Journal of Neurology https://doi.org/10.1007/s00415-018-8751-9

REVIEW

Myasthenia gravis and infectious disease Nils Erik Gilhus1,2   · Fredrik Romi2 · Yu Hong1 · Geir Olve Skeie2 Received: 29 December 2017 / Revised: 11 January 2018 / Accepted: 11 January 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract Background and purpose  Myasthenia gravis (MG) is an autoimmune disease with muscular weakness as the only symptom, and often with immunosuppressive treatment. All these aspects could have relevance for the risk of infections as well as their prophylactic and curative treatment. Methods  This is a review article, where Web of Science has been searched for relevant key words and key word combinations. Full papers were selected first by title and then by abstract. Results and conclusions  MG can be triggered and worsened by infections. No virus or other pathogen has been proven to have a specific link to MG. Treatment with immunosuppressive drugs and thymectomy implies a slightly increased risk for infections. Infections should be actively treated, but a few antibiotics are avoided due to potential interference with neuromuscular transmission. Hospitalization and intensive care may be necessary during infections because of MG deterioration and risk of insufficient respiration. Vaccinations are generally recommended in MG, but live microorganisms should be avoided if possible in immunosuppressed patients. Keywords  Myasthenia gravis · Infection · Vaccination · Antibiotics · Immunosuppression · Thymus · Autoimmunity

Introduction Myasthenia gravis (MG) is a prototype autoimmune disease where the muscle weakness is induced by autoantibodies binding to the postsynaptic region and impairing the function of acetylcholine receptors (AChR) [26]. Specific MG subgroups defined from autoantibody pattern, thymus pathology, age at debut, and localization of muscle weakness differ in pathogenesis and therapeutic response [24]. However, they have in common muscle weakness, an autoimmune disease mechanism, and immunosuppressive treatment. These three aspects may all predispose for infectious disorders, and also influence prophylaxis and treatment for infections. Microorganisms have been suggested as candidates for both induction and precipitation of autoimmune disease [5, 31], and infections represent a common cause of autoimmune disease exacerbation. MG patients should, * Nils Erik Gilhus [email protected] 1

Department of Clinical Medicine, University of Bergen, Bergen, Norway



Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway

2



therefore, try to avoid infections, and they need optimal treatment when being infected. Respiratory insufficiency represents a particular threat in MG [24]. Our aim in this review is to survey the complex interaction between MG as an autoimmune neuromuscular disease and infections. We will give our recommendations for antimicrobial treatment, vaccination and supportive therapy in MG. Conclusions are based on evidence from human studies. Most recommendations do not rely on prospective and controlled studies as these rarely exist, but rather on studies of MG patient cohorts and single-patient observations. Relevant guidelines and consensus papers have been scrutinized, but are similarly hampered by the lack of wellcontrolled studies. Web of Science has been searched for all relevant key words and key word combinations up till November 2017. For MG and infection we obtained 413 hits, for MG and antibiotics 39, and for MG and vaccination 48. When replacing MG with autoimmune disease, we obtained 14,428—692 hits. Infection was also searched for combined with thymus, thymectomy and immunosuppressive drugs, hits varying between 3348 and 43. Several more detailed searches were in addition undertaken. Full papers were selected first from title and then from abstract. Only

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papers in English language were included, and publications in high-impact journals were preferred.

Infection as a cause of MG In 10% of cases, MG is a paraneoplastic disease caused by a thymoma [24, 44, 60]. For the remaining 90%, including AChR-, MuSK-, and LRP4-associated MG, the cause of MG is not known. A genetic MG predisposition has been well documented, and with the strongest association to HLA genes [7]. Specific HLA-associations vary for MG subgroups [43]. However, genetic factors account for less than fifty per cent of the total disease risk [7]. Some risk genes either increase or reduce the chance for developing autoimmune disorders in general, whereas other genes are specific for MG and MG subgroups [59]. Infections have been suggested as the major external causal factor for nearly all autoimmune disorders. Microbes are thought to precipitate an unwanted immunological reaction against self-antigens. The simplest explanation would be similarity between a virus antigen and a self-antigen, leading to cross-reactivity for T-cells, B-cells and antibodies through molecular mimicry [5]: Such a post-infectious autoimmune disease mechanism is well established for acute inflammatory demyelinating polyneuropathy [79], also defining specific culprits such as Campylobacter jejuni, and for focal and disseminated autoimmune encephalitis [10]. No such link between a specific preceding infection and MG has been documented. However, local inflammation caused by an infection increases the expression of molecules involved in antigen recognition [5, 31], this being a potential mechanism for induction of autoimmune disease. Furthermore, infections will induce a polyclonal activation of immunoactive cells that can include autoreactive B- and T-lymphocytes. Such mechanisms are hypothesized but not proven for MG etiology. Some data indicate that infections can protect against autoimmune disease. Epidemiological studies show that both incidence and prevalence of most autoimmune disorders have increased during the last decades [2, 31]. This has occurred in parallel with a reduction of all types of infections, the reduction being especially pronounced during childhood [31]. There is a north–south gradient for many autoimmune disorders, and this gradient correlates with the occurrence of major infections as well as socio-economic conditions that influence infection risk in childhood. The hypothesis that less infections and a better hygiene increase the risk for autoimmune disorders, as indicated by epidemiological data, is difficult to prove. The gut microbiome is thought to influence the risk for

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several disorders [37], but no data exist for MG risk and the load and composition of gut bacteria. Autoreactive immune responses can influence immune reactivity against microbes [50]. Increased, decreased and divert reactions have all been described in animal models, and through various mechanisms. The same genetic factors can influence reactivity against self and microbe antigens [50]. When patients are retrospectively asked for triggering events preceding their MG, they will frequently list infections [9]. However, they will even more often point to emotional or physical stress, and also factors such as trauma, surgery and pregnancy are listed. The debut of MG in connection with a specific infection has been reported in several case series, and sometimes also with antibodies against the neuromuscular junction appearing simultaneously. Hepatitis B and C, herpes simplex, and HIV are examples of virus infections that can co-exist with MG [19, 30, 46, 70]. Recently, MG debut has been described in patients with active West Nile virus infection [39] and Zika virus infection [48], these two viruses being related, and also with dengue virus infection [40]. Underlying predisposing factors are necessary to develop MG during such infections. Some of the reported patients had thymoma as a co-factor, and others had family members with autoimmune disorders. Molecular mimicry, cryptic antigens, epitope spreading, bystander activation, and polyclonal activation have all been suggested as mechanisms for the induction of MG by viral agents [39]. Epstein–Barr virus has for many years been a major candidate for induction of autoimmune disorders. This herpes-type virus has the capacity to promote abnormal activation and survival of B-lymphocytes [12, 51]. In MG, a triggering event has been hypothesized inside thymus, via a direct influence of local viruses on T-lymphocyte receptors. This hypothesis got a boost with the report of Epstein–Barr virus detection in both hyperplastic and involuted thymus from MG patients, but not in control thymus [13]. However, an infection of Epstein–Barr virus in thymus with detection of virus particles could not be confirmed in independent control studies using the same methodology [32, 34, 47]. Still virus infection as the initial event in MG pathogenesis represents a putative model, perhaps with a local infection in thymus. Previous infection as a cause of MG is supported by the pattern of gene expression in AChR-MG patients as examined by the molecular signature of RNA transcripts in peripheral blood [6], and also by the intrathymic signaling processes in MG [12]. Experimental Epstein–Barr virus infection has an effect on human B-lymphocytes that is thought to promote autoimmunity in general [49].

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Effect of infection on MG Infection is commonly reported by MG patients as an event that can deteriorate their MG. One-third of Australian patients claimed that infections lead to MG exacerbations, and nearly one half of them reported seasonal variation in MG severity [9]. Seasonal variation in MG was confirmed in a large US cohort, with a peak in late winter and late summer [45]. Infection was regarded as the most probable explanation, and particularly respiratory and urinary tract infections. In a population-based study from Spain, they found that infection was the most common factor to precipitate a life-threatening event in MG with respiratory impairment and dysphagia [57], infection being identified as a cause in nearly one-third of all episodes. Similarly, in a Chinese cohort with MG onset in childhood, infection was the second most common event triggering a MG relapse, only discontinuation of MG treatment being more common [27]. Additionally, in India, infections tend to precipitate severe MG exacerbations [35]. MG exacerbations induced by infections have not been associated with any specific microorganisms. Virus, bacteria and other microbes have all been implicated in case reports. The mechanism includes most probably a broad activation of the immune system by the infection. Virus can trigger autoimmunity through molecular mimicry, bystander activation, epitope spreading, enhanced T cell signaling, and up-regulation of a series of cytokines and costimulatory molecules [50]. It is not clear whether the specific autoantibody concentrations against AChR, MuSK and LRP4 increase during infection. Infection of the respiratory tract can occur as a complication to an established MG exacerbation due to respiratory muscle weakness and secret stagnation. Plasma exchange and intravenous immunoglobulin are the preferred treatments for an MG crisis [24], and they should be regarded as equally effective with or without infection as the precipitating event. In addition, anti-infectious treatment is crucial. The long-term immunosuppressive treatment should be intensified after a severe MG exacerbation irrespective of precipitating events. It has been speculated that MG patients have a specific resistance to rabies infection as the rabies virus binds to AChR in skeletal muscle, receptors that are already dysfunctional in MG [76].

Thymus, thymectomy and infection Thymus pathology is a typical characteristic for AChRantibody associated MG. Early onset patients have thymic hyperplasia, and another 10% of all patients have

a thymoma. Thymus is essential in AChR-MG pathogenesis. The epithelial cells are capable of expressing epitopes cross-reactive with skeletal muscle proteins, and these are presented to T-cells together with costimulatory molecules. In a second step, thymic myoid cells activate antigen-presenting cells and diversify the antibody response [24, 44]. Virus might influence the initial expression of muscle-like epitopes within thymus, as well as T-cell regulation (Fig. 1). MuSK-MG and LRP4-MG have in contrast a normal thymus. Total thymectomy is established as effective therapy for generalized MG with AChR antibodies [77]. In thymoma–MG, thymectomy should be undertaken in all patients to remove the tumour. Thymus is a primary lymphoid organ that is essential for the differentiation of T-lymphocytes, and therefore, for the immune response against pathogens. Thymus is fully developed at birth and reaches its largest size in early childhood. Although the intrathymic T-lymphocyte production and export to the periphery decreases during puberty and adulthood, the gland continues to be active throughout life. T-cells and T-cell subpopulations become reduced after thymectomy, and especially in patients who had an active thymopoiesis prior to thymectomy [65]. Long-term changes are less consistent, and also influenced by immunosuppressive drug therapy. Thymectomy in childhood, including in early childhood below age 2 years, influenced T-cells and in particular D8+ T-cells [80]. However, the immune system demonstrated unchanged efforts of homeostatic proliferation of T-cells. It has even been speculated that the removal of thymus very early in life has less long-term influence on T-cells than later thymectomy due to a higher reparative potential in the younger children [80]. Thymectomy early in life lead to a delayed antibody response to viral antigens in some patients [55]. However, none of the responses were totally abrogated, and the changes were considered as minor when compared to the responses in healthy controls. There are no prospective studies of infection frequency and severity in MG before and after thymectomy, nor has the occurrence of infectious disease in MG been systematically evaluated. In a national cohort study, we found that MG patients both before and after age 50 years used more anti-infectious drugs than the rest of the population, with an odds ratio of 1.2–1.3 [3]. Early antibiotic treatment, also for mild infections, is recommended in MG, and this is the most likely explanation for the observed increased use of antibiotics, rather than more frequent and severe infections. However, there are reports of an increased risk in patients with autoimmune disorders in general for tuberculosis and HIV infection [41, 56, 74]. MG does not seem to infer an extra risk, even with previous thymectomy in some MG patients. Thymoma patients tend to have more frequent and severe infections, especially of the respiratory tract [29].

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Thymus epithelial cell Virus infection

Plasma cell

B cell

CD4+T cell

Treg cell

CD4+T cell

APC

Myoid cell

Virus

AIRE

Unfolded AChR

Folded AChR

Treg cell

AChR Ab

Fig. 1  A model for the intrathymic immunization in myasthenia gravis (MG) with AChR antibodies. Infectious particles (virus) may influence antigen presentation and T-cell regulation, and thus initi-

ate the two-step immunization involving the thymic epithelial cells, myoid cells, antigen-presenting cells in addition to several lymphoid cell populations [44, 61]

This could be caused by a thymoma-induced immune dysregulation. It is possible that frequent infections trigger autoimmunity with autoantibody production, but it is more probable that the thymoma leads to a loss of self-tolerance, causing MG, autoimmune reactivity and at the same time a reduced resistance to microbes. Acquired T-cell immunodeficiency with or without hypogammaglobulinemia (Good’s syndrome) represents a particular complication in a small minority of thymoma patients, coexisting with MG or other autoimmune manifestations [16, 44].

A slightly increased risk for infections has been reported in most autoimmune disorders. Risk factors are generally severe disease, high age, comorbidity, and immunosuppressive drug therapy [42, 53, 71, 72]. Because immunosuppressive drugs are generally given in higher doses and in combination for more severe autoimmune disease, it is difficult to separate the risk caused by the drugs and the risk due to MG severity. Best estimates indicate that the risk for infections when on corticosteroids increases 20–50% [18, 20, 62]. Although the various traditional immunosuppressive drugs act differently on the immune system their infection rates tend to be similar [21]. Rituximab is recommended as a second-line drug for severe and moderately severe MG [24]. Hepatitis B virus can be reactivated by rituximab treatment, and patients should be screened before treatment [58]. Rituximab in combination with other immunosuppressive drugs further increases the risk for infections. Progressive multifocal leukoencephalopathy (PML) is the most feared rituximab-induced infection. The risk has been estimated to 1:20,000–1:30,000 for rheumatoid arthritis patients treated with rituximab [11, 14, 58]. PML has so far been reported in one patient with MG on polytherapy including rituximab [36]. The added risk for PML in rituximab-treated patients with MG or other autoimmune disorders is regarded as so small that JC-virus testing

Immunosuppressive drug therapy and infection Most patients with generalized MG receive immunosuppressive drug therapy for many years [24]. None of the drugs have a selective action on AChR, MuSK, or LRP4 antigen responses. They all influence and suppress immune reactivity broadly, including the reactivity against microbial antigens. Drugs with a selective action in the immune system, such as rituximab, still have widespread and diverse consequences for immune responses to both self and foreign antigens.

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before rituximab treatment is not recommended, as a positive result should not influence the indication for treatment with this drug. The complement component inhibitor eculizumab is a therapeutic option for rare MG patients [23]. This drug markedly increases the risk for meningococcal infection. Meningococcal vaccination should be undertaken for more than 2 weeks before starting treatment with eculizumab [52]. Antibiotic drug treatment should be started in patients on eculizumab that develop fever [52]. Immunosuppressive drugs, and in particular corticosteroids, increase the risk for pneumocystic pneumonia. However, this is a rare disease in the non-HIV population, with an annual death rate of one per million in USA [75]. Prophylactic antibiotic treatment is effective, but should only be considered in high-risk patients with proven immunodeficiency [67]. Prophylactic treatment is not recommended for the great majority of MG patients on immunosuppressive treatment. Intravenous immunoglobulin should temporarily increase the resistance to infections, whereas plasma exchange in contrast reduces the concentration of protective antibodies in the same way as for the pathogenic autoantibodies [28].

Muscle weakness and infection MG patients have as their only symptom muscle weakness. Weakness in the respiratory muscles predisposes for infections in the lower respiratory tract, and such infections combined with respiratory muscle weakness tend to be more severe. Dysphagia can add to the risk due to aspiration. Weakness in pelvic muscles can predispose for urinary tract infections. MG muscle weakness thus adds to the total risk for infections, and should also be considered when treating the infections.

Vaccination in MG Vaccinations are generally recommended for MG patients. As infections can deteriorate and complicate their MG, patients should try to avoid infections. Vaccination coverage for influenza tend to be high for MG [4]. Influenza vaccination does not lead to MG deterioration [63], in contrast to ordinary respiratory infections [66], and is recommended for MG patients. Most MG patients receive immunosuppressive treatment. Theoretically, vaccination could, therefore, lead to insufficient disease protection in MG. However, systematic studies have found that vaccine-induced immunity against diphtheria and tetanus is comparable in patients with MG (and SLE) and healthy individuals [17, 69]. Similar results have been

found for immunity against measles, mumps and rubella in thymectomized children with MG [81]. In contrast, these MG patients had a delayed humoral immune response to tick-born encephalitis virus after vaccination. This delay was modest, and no significant difference from controls was seen after some years. Vaccination programs should in general be undertaken in the same way in MG patients and healthy individuals. However, caution should be exerted for vaccines using live microorganisms in all immunosuppressed patients [22, 63], inactivated vaccines should be preferred, and risk for disease without vaccination should be compared to risk by vaccination with live vaccines [22]. Vaccination with live-attenuated vaccines should preferentially be undertaken before initiation of immunosuppressive therapy. Such therapy is not an emergency in MG. Combination therapy with several immunosuppressive drugs and in high doses represents a particular risk for live vaccine microbial activation. Ideally, vaccination should precede the insert of immunosuppressive drugs with 2–4 weeks, this also to ensure vaccination efficacy [1, 78]. Vaccination is not recommended in periods of acute exacerbations [1]. Rituximab impairs vaccine responses and protection after vaccination is less reliable [22]. Necessary vaccinations should, therefore, be performed before rituximab therapy [15]. For patients on rituximab already, vaccine immunogenicity should be examined after vaccination, for example by antibody testing. Repeated vaccinations may be necessary. Ideally one should wait with vaccination until 6 months after the last rituximab dose [1]. Herpes zoster is a common disease, having an annual incidence of up to 1 per 100 in the oldest age group [64]. Immunosuppressive treatment doubles that risk. Both routine and selective vaccination against herpes zoster has been proposed [38, 64]. The well established, live-attenuated vaccine markedly reduces the incidence of both herpes zoster and post-herpetic neuralgia for 10 years. New and non-live vaccines may have a similar efficacy [68]. MG patients above 60 years and on immunosuppressive treatment should be a target group for herpes zoster vaccination. Vaccination triggering autoimmune disease including MG has been reported in single cases. The question usually remains whether this represents a cause–effect relationship or merely a temporal association. It is not possible to identify individuals with a particular risk. The overall benefits of recommended vaccination programs by far outweigh the risk of triggering MG or any other autoimmune disorder.

Treatment of infections in MG As infections can lead to MG deterioration, early and effective treatment is important. Even mild infections should be taken seriously, trying to avoid generalization and

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Table 1  Antibiotic drugs to avoid if possible in patients with myasthenia gravis

Journal of Neurology Antibiotic drug Telithromycin Fluoroquinolones Macrolides Aminoglycosides

prolongation of the infection. All MG patients should receive information on how to prevent infectious disease. Immunosuppressive therapy for MG should be maintained during infections. Drug dose should not be reduced when having an active infection. During lower respiratory tract infection, and especially with threatening impairment of respiratory function, the threshold for hospitalization and intensive care treatment should be very low. Intravenous immunoglobulin or plasma exchange represent effective and fast-acting treatment for acute exacerbations of MG [24]. Some medications, including antibiotic drugs, have been reported to worsen the muscle weakness in MG. Drugs have been shown to interfere with neuromuscular transmission in experimental studies. However, MG deterioration during infection is much more commonly caused by the infection than by antibiotic drugs. Telithromycin should not be used in MG. Several cases have been described with severe and rapid MG deterioration shortly after intake of this drug [54]. Fluoroquinolones, including ciprofloxacin and levofloxacin, are in rare cases associated with MG worsening, and they should be used only cautiously, if at all [33]. Similar considerations are true for macrolide and aminoglycoside antibiotics. They should be used cautiously and only if no equally good alternative antibiotic treatment is available [8] (Table 1). There have been single case reports for several additional antibiotics as well [73], and some patient foundations have gathered long lists of drugs to avoid or use with caution. However, reports of single cases, often with a dubious cause–effect relationship, do not imply that the drugs should not be used at all. The important and general precaution should in our opinion be that both patient and doctor need to be aware of the possibility of drug-induced MG deterioration after starting any new medication. Most antibiotic drugs are well tolerated by MG patients, in exactly the same way as for the non-MG population.

Conclusions Comorbidity represents one of the greatest challenges in MG treatment, and is increasing with the general ageing of the MG population [25]. Infections will usually lead to a local functional deficit, general fatigue with a feeling of weakness,

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but can also cause a specific deterioration of MG. Similarly, infections can precipitate MG in predisposed individuals. Effective and early treatment of infections is highly important in MG. Most antibiotic drugs are safe, but telithromycin, fluoroquinolones, macrolides and aminoglycosides should be avoided in MG. Immunosuppressive treatment with drugs and thymectomy induces changes that predispose for infections, but most MG patients do not seem to have any clinically relevant increase in rate of infections. Vaccinations are recommended for MG patients, but live-attenuated vaccines should be avoided in immunosuppressed individuals.

Compliance with ethical standards  Conflicts of interest N.E. Gilhus has received speaker’s honroraria from Octapharma, and honoraria for committee work from Argenx. There are no other conflicts of interest.

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