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Post-vaccination myositis and myocarditis in a previously healthy male Cheng, Matthew P; Kozoriz, Michael G; Ahmadi, Amir A; Kelsall, John; Paquette, Katryn; Onrot, Jake M Feb 11, 2016

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Cheng et al.  Allergy Asthma Clin Immunol  (2016) 12:6 DOI 10.1186/s13223-016-0114-4CASE REPORTPost-vaccination myositis and myocarditis in a previously healthy maleMatthew P. Cheng1*, Michael G. Kozoriz2, Amir A. Ahmadi3, John Kelsall4,5, Katryn Paquette6 and Jake M. Onrot5Abstract Background: The immunological literature has been redefining clinical phenomena as hypotheses emerge regard-ing causal links between triggers, immunologic manifestations, and their specific inflammatory cascades. Of late, autoimmune manifestations that appear to be caused by an external adjuvant have been grouped into a complex syndrome referred to as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This syndrome may present with diverse clinical problems, which may include neurocognitive impairment, inflammatory musculoskeletal changes, and constitutional symptoms. There is evidence in the literature linking vaccines to different auto-immune manifestations. Vaccines have not traditionally been reported to trigger ASIA, although reports are emerging linking the human papilloma virus and hepatitis B vaccines to it.Case presentation: We report the first suspected case of ASIA in a previously healthy patient who received the Fluad seasonal influenza vaccine, which contains the MF59 adjuvant. He presented to hospital with profound weakness and was diagnosed with severe rhabdomyolysis. He also had elevated troponin-I and extensive cardiac investigations enabled the diagnosis of myocarditis. His infectious and rheumatologic work-ups were negative. He responded well to conservative management and did not require immune suppressive therapy.Conclusion: Given the benefits of the influenza vaccine, and the low incidence of clinically significant complications, we encourage ongoing seasonal influenza immunization. However, ongoing surveillance is required to evaluate the occurrence of rare adverse events, including ASIA.Keywords: Vaccine, Myocarditis, Rhabdomyolysis, Autoimmune, ASIA© 2016 Cheng et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BackgroundAdjuvants are elements that induce an inflammatory response. In the case of vaccines, adjuvants increase the antigen-specific immune response, to ultimately improve vaccine immunogenicity. This process may also have negative repercussions, inducing autoimmun-ity. Since 2011, autoimmune manifestations that appear to be caused by an external adjuvant have been grouped into a complex entity referred to as autoimmune/inflammatory syndrome induced by adjuvants (ASIA) [1, 2]. Previously referred to as Shoenfeld’s syndrome, the disorder has been redefined; it is characterized by neurocognitive, inflammatory musculoskeletal, and/or constitutional symptoms upon exposure to an exter-nal stimulus, improvement following withdrawal of the offending agent, and may involve the development of autoantibodies, specific HLA phenotypes or evolution into a rheumatological disorder [3]. The exact mecha-nisms linking external adjuvants to the various immune responses described are not known.There is longstanding literature linking vaccines to dif-ferent auto-immune manifestations [4]. In recent years, immunizations [5–7], especially the human papilloma virus and hepatitis B virus vaccines [8], and various vac-cine adjuvants [9, 10] have been linked to ASIA. However, the seasonal influenza vaccine is an uncommon trigger for autoimmune disease, and is not commonly associated with rhabdomyolysis or myocarditis. One study showed a tendency for autoantibody production in adults fol-lowing the influenza vaccine, but without clinical disease Open AccessAllergy, Asthma & Clinical Immunology*Correspondence:  matthew.cheng@mail.mcgill.ca 1 Division of Infectious Diseases and Department of Medical Microbiology, Glen site, McGill University Health Centre, 1001 Boulevard Décarie, Room E05. 1811.2, Montreal, QC H4A 3J1, CanadaFull list of author information is available at the end of the articlePage 2 of 6Cheng et al. Allergy Asthma Clin Immunol  (2016) 12:6 correlation [11]. We report the first suspected case of a seasonal influenza vaccine induced-ASIA in a previously healthy male who presented to hospital with simultane-ous rhabdomyolysis and myocarditis.Case presentationA 65 year old previously healthy male presented to hospi-tal with profound weakness. Five days before admission, he had received the Fluad seasonal influenza vaccine, comprised of one influenza A H1/N1 virus, one influ-enza A H3/N2 virus, one influenza B virus, and the MF59 adjuvant. Two days later, he developed bilateral crampy leg pain, muscle tenderness, and progressive weakness. He became unable to weight-bear and was brought to the emergency department by his wife. He denied expe-riencing headaches, paresthesias, arthralgias, skin lesions or constitutional symptoms. An infectious review of sys-tems was unremarkable. He was not taking any medica-tions or herbal preparations prior to admission, nor did he use recreational drugs.On physical exam his vital signs were: pulse 92/min-ute, blood pressure 124/84, respiratory rate 20/minute, oral temperature 36.7  °C, and his oxygen saturation was 100  % on room air. His neurological exam was signifi-cant for 4/5 strength in bilateral hip flexors, hip exten-sors, hip abductors and hip adductors. He could not stand from the sitting position without the aid of his arms. The large muscle groups of his arms and legs were tender. Cardiac examination revealed a jugular venous pressure (JVP) two cm above the sternal angle, a normal apical beat, a normal S1 and S2 without any extra heart sounds, murmurs or rubs. His respiratory exam revealed mild crackles in the left lower lobe. The remainder of the examination was unremarkable.His blood counts were WBC 11  ×  99/L, hemo-globin 123  g/L (MCV 83  fL) and platelets 134 ×  109/L. Electrolytes included sodium 126  mmol/L, potas-sium 3.2  mmol/L, chloride 101  mmol/L, bicarbonate 17  mmol/L, phosphate 0.75  mmol/L and magnesium 0.97 mmol/L. Other laboratory parameters included urea 11.6  mM/L, creatinine 157  mM/L, creatine kinase (CK) 7736 U/L (normal < 150 U/L) and troponin-I 9.44 mcg/L (normal < 0.2 mcg/L). A blood ethanol level was negative. His EKG revealed normal sinus rhythm and a right bun-dle branch block, without ischemic features. A chest radi-ograph and contrast enhanced computed tomography scan of the chest revealed a hiatus hernia, left lower lobe opacification, without evidence of pulmonary embolism.Acute rhabdomyolysis was diagnosed and the patient received four liters of fluid over the ensuing 24  h. Dur-ing volume resuscitation, he developed pulmonary crack-les, his JVP increased to 5  cm above the sternal angle, and his oxygen saturation decreased to 90 % on room air. Supplemental oxygen and a single dose of furosemide 40 mg IV were provided, to which he responded well. He also initially received piperacillin–tazobactam for pos-sible left lower lobe pneumonia. No steroids were pre-scribed. His creatinine, CK and troponin levels trended downwards after 12 h of therapy, and almost normalized within 5 days (see Fig. 1).A basic immunological workup was within normal limits, with an antinuclear antibody test (ANA) of 1:160, homogeneous pattern (non-specific), and negative anti-dsDNA, ENA panel, C3, C4, rheumatoid factor, and ANCA tests. Serum protein electrophoresis (SPEP) was consistent with an acute phase reaction and urine protein electrophoresis (UPEP) was negative. Dipstick urinalysis revealed 1+ protein and 1+ blood and his urine was pos-itive for myoglobin. Microscopy revealed granular casts, urate crystals and no evidence of red blood cells. HIV, hepatitis B and C serological tests were negative. Blood and urine cultures yielded no growth. Computed tomog-raphy scans of the head and lumbar spine were negative; no other cause was found to explain the patient’s weak-ness. An echocardiogram performed on day three of admission revealed normal biventricular systolic func-tion without regional wall motion abnormalities. Cardiac MRI on day four confirmed the diagnosis of myocarditis. A muscle biopsy was not performed as the patient recov-ered promptly; he was discharged home on day six.DiscussionThis patient presented with a gradual onset of weakness and muscular pain. He had received the influenza vac-cine 5  days prior to the onset of symptoms. Laboratory investigations indicated rhabdomyolysis, myocarditis, and acute kidney injury, which all resolved by the sixth day of admission.In rhabdomyolysis, there is breakdown of skeletal mus-cle cells, resulting in the release of cellular constituents such as electrolytes, myoglobin and cellular enzymes, including creatine kinase. The consequences thereof can include life threatening disseminated intravascular coag-ulation, electrolyte disturbances, and acute kidney injury. There are numerous known causes of rhabdomyolysis [12, 13]; they are summarized in Table 1.Aggressive fluid management is key in avoiding myo-globin-induced oxidative damage to the kidney [13]. This patient was treated with modest fluid resuscitation, due to the concern of circulatory overload in the context of suspected cardiac myositis. He did indeed develop signs of volume overload (increased JVP and respira-tory crackles), with favorable response to decreased fluid administration and a diuretic. In addition to the nephro-toxic effects of myoglobin, recent evidence suggests that pro-inflammatory cytokines, chemokines and NLRP3 Page 3 of 6Cheng et al. Allergy Asthma Clin Immunol  (2016) 12:6 inflammasomes partake in the pathogenesis of rhabdo-myolysis-induced acute kidney injury [14], highlighting the importance for additional research in the manage-ment of this condition.As the history, physical examination, and laboratory markers did not suggest an alternative cause for rhab-domyolysis, we believe that his presentation was most in keeping with ASIA. Furthermore, he fulfilled many of the major suggested criteria for the diagnosis of ASIA (see Table 2). Connective tissue causes of myositis were ruled out by the normal ANA titer, and negative ENA, C3, C4, RA, and ANCA panels. Illness resolution without anti-inflammatory or immunomodulatory medication also goes against connective tissue diseases. The physical examination, SPEP, UPEP, and CT scans were not sugges-tive of Guillain–Barré syndrome. His cardiac evaluation suggested myocarditis and not myocardial infarction as a cause for the troponinemia. Unfortunately, while the patient’s blood cultures were negative, the patient did not produce any sputum for culture, and a respiratory poly-merase chain reaction (PCR) panel to detect common respiratory pathogens was not obtained. Although infec-tious etiologies of rhabdomyolosis have been previously well described [15–18], we suspect these to be less likely, Fig. 1 Trend of patient’s creatine kinase and troponin-ITable 1 Common causes of rhabdomyolysisCategory ExampleAutoimmune diseases Dermatomyositis and polymyositisDrugs and toxins Numerous: including alcohol, cocaine, heroin, fibrates and statinsElectrolyte disorders Hypokalemia, hypernatremia, hyponatremia, hypophosphatemia, hypocalcemia, hyperosmolarity, ketoacidosisEndocrine disorders Hypothyroidism, hyperaldosteronismExcessive muscle activity Alcohol withdrawal, exercise, seizuresGenetic disorders Numerous: including disorders of glycolysis, glycogenolysis, lipid metabolism, mitochondrial pathways and nucleotide metabolismHypoxia Prolonged immobilization, artery occlusionIdiopathic Infections Viral (coxsackievirus, Epstein–Barr virus, herpes viruses, HIV, influenza A and B) Bacterial (Clostridium spp., F. tularensis, L. pneumophilia, Salmonella spp., S. pyogenes, S. aureus) Parasitic (malaria) Temperature Heatstroke, malignant hyperthermia, malignant neuroleptic syndrome, hypothermia Trauma and compres-sionCrush injury syndrome, electrical injuryPage 4 of 6Cheng et al. Allergy Asthma Clin Immunol  (2016) 12:6 as the patient denied upper and lower respiratory tract infection symptoms.Few reports propose an association between the influ-enza vaccine and rhabdomyolysis and/or myocarditis. There are three case reports of rhabdomyolysis follow-ing influenza immunization. However, unlike our case, all three patients were taking a statin drug, and none had features of myocarditis. The first two reports describe patients on statin therapy who developed myalgia and progressive weakness within 24  h of receiving the flu vaccine, who were diagnosed with rhabdomyolysis and acute kidney injury [19, 20]. The third published case of rhabdomyolysis was described 1 week post influenza vac-cination in a 57 year old renal transplant patient on simv-astatin and cyclosporin A [21]. A final case was reported in the literature: a 60 year old gentleman who developed polyarthropathy, orbital myositis and posterior scleri-tis 10 days after receiving the 1993 Fluvirin vaccine [22]. Given the ocular involvement, he received oral predni-solone and acetazolamide, with dramatic improvement over the next four months.Shoenfeld et  al. [23] suggest grouping different auto-immune manifestations that are seemingly triggered by an external adjuvant into a syndrome complex, referred to as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Numerous mechanisms have been proposed to explain the interaction between adjuvants, immunogenicity, and autoimmunity. Many researchers postulate that individuals who develop autoimmune phe-nomena following vaccination have a genetic risk or an underlying disease that activates inappropriate immune responses [1, 7, 24, 25]. ASIA is characterized by a myr-iad of neurocognitive manifestations, including chronic fatigue, cognitive impairment and amnesia, as well as the development of inflammatory musculoskeletal find-ings including arthritis and myositis [3]. Our patient’s presentation would be more in keeping with the latter end of the disease spectrum. He fulfills the original diag-nostic requirements proposed by Shoenfeld et  al. (see Table  2) [23]. Although inflammatory myopathies have been well described following vaccination [25], includ-ing macrophagic myofaciitis (MMF) [26], the occurrence of myocarditis has not. Furthermore, our patient did not manifest a locally stereotyped or immunologically active lesion at the site of inoculation, which would argue against MMF. Despite the atypical nature of our patient’s presentation, including cardiac involvement, we believe that his profound inflammatory response may be attrib-uted to the recent vaccine in the absence of other causes, especially given the timing of adjuvant exposure.As described in a recent systematic literature review and meta-analysis, while local injection site pain and head-ache are known reactions, serious adverse effects follow-ing influenza immunization are rare [27]. Though cases of myositis have been described in adults after hepatitis B or BCG vaccination [28, 29], cases linking the influenza vaccine to myositis without confounding factors are rare. Although an argument can be made regarding the patient’s radiographic opacification as a possible confounder, we are not convinced that the patient had an infectious process. Based on the patient’s clinical and laboratory findings, a presumptive diagnosis of ASIA was made.As mentioned, there is convincing data in the litera-ture that the influenza vaccine is safe and effective (27). Significant complications are rare. In addition to hand-hygiene and respiratory etiquette, immunization is an Table 2 Criteria suggested ASIA diagnosisFor the diagnosis of ASIA, the presence of at least 2 major or 1 major and 2 minor criteria must be apparent. Table reprinted from Journal of Autoimmunity, vol. 36(1), Yehuda Shoenfelda and Nancy Agmon-Levin, ‘ASIA’—Autoimmune/inflammatory syndrome induced by adjuvants, pages 4–8, Copyright 2011, with permission from ElsevierExposure to an external stimuli (Infection, vaccine, silicone, adjuvant) prior to clinical manifestationsMajor criteria  The appearance of ’typical’ clinical manifestations:    Myalgia, Myositis or muscle weakness  Arthralgia and/or arthritis    Chronic fatigue, un-refreshing sleep or sleep disturbances  Neurological manifestations (especially associated with demyelination)  Cognitive impairment, memory loss  Pyrexia, dry mouthRemoval of inciting agent induces improvementTypical biopsy of involved organsMinor criteria The appearance of autoantibodies or antibodies directed at the suspected adjuvantOther clinical manifestations (i.e. irritable bowel syn.)Specific HLA (i.e. HLA DRB1, HLA DQB1)Evolvement of an autoimmune disease (i.e. MS, SSc)Page 5 of 6Cheng et al. Allergy Asthma Clin Immunol  (2016) 12:6 effective tool to curb the spread of the influenza virus [30]. Annual vaccination has been shown to protect indi-viduals of all ages from the flu, decreasing rates of emer-gency room visits, hospitalization, and death [31]. These benefits outweigh the mild adverse effects, prompting many countries to continue wide-reaching annual influ-enza vaccination campaigns [32].ConclusionWe report the case of a 65-year-old previously healthy male who presented to hospital with acute rhabdomy-olysis and myocarditis 5 days after the administration of a seasonal influenza vaccine. This may have been due to the adjuvant in the vaccine, although alternate etiolo-gies cannot be eliminated. At this time, the incidence of rhabdomyolysis and myocarditis post vaccination is lim-ited to case reports. ASIA is an emerging clinical entity, with its share of case reports hypothesizing a causal link with vaccines. Given the benefits of the influenza vaccine, especially in the health care setting and in many vulner-able populations, compared to the rarity of this and other putative complications, we encourage ongoing seasonal influenza immunization campaigns. Furthermore, most available seasonal flu vaccines do not contain any adju-vants. Ongoing surveillance to establish the existence of this posited entity and to evaluate its risks should be pursued.ConsentWritten informed consent was obtained from the patient for publication of this case report.Authors’ contributuionsAll of the authors contributed to the conception and design of the article, col-lected and interpreted the data, drafted the article and revised it for important intellectual content. All authors read and approved the final manuscript.Author details1 Division of Infectious Diseases and Department of Medical Microbiology, Glen site, McGill University Health Centre, 1001 Boulevard Décarie, Room E05. 1811.2, Montreal, QC H4A 3J1, Canada. 2 Department of Radiology, University of British Columbia, Vancouver, BC, Canada. 3 Department of Cardiology, Uni-versity of British Columbia, Vancouver, BC, Canada. 4 Division of Rheumatology, University of British Columbia, Vancouver, BC, Canada. 5 Division of Internal Medicine, University of British Columbia, Vancouver, BC, Canada. 6 Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. AcknowledgementsWe thank Dr. Caroline Quach (Montreal, Canada) for critical review and insight on earlier versions of this manuscript.Competing interestsThe authors declare that they have no competing interests.FundingThis study was conducted as part of our routine work.Received: 25 September 2015   Accepted: 17 January 2016References 1. Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun. 2013;47:1–16. doi:10.1016/j.jaut.2013.10.004. 2. Shoenfeld Y, Agmon-Levin N. ‘ASIA’–autoimmune/inflammatory syn-drome induced by adjuvants. J Autoimmun. 2011;36(1):4–8. doi:10.1016/j.jaut.2010.07.003. 3. Carvalho JF, Barros SM, Branco JC, Fonseca JE. Asia or Shoenfeld’s syn-drome: highlighting different perspectives for diffuse chronic pain. Acta Reumatol Port. 2011;36(1):10–2. 4. Cohen AD, Shoenfeld Y. Vaccine-induced autoimmunity. 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