cases, other neuroimmunological conditions100,114. Preparation for the transplantation involves

profound immunosuppression or immunoablation, which carries a high risk of infection. The consensus is that patients who underwent HSCT within the past 6–12 months are at risk of severe

COVID-19 (Table 1, Question 16). ASYMPTOMATIC, MILD AND SEVERE COVID-19 ASYMPTOMATIC OR MILD COVID-19 Worldwide SARS-CoV-2 infection rates are increasing, and evidence indicates that a high

number of people who are infected have no symptoms115. For example, in a study conducted in Iceland, 43% of people who tested positive for SARS-CoV-2 exhibited no symptoms116. On this basis,

there are undoubtedly patients who are receiving immunotherapy and are unknowingly infected with SARS-CoV-2. No consensus exists about how to manage ongoing immunotherapy in patients who

are at high risk of exposure to SARS-CoV-2, have asymptomatic infection or who develop mild symptoms of COVID-19 (Table 1, Question 22). In making the decision to stop or continue

immunotherapy, health-care providers should consider the duration of the therapeutic effects, the risk of relapse, the postulated duration of COVID-19 and patient-related factors (Box 2). In

the literature, general agreement exists that local recommendations for disease control, such as social distancing, should be followed by individuals receiving immunotherapy (Table 1,

Question 1). However, there is no clarity about regular laboratory tests for safety monitoring, which might require the patient to travel to a collection facility or hospital, thereby

increasing the risk of exposure to SARS-CoV-2. The risk of infection in local infusion centres and hospitals depends strongly on local infection rates and the precautions taken; in high-risk

areas, postponing treatment should be considered whenever possible. If collection and infusion are possible at home, this approach would be preferable. The risks of complying with

monitoring procedures versus those of failing to do so depend heavily on local circumstances. Another important consideration is the effect of immunotherapy on SARS-CoV-2 viral shedding. The

time for which viral shedding continues can vary widely, and a high viral load can persist in otherwise healthy people without comorbidities for >2 months117, and evidence from previous

studies suggests that immunosuppression can prolong viral shedding further. For example, viral shedding of MERS-CoV was prolonged in immunocompromised macaques even though the disease course

was not more severe in these animals than in immunocompetent animals118. In humans, prolonged viral shedding of various respiratory viruses has been described in patients receiving

immunotherapy after transplantation119. The possibility of prolonged shedding of SARS-CoV-2 could, therefore, influence recommended isolation periods and re-testing strategies during

convalescence for people receiving immunotherapy. Although no vaccination against SARS-CoV-2 is yet available, viral co-infection has been found in 13.1% of individuals who are positive for

SARS-CoV-2 (ref.120) and bacterial and fungal co-infections have been observed in at least 8%121. Therefore, vaccinations against influenza and/or pneumococcus might be helpful in patients

receiving immunotherapy to reduce the risk, but few recommendations have been made on this topic (Table 1, Question 7). An important question for future management is whether and how the

efficacy of a SARS-CoV-2 vaccine might be influenced by immunotherapy. Responses to vaccinations can be altered by immunotherapy, depending on the particular mechanism of action of the drug.

For example, response rates to seasonal influenza vaccination were low among patients with MS who were being treated with natalizumab or fingolimod122,123. In patients who are receiving

immune-depleting therapies, vaccination response rates are attenuated but some extent of immune response is seen even after B cell depletion98. The possibility of altered responses to

certain types of vaccination with some immunotherapies is already included in the ‘checklist’ for de-risking immunotherapy124. Ideally, vaccinations are performed before initiation of an

immune therapy, particularly high-efficacy immunotherapy. In the case of immune-depleting, pulsed therapies, vaccinations should be administered during phases of immune system recovery (≥6

months after a course of immune-depleting therapy with alemtuzumab; ≥2–4 months after a course of CD20-depleting therapy). This approach holds true for seasonal vaccines (for example

influenza). To date, the potential for altered vaccination responses has not been a major factor in choosing immunotherapies, as the problem can be mitigated by vaccinating before therapy

initiation or some immunotherapies still allow sufficient immune responses. Whether the same will hold true in the context of a SARS-CoV-2 vaccine remains to be determined when the

properties of any vaccine are known. SEVERE COVID-19 Neuroimmunological disease alone is probably not a risk factor for symptomatic infection with SARS-CoV-2 or for severe COVID-19 (Table 1,

Question 19). However, some immunotherapies seem to increase susceptibility to SARS-CoV-2 infection, so stopping therapy might seem reasonable based on the assumption that immunotherapy and

associated dampening of primary infection control (the innate immune system) could negatively impact the disease course. However, the influence of immunotherapy on the risk of SARS-CoV-2

infection might differ from that on the risk of a severe disease course. Innate immunity, natural killer cells and type I interferons are considered to be the first line of defence in viral

infection125. Adaptive immune responses to viral infections consist of humoral immunity involving antibodies and cytotoxic T cells. In severe COVID-19, however, the host response to

SARS-CoV-2 infection leads to fulminant inflammation that includes peripheral lymphopenia, sequestration of mononuclear cells in the infected tissues and reduction of CD8+ lymphocytes in the

blood126. In addition, upregulation of cytokines can lead to a cytokine storm127. In this second phase of severe COVID-19, some immunotherapies might have the potential to attenuate or even

prevent critical illness93,128, although this potential is largely theoretical at present and there is a long history of similar hypotheses that have rarely come to fruition. Low levels of

immunoglobulins are associated with B cell-depleting therapies and anti-CD52 therapy101. These low levels are unlikely to reduce primary responses to SARS-CoV-2 infection because these

responses involve CD8+ T cells and innate immune components. However, low levels of immunoglobulins could attenuate antibody-dependent cellular cytotoxicity, which is thought to contribute

to severe secondary hyperinflammation in COVID-19. This hypothesis has been proposed as an explanation as to why higher IgG levels are a risk factor for severe COVID-19 (ref.129). Individual

cytokines can be blocked, with the potential to attenuate the cytokine storm in COVID-19. IL-6 receptor antagonists (for example, tocilizumab), IL-1 blockers (for example, anakinra) and

Janus kinase (JAK) inhibitors (for example, baricitinib) are either being tested in clinical trials or have been proposed as therapeutic agents to target the excessive inflammation130,131.

Another target of therapies that are currently being trialled in COVID-19 is the complement system, activation of which might contribute to the secondary inflammatory response and

microvascular injury in patients with severe COVID-19 (ref.132). Reports of patients with COVID-19 being successfully treated with the compstatin-based complement inhibitor AMY-101 (ref.133)

and the anti-C5 therapy eculizumab have been published134. Early reports indicate that patients who are receiving immunotherapy after solid organ transplantation or for inflammatory bowel

disease do not have an increased risk of developing severe COVID-19 (refs135,136). On this basis, one possibility is that an increased risk of infection due to the immunotherapy is

outweighed by the anti-inflammatory effects of immunosuppression137. FACTORS TO CONSIDER IN DECISION MAKING The COVID-19 pandemic presents a new situation that challenges the field of

neuroimmunology. Owing to the rapid and novel evolution of the pandemic, decision-making processes remain largely non-evidence-based but are assisted by several national and international

society recommendations and opinion papers. Nevertheless, several relevant questions are not addressed and conflicting advice has been given about some aspects. The decision-making process

involves several dimensions and key contributing factors (Box 2). The complexities of the existing dimensions — dimensions one and two — are now complicated further by a third dimension,

which comprises SARS-Cov-2-related factors. Importantly, however, the COVID-19 pandemic has not led to a complete modification of how the initiation, continuation and optimization of

neurological immunotherapy should be managed. The novelty comes from what is not known about SARS-CoV-2 and from the different conditions that individual health-care systems face.

Nevertheless, it is unlikely that all patients receiving immunotherapy have a substantially increased risk of severe COVID-19, except for patients who are receiving potent immunosuppression

or who have confounding factors that further increase the risk of poor outcomes (such as old age, smoking or cardiovascular comorbidities)138. CONCLUSIONS During the COVID-19 pandemic,

initiation, continuation and optimization of treatment for neuroimmunological disease that requires disease-modifying immunotherapy should be based on the features of the underlying disease,

the characteristics of the patient, and caregiver considerations. In general, delaying treatment could risk a poor long-term prognosis and persistent disability, especially with very active

neuroimmunological disease or when the pathology is irreversible. Some questions about the use of disease-modifying immunotherapies in the context of the COVID-19 pandemic cannot currently

be answered on the basis of good evidence or even on the basis of consensus, although a strong consensus exists for some questions (Box 3). Collection of data in registries of all patients

with neuroimmunological disease and SARS-CoV-2 infection should be an important goal to gain additional information on outcomes and inform future management approaches. In addition, most of

the available information in this field — demonstrated by the sources included in our Delphi-like analysis — relates to MS, leaving many unanswered questions and/or limited consensus in

relation to other areas of neuroimmunology. These questions include whether people with neuroimmunological disease are at increased risk of severe COVID-19; which immunotherapies and which

comorbidities and confounding factors increase the risk of severe COVID-19; and which therapies should be discontinued in those with confirmed SARS-CoV-2 infection if possible. Until we know

the answers to these questions, the practice of neuroimmunology during the COVID-19 pandemic requires a thorough understanding of first principles and a careful balancing of the risks that

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E. East for native language editing. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Neurology with Institute of Translational Neurology, University of Muenster, Muenster,

Germany Catharina Korsukewitz & Heinz Wiendl * Department of Neurology, Concord Hospital and The Brain and Mind Centre, University of Sydney, Sydney, Australia Stephen W. Reddel * Center

for Neuroinflammation and Neurotherapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA Amit Bar-Or Authors * Catharina

Korsukewitz View author publications You can also search for this author inPubMed Google Scholar * Stephen W. Reddel View author publications You can also search for this author inPubMed 

Google Scholar * Amit Bar-Or View author publications You can also search for this author inPubMed Google Scholar * Heinz Wiendl View author publications You can also search for this author

inPubMed Google Scholar CONTRIBUTIONS C.K. and H.W. researched data for the article and wrote the article. All authors made substantial contributions to discussion of the content and

reviewed and edited the manuscript before submission. CORRESPONDING AUTHOR Correspondence to Heinz Wiendl. ETHICS DECLARATIONS COMPETING INTERESTS C.K. has received travel support and/or

speaking honoraria from Biogen, Sanofi Genzyme, Roche, Merck and Teva within the past years. S.R. has received funds within the past 5 years for (but not limited to) travel support,

honoraria, trial payments, research and clinical support to the neurology department of which he is a member from several bodies and charities such as Lambert Initiative, Beeren Foundation

and anonymous donors, and from Baxter, Bayer Schering, Biogen Idec, CSL, Sanofi Genzyme, Grifols, Octapharma, Merck, Novartis, Roche, Sanofi Aventis Genzyme, Servier and Teva. S.R. also

declares the following competing interests: co-founder and shareholder of Medical Safety Systems trading as RxMx (including grant and/or contracts with Genzyme, Novartis, Roche and Janssen);

receives payment for contributions to the National IVIg Governance Advisory Council & Specialist Working Group Australia (Neurology) and the Australian Medical Services Advisory

Committee ad hoc sub-committee on IVIg; unpaid member of the Australian Technical Advisory Group on Immunization Varicella Zoster working party; receives a public salary as a staff

specialist neurologist from Concord Hospital Sydney Local Health District; receives private billings from patients and Medicare Australia reimbursement as a private practice neurologist; and

is an unpaid medical adviser to various patient and advocacy groups. A.B.-O. serves on scientific advisory boards for Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Janssen/Actelion,

Merck/EMD Serono, Novartis, Roche/Genentech and Sanofi Genzyme, and has sponsored research agreements with Biogen Idec, Novartis and Roche/Genentech. H.W. receives honoraria for acting as a

member of scientific advisory boards for Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG and Sanofi-Aventis, as well as speaker honoraria and travel

support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Genzyme, Teva and WebMD Global. H.W. is also a paid

consultant for Abbvie, Actelion, Biogen, IGES, Johnson & Johnson, Merck, Novartis, Roche and Sanofi. His research is funded by the German Ministry for Education and Research (BMBF),

Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, the European Union, Hertie Foundation, NRW Ministry of Education and Research,

Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG and Sanofi Genzyme. ADDITIONAL INFORMATION PEER

REVIEW INFORMATION _Nature Reviews Neurology_ thanks G. Giovannoni, S. Pittock, V.W. Yong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Korsukewitz, C., Reddel, S.W., Bar-Or, A. _et al._ Neurological immunotherapy in the era of COVID-19 — looking for

consensus in the literature. _Nat Rev Neurol_ 16, 493–505 (2020). https://doi.org/10.1038/s41582-020-0385-8 Download citation * Accepted: 17 June 2020 * Published: 08 July 2020 * Issue Date:

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