Sex: F
Vaccine: FLUX
Symptoms: Anion gap, Antiacetylcholine receptor antibody positive, Antibody test negative, Aspartate aminotransferase increased, Asthenia
Clinical narrative: generalised pain; Proximal weakness/ too weak to ambulate; left arm swelling/left upper extremity was diffusely swollen from the bicep to the dorsum of the hand; left arm swelling and pain; progressive weakness that involved her bilateral upper and lower extremities; dyspnoea on exertion; palpitations; polydipsia; polyuria; non-bilious non-bloody emesis; hypertensive; ECG demonstrated sinus tachycardia/tachycardic; non-pitting oedema; mild leucocytosis; severe hypercalcaemia/granulomatous hypercalcaemia; fever; subsequently intubated for progressive respiratory insufficiency/ neuromuscular respiratory failure; critical illness myopathy; MRI of her left upper extremity and right thigh revealed diffuse oedema throughout the musculature compatible with myositis; dense lymphohistiocytic infiltrate; cytomegalovirus (CMV) viremia; diverticulitis with associated perforation; dysphagia; acid-fast bacilli bacteraemia; intrabdominal polymicrobial abscesses; beta-lactamase producing Escherichia coli bacterial urinary tract infection; Giant cell myositis (GCM); autoimmune/inflammatory syndrome induced by adjuvants (ASIA); This case was reported in a literature article and described the occurrence of myositis in a adult female patient who received Flu unspecified (Influenza vaccine) for prophylaxis.  The patient's past medical history included exeresis (for thymoma) and radiation therapy (for thymoma). Concurrent medical conditions included myasthenia gravis, systemic lupus erythematosus, thymoma (8 years earlier), pleural metastases (residual tumour with pleural metastases) and ill-defined disorder. Additional patient notes included She had no history of a myasthenic crisis.. Concomitant products included prednisone, azathioprine, hydroxychloroquine and vitamins nos (Vitamin Supplements).   On an unknown date, the patient received Influenza vaccine. On an unknown date, 3 days after receiving Influenza vaccine, the patient experienced myositis (serious criteria hospitalization), autoimmune/inflammatory syndrome induced by adjuvants (serious criteria GSK medically significant), generalized aching (serious criteria hospitalization), weakness (serious criteria hospitalization), peripheral swelling (serious criteria hospitalization), pain in arm (serious criteria hospitalization), weakness in extremity (serious criteria hospitalization), exertional dyspnea (serious criteria hospitalization), palpitation (serious criteria hospitalization), polydipsia (serious criteria hospitalization), polyuria (serious criteria hospitalization), vomiting (serious criteria hospitalization), hypertension (serious criteria hospitalization), sinus tachycardia (serious criteria hospitalization), non-pitting edema (serious criteria hospitalization), leukocytosis (serious criteria hospitalization), hypercalcemia (serious criteria hospitalization), fever (serious criteria hospitalization), respiratory insufficiency (serious criteria hospitalization, GSK medically significant and clinically significant/intervention required), critical illness myopathy (serious criteria hospitalization), macular diffuse edema (serious criteria hospitalization and GSK medically significant), lymphocytic infiltrates nos (serious criteria hospitalization), cytomegalovirus viremia (serious criteria hospitalization, GSK medically significant and clinically significant/intervention required), diverticular perforation (serious criteria hospitalization, GSK medically significant and clinically significant/intervention required), dysphagia (serious criteria hospitalization and clinically significant/intervention required), bacillus bacteraemia (serious criteria hospitalization and GSK medically significant), abdominal abscess (serious criteria hospitalization, GSK medically significant and clinically significant/intervention required) and escherichia urinary tract infection (serious criteria hospitalization). The patient was treated with immunoglobulins nos (Immune Globulin, Intravenous), methylprednisolone, operations and procedures (Plasma Exchange), valganciclovir, calcitonin, zoledronic acid (Zolendronic Acid), medication unknown (Fluids) and antibiotics nos (Broad Spectrum Antibiotics (Ingredients Unknown)). On an unknown date, the outcome of the myositis, autoimmune/inflammatory syndrome induced by adjuvants, generalized aching, peripheral swelling, pain in arm, exertional dyspnea, palpitation, polydipsia, polyuria, vomiting, hypertension, sinus tachycardia, non-pitting edema, leukocytosis, fever, respiratory insufficiency, critical illness myopathy, macular diffuse edema, lymphocytic infiltrates nos, cytomegalovirus viremia, diverticular perforation, bacillus bacteraemia, abdominal abscess and escherichia urinary tract infection were unknown and the outcome of the weakness and weakness in extremity were recovering/resolving and the outcome of the hypercalcemia and dysphagia were recovered/resolved.   The reporter considered the myositis, autoimmune/inflammatory syndrome induced by adjuvants, generalized aching, weakness, peripheral swelling, pain in arm, weakness in extremity, exertional dyspnea, palpitation, polydipsia, polyuria, vomiting, hypertension, sinus tachycardia, non-pitting edema, leukocytosis, hypercalcemia, fever, respiratory insufficiency, critical illness myopathy, macular diffuse edema, lymphocytic infiltrates nos, cytomegalovirus viremia, diverticular perforation, dysphagia, bacillus bacteraemia, abdominal abscess and escherichia urinary tract infection to be possibly related to Influenza vaccine.     Additional Information: GSK Receipt Date: 06-JUL-2022 Reporter Comment: A woman in her late 50s with a history of myasthenia gravis MG, systemic lupus erythematosus and stage IV thymoma with pleural metastases, presented with 3 weeks of generalized pain and weakness after receiving the influenza vaccine. At baseline, the patient was active and independent, on a home medication regimen that included prednisone 5 mg, azathioprine 125 mg and hydroxychloroquine 200 mg daily. She was in her usual state of health until she went for her annual influenza vaccine which she received in her left arm. Three days later, she developed left arm swelling and pain, with progressive weakness that involved her bilateral upper and lower extremities, eventually becoming too weak to ambulate. During this time, she also developed dyspnoea on exertion, palpitations, polydipsia, polyuria and non-bilious non-bloody emesis. Review of systems was negative for diplopia, fevers, chest pain, diarrhea or dysuria. Regarding her thymoma and MG history, the patient was diagnosed with a thymoma 8 years earlier for which she underwent a resection and radiation therapy the following year. Pathological examination revealed a mixed type B2 and B3 thymoma with positive margins, stage IVa, pT4N0, and she was noted to have residual tumour with pleural metastases that were slowly growing and being monitored. She was subsequently diagnosed with MG the year prior to presentation after developing bulbar symptoms and testing positive for acetylcholine binding receptor antibody. She had no history of a myasthenic crisis, and her symptoms were well controlled prior to presentation. On admission, the patient was tachycardic and hypertensive but did not appear in acute distress. She had proximal greater than distal weakness in her bilateral upper and lower extremities (Medical Research Council Scale for muscle strength: 4/5 in deltoids, biceps brachii and triceps but 4+/5 in finger flexors and extensors; 3/5 in iliopsoas and 4/5 at tibialis anterior), 4/5 strength with neck flexion and maximal inspiratory pressure of -30 cm H2O. Her left upper extremity was diffusely swollen from the bicep to the dorsum of the hand with non-pitting oedema. Laboratory studies were notable for a mild leucocytosis, severe hypercalcaemia to 14.2 mg/dL, an elevated creatine kinase (CK) to 1541 U/L, as well as elevated C reactive protein, erythrocyte sedimentation rate, transaminases and lactate dehydrogenase. Her hypercalcaemia was treated with fluids, calcitonin and zolendronic acid. Her home azathioprine and prednisone were continued. She was admitted to the intensive care unit (ICU) for respiratory monitoring and started on a 5-day course of intravenous immune globulin (IVIG) given concern for a myasthenic crisis. On hospital day 2, she developed a fever without a clear infectious source which was treated empirically with broad spectrum antibiotics and was subsequently intubated for progressive respiratory insufficiency. She required mechanical ventilation in the ICU but did not require sedation for the remainder of her hospital course. During her fever workup, a CT of the abdomen and pelvis demonstrated abnormal signal of the proximal thighs and pelvic girdle musculature concerning for myositis. She underwent electromyography of the left arm which demonstrated a diffuse myopathic process without membrane irritability, most consistent with a critical illness myopathy rather than an inflammatory myopathy. Moreover, myositis autoantibody panel and serology for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase antibody were negative. Subsequently, MRI of her left upper extremity and right thigh revealed diffuse oedema throughout the musculature compatible with Myositis. A muscle biopsy of the right biceps brachii was then performed, which revealed a dense lymphohistiocytic infiltrate with abundant multinucleated giant cells and frequent degenerating/regenerating muscle fibres. Immunohistochemistry revealed abundant CD68-positive macrophages and giant cells, a dense endomysial population of CD3-positive T-lymphocytes and only scattered CD20-positive B-lymphocytes. Immunohistochemistry for Major Histocompatibility Complex I (MHC-I) showed strong and diffuse sarcolemmal staining of the muscle fibres, indicative of upregulation of MHC-I. A stain for acid-fast bacilli did not reveal any acid-fast microorganisms. Notably, this pathology was not characteristic of a hydroxychloroquine myopathy4 and demonstrated an alternate diagnosis of GCM. On admission, her troponin level was normal, and ECG demonstrated sinus tachycardia. On diagnosis of GCM, the patient underwent an echocardiogram to assess for potential cardiac involvement which revealed normal biventricular function. Workup for hypercalcaemia demonstrated a significantly elevated vitamin D 1,25 dihydroxy, which was consistent with a parathyroid hormone independent, granulomatous aetiology. The patient's home vitamin supplements were reviewed by hospital nutritionists and there was no evidence of a supplement that could account for an elevation in vitamin D 1,25 dihydroxy. CT of the chest and abdomen/pelvis obtained during the hospitalisation did not reveal hilar adenopathy or other lesions concerning for sarcoidosis or lymphoma. Her CT chest showed an interval size increase in multiple left pleural droplet thymoma metastases. After initial temporizing treatments on admission and with treatment of the patient's GCM as described below, the patient's hypercalcaemia did not recur during the remainder of her hospital course. She was treated with a 5-day course of IVIG on admission for a presumed myasthenic crisis, and empiric treatment of myositis was initiated on hospital day 10 with 1 mg/kg/day of IV methylprednisolone after the muscle biopsy was obtained. Her CK levels began to decrease within 48 hours of treatment, but her proximal and respiratory weakness remained unchanged. A tracheostomy was performed on hospital day 13. She was treated with 5 days of plasma exchange (PLEX) starting on hospital day 15 for a presumed component of myasthenic crisis to her respiratory weakness. On hospital day 18, she received 3 days of pulse steroids (1 g/day IV methylprednisolone) after her muscle biopsy pathology provided the diagnosis of GCM, after which she resumed 1 mg/kg/day dosing. Her course was complicated by cytomegalovirus (CMV) diverticulitis with associated perforation requiring emergent exploratory laparotomy and hemicolectomy with Hartmann's ostomy on hospital day 22. She was treated with a 3-week course of valganciclovir for CMV viremia that was completed as an outpatient. A gastrostomy tube was placed on hospital day 35 for ongoing dysphagia but she subsequently regained swallowing function and resumed a regular diet while in the hospital. She was discharged home with services after a 6-week hospital course with a tracheostomy and gastrostomy tube still in place, with planned decannulation and closure as an outpatient. At the time of discharge, her proximal strength was slowly improving but the patient was still bed-bound. Her discharge medications included her home azathioprine and prednisone 60 mg daily with plans to complete a slow taper as an outpatient. On returning home, her strength continued to improve, and she was decannulated and took her first steps with a walker approximately 1 month after discharge. She was readmitted to the hospital 2 months after discharge with acid-fast bacilli bacteraemia and intraabdominal polymicrobial abscesses that required percutaneous drainage by an interventional radiologist, and a prolonged antimicrobial course. She was also treated for an extended spectrum beta-lactamase producing Escherichia coli bacterial urinary tract infection during this admission. Her prednisone dose had been decreased to 30 mg daily at time of readmission. Her outpatient rheumatologist and oncologist opted to avoid further immunosuppressive agents given the patient's numerous infections, thus rituximab treatment was deferred in favour of monthly 2 g/kg IVIG treatments. The patient continued to be followed as an outpatient and was more than 6 months post-biopsy. The above case demonstrated important clinical considerations when managing a patient with GCM. While the patient in this case did not develop giant cell myocarditis, it was critical to assess for cardiac involvement in the acute setting, as GCM has been associated with giant cell myocarditis in over 40% of cases reported to date which could lead to a rapid clinical deterioration with a high mortality rate. Regarding treatment, this patient responded to a combination of steroids, IVIG and PLEX therapy for treatment of her comorbid MG. This patient's comorbid MG presented a challenge in selecting an appropriate treatment regimen, as throughout her hospital course, it was unclear if her respiratory failure was secondary to a concomitant myasthenic crisis or diaphragmatic involvement of GCM or both, which could not be delineated in the absence of a diaphragm biopsy. Regarding the patient's diagnosis of GCM, it was important to consider sarcoid myopathy in this case, which could also present as an acute granulomatous myositis. Histologically, sarcoid myopathy presenting as a granulomatous myositis could not definitively be differentiated from GCM given significant overlapping morphologic feature; however, the diagnosis of sarcoid myopathy requires evidence of sarcoid involvement in at least one additional organ system. In this case, there was no clinical evidence of multisystem sarcoidosis, nor identification of non-myopathic sarcoid lesions from extensive imaging which was obtained throughout her hospital course. This case also had several unique clinical features that have thus far only rarely been reported. First was the patient's presentation with severe hypercalcaemia, which was consistent with a granulomatous driven process. Granulomatous hypercalcaemia has been described in cases of sarcoidosis and lymphoma; however, no evidence of these conditions was identified during the patient's workup. Moreover, the patient's hypercalcaemia did not recur after treatment of her GCM. Thus, the aetiology of her granulomatous hypercalcaemia was favoured to be secondary to her GCM, as macrophages and giant cells convert 25-hydroxy vitamin D to 1,25 dihydroxy via increased 1alpha-hydroxylase activity. Still, considering the high morbidity and mortality associated with GCM, clinicians should consider this diagnosis when caring for patients with metastatic thymoma who present with weakness and muscular pain. Finally, it was notable that this patient's symptoms began shortly after receiving the influenza vaccine, suggesting that the effects of the vaccination may have precipitated the onset of GCM in this individual. Previous reports have highlighted an association between vaccine administration and symptom onset of immune-mediated conditions, possibly explained by vaccine adjuvants with inflammatory properties. Such conditions were referred to as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Within this spectrum of conditions, inflammatory myopathies associated with vaccine administration have been described. Given the temporal association between the patient's receipt of the influenza vaccine and myopathy symptom onset, a diagnosis of ASIA could not be excluded in this case. Importantly, ASIA was an extremely uncommon condition, and a review of the literature found no significant increase in the incidence of inflammatory myopathies following previous vaccination campaigns. Thus, the risk of developing a reactive inflammatory myopathy following vaccine administration pales in comparison to the significant benefits of protection against infection conferred by vaccination. Additional supportive information: This article is not available for regulatory reporting due to copyright restriction.