Recurring Weakness in Rhabdomyolysis Following Pfizer–BioNTech Coronavirus Disease 2019 mRNA Vaccination

Kamura Y., Terao T., Akao S., Kono Y., Honma K., Matsue K.

We report a case of a Japanese man with severe rhabdomyolysis and multiple thrombosis of arterioles after the first dose of mRNA-1273 vaccine. He developed rapidly progressive rhabdomyolysis and infarctions of multiple organs. Antiplatelet factor 4 antibody test was negative. Despite the intensive supportive care, including aggressive fluid administration, hemodialysis, administration of anticoagulants, high-dose steroid, and eculizumab, the patient ultimately died of multiple organ failure. Autopsy revealed multiple thrombosis in the arterioles and organ necrosis. Low serum complements and C3 deposition in the renal glomeruli detected by immunofluorescence suggested a possible immune-mediated mechanism. To our knowledge, this is the first case report of rhabdomyolysis and multiple thrombosis of the arterioles as an adverse event following COVID-19 vaccination.

Al-Rasbi S., Al-Maqbali J.S., Al-Farsi R., Al Shukaili M.A., Al-Riyami M.H., Al Falahi Z., Al Farhan H., Al Alawi A.M.

Hakroush S., Tampe B.

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for COVID-19 vaccines to control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge with regard to adverse events of COVID-19 vaccines during post-marketing surveillance. Interestingly, four cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) presenting with pauci-immune crescentic glomerulonephritis (GN) after COVID-19 mRNA vaccination have already been reported. We here expand our current knowledge of this rare but important association and report a case of AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN after Pfizer-BioNTech COVID-19 mRNA vaccination. As huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must continue to assess vaccine safety important for the detection of any events associated with COVID-19 vaccination. This is especially relevant in complex diseases where diagnosis is often challenging, as in our patient with AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN.

Wu H., Pan C., Cheng C., Lin C., Chang S., Chen Y., Wang C., Chen Y., Chen C., Ma M.H., Hwang J.

Since December 2019, the outbreak of coronavirus disease 2019 (COVID-19) has spread rapidly around the world. The severity of COVID-19 ranges from asymptomatic carriers to severe acute respiratory distress syndrome (ARDS). Accumulating evidence has shown that COVID-19 may be associated with multiple organ complications including cardiac injury, viral myositis and neurological deficits. Numerous laboratory biomarkers including lymphocytes, platelets, lactate dehydrogenase and creatine kinase (CK) have been associated with the prognostic outcomes of patients with COVID-19. However, dynamic correlations between levels of biomarkers and clinical course have not been studied. Herein, we report a 74-year-old female patient with severe COVID-19 which progressed to ARDS requiring intubation and mechanical ventilation. The laboratory findings showed lymphopenia, hypogammaglobulinemia, and elevated inflammatory biomarkers and CK. She received intensive therapy with hydroxychloroquine, lopinavir/ritonavir, and azithromycin with limited effects. Immunomodulatory treatments with high dose intravenous immunoglobulin and baricitinib were prescribed with satisfactory biochemical, radiographic and clinical recovery. We found an interesting correlation between serum CK elevation and inflammatory biomarkers, which reflected clinical improvement. This case demonstrates that inflammatory biomarkers, cytokines, and CK level correlated with disease severity and treatment response, and combined use of intravenous immunoglobulin and baricitinib is a potential treatment in patients with severe COVID-19.

Elias C., Cardoso P., Gonçalves D., Vaz I., Cardoso L.

Introduction: Vaccination against COVID-19 is essential to control the pandemic. The vaccines developed so far have good safety profiles but full knowledge of adverse effects will only be acquired with time and through case reports. Case Description: We present the case of a man admitted with rhabdomyolysis 3 days after receiving his first dose of the Pfizer coronavirus vaccine Comirnaty® Other traumatic, infectious, endocrine, electrolyte disturbance and autoimmune causes of rhabdomyolysis were excluded. The temporal relationship between vaccine administration and disease onset indicated possible causality. The patient had a favourable evolution after receiving fluids and completely recovered. To our knowledge, there have been only 69 reports of rhabdomyolysis following Comirnaty® administration in Europe, as stated by the European Medicines Agency, and this is the first case report in Portugal. Discussion: When a patient presents with rhabdomyolysis without an obvious traumatic or exertional cause, other aetiologies need to be excluded. Drug use is one of the most common causes of rhabdomyolysis in adults. Conclusion: We present a case compatible with an adverse effect of Comirnaty® in order to raise awareness of this condition in vaccinated patients.  

Gelbenegger G., Cacioppo F., Firbas C., Jilma B.

We report the case of a 19-year-old male who complained of myalgia, muscle weakness, and darkened urine two days after receiving his Ad26.COV2.S (Johnson & Johnson, New Brunswick, New Jersey, United States) COVID-19 vaccination. Blood examination revealed an increased creatine kinase (CK) level, and his urinary dipstick tested positive for blood, indicative of acute rhabdomyolysis. Serum creatinine levels were normal. Rhabdomyolysis due to strenuous physical activity was ruled out and further diagnostics excluded an autoimmune cause. Under repeated treatment with intravenous fluid resuscitation (outpatient treatment), his symptoms resolved and peak CK levels of 44,180 U/L returned to almost normal levels within two weeks. Rhabdomyolysis is a rare, potentially fatal vaccine-induced reaction. Further research is needed to better understand the underlying pathomechanism and to investigate whether subcutaneous injection of vaccines may be able to prevent rhabdomyolysis.

Faissner S., Richter D., Ceylan U., Schneider-Gold C., Gold R.

Arunachalam P.S., Scott M.K., Hagan T., Li C., Feng Y., Wimmers F., Grigoryan L., Trisal M., Edara V.V., Lai L., Chang S.E., Feng A., Dhingra S., Shah M., Lee A.S., et. al.

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer–BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14+CD16+ inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization. Profiling the immune responses of 56 volunteers vaccinated with BNT162b2 reveals how this mRNA vaccine primes the innate immune system to mount a potent response to SARS-CoV-2 after booster immunization.

Nassar M., Chung H., Dhayaparan Y., Nyein A., Acevedo B.J., Chicos C., Zheng D., Barras M., Mohamed M., Alfishawy M., Nso N., Rizzo V., Kimball E.

Tan A., Stepien K.M., Narayana S.T.

Carnitine palmitoyltransferase II (CPT II) deficiency is a disorder affecting fatty acid oxidation. The myopathic form of the condition is the most common among adults and manifests itself with a high serum creatine kinase (CK) concentration. Triggers of very high CK concentrations include periods of fasting, infection, exercise, stress, and exposure to extreme temperatures. A 27-year-old man known to have CPT II deficiency presented feeling generally unwell after his COVID-19 vaccine. His CK concentration of 105,000 U/L and deranged liver function tests (ALT 300 U/L and AST 1496 U/L) were in keeping with rhabdomyolysis. His biochemical parameters and myopathy resolved with continuous intravenous dextrose 10% and a high carbohydrate diet. Caution should be exercised when administering vaccinations (including the COVID-19 vaccination) to this population. Clinicians should be wary for signs and symptoms of CPT II deficiency exacerbations and be vigilant in monitoring serum CK.

Rajaratnam N., Govil S., Patel R., Ahmed M., Elias S.

Polack F.P., Thomas S.J., Kitchin N., Absalon J., Gurtman A., Lockhart S., Perez J.L., Pérez Marc G., Moreira E.D., Zerbini C., Bailey R., Swanson K.A., Roychoudhury S., Koury K., Li P., et. al.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)

Laczkó D., Hogan M.J., Toulmin S.A., Hicks P., Lederer K., Gaudette B.T., Castaño D., Amanat F., Muramatsu H., Oguin T.H., Ojha A., Zhang L., Mu Z., Parks R., Manzoni T.B., et. al.

Cabral B.M., Edding S.N., Portocarrero J.P., Lerma E.V.

Rhabdomyolysis is caused by the breakdown and necrosis of muscle tissue and the release of intracellular content into the blood stream. There are multiple and diverse causes of rhabdomyolysis but central to the pathophysiology is the destruction of the sarcolemmal membrane and release of intracellular components into the systemic circulation. The clinical presentation may vary, ranging from an asymptomatic increase in serum levels of enzymes released from damaged muscles to worrisome conditions such as volume depletion, metabolic and electrolyte abnormalities, and acute kidney injury (AKI). The diagnosis is confirmed when the serum creatine kinase (CK) level is > 1000 U/L or at least 5x the upper limit of normal. Other important tests to request include serum myoglobin, urinalysis (to check for myoglobinuria), and a full metabolic panel including serum creatinine and electrolytes. Prompt recognition of rhabdomyolysis is important in order to allow for timely and appropriate treatment. A McMahon score, calculated on admission, of 6 or greater is predictive of AKI requiring renal replacement therapy. Treatment of the underlying cause of the muscle insult is the first component of rhabdomyolysis management. Early and aggressive fluid replacement using crystalloid solution is the cornerstone for preventing and treating AKI due to rhabdomyolysis. Electrolyte imbalances must be treated with standard medical management. There is, however, no established benefit of using mannitol or giving bicarbonate infusion. In general, the prognosis of rhabdomyolysis is excellent when treated early and aggressively.

Pereira F., Moraes R.D., Bavel D., Lorenzo A.R., Tibirica E.

Lee S., Lee J., Cho S., Roh G., Park H., Lee Y., Jeon H., Lee Y., Bae S., Youn S.B., Cho Y., Oh A., Ha D., Lee S., Choi E., et. al.

AbstractThe implications of administration of mRNA vaccines to individuals with chronic inflammatory diseases, including myocarditis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), are unclear. We investigated mRNA vaccine effects in a chronic inflammation mouse model implanted with an LPS pump, focusing on toxicity and immunogenicity. Under chronic inflammation, mRNA vaccines exacerbated cardiac damage and myocarditis, inducing mild heart inflammation with heightened pro-inflammatory cytokine production and inflammatory cell infiltration in the heart. Concurrently, significant muscle damage occurred, with disturbances in mitochondrial fusion and fission factors signaling impaired muscle repair. However, chronic inflammation did not adversely affect muscles at the vaccination site or humoral immune responses; nevertheless, it partially reduced the cell-mediated immune response, particularly T-cell activation. These findings underscore the importance of addressing mRNA vaccine toxicity and immunogenicity in the context of chronic inflammation, ensuring their safe and effective utilization, particularly among vulnerable populations with immune-mediated inflammatory diseases.

Sheka M., Coattrenec Y., Lorenzini K.I., Nendaz M.

AbstractThe identification of rhabdomyolysis as a potential fatal adverse reaction to recent COVID‐19 vaccines is essential. As the symptoms of rhabdomyolysis are not specific, the threshold to actively search for this complication should be low.

Tuchmann‐Durand C., Roda C., Renard P., Mortamet G., Bérat C., Altenburger L., de Larauz M.H., Thevenet E., Cottart C., Moulin F., Bouchereau J., Brassier A., Arnoux J., Schiff M., Bednarek N., et. al.

Chatterjee A., Chakravarty A.

A variety of neurological complications have been reported following the widespread use of the COVID-19 vaccines which may lead to vaccine hesitancy and serve as a major barrier to the public health aim of achieving protective herd immunity by vaccination. In this article, we review the available evidence regarding these neurological adverse events reported, to provide clarity regarding the same so that unfounded fears maybe put to rest. There is a greater than expected occurrence of severe neurological adverse events such as cortical sinus venous thrombosis, Bell’s palsy, transverse myelitis, and Guillain–Barré syndromes along with other common effects such as headaches following different kinds of COVID-19 vaccination. Precipitation of new onset demyelinating brain lesions with or without detection of specific antibodies and worsening of pre-existing neurological disorders (like epilepsy, multiple sclerosis) are also a matter of great concern though no conclusive evidence implicating the vaccines is available as of now. The COVID-19 pandemic is far from being over. Till such time that a truly effective anti-viral drug is discovered, or an appropriate therapeutic strategy is developed, COVID-appropriate behavior and highly effective mass vaccination remain the only weapons in our armamentarium to fight this deadly disease. As often occurs with most therapeutic means for the treatment and prevention of any disease, vaccination against COVID-19 has its hazards. These range from the most trivial ones like fever, local pain and myalgias to several potentially serious cardiac and neurological complications. The latter group includes conditions like cerebral venous thrombosis (curiously often with thrombocytopenia), transverse myelitis and acute inflammatory demyelinating polyneuropathy amongst others. Fortunately, the number of reported patients with any of these serious complications is far too low for the total number of people vaccinated. Hence, the current evidence suggests that the benefits of vaccination far outweigh the risk of these events in majority of the patients. As of now, available evidence also does not recommend withholding vaccination in patients with pre-existing neurological disorders like epilepsy and MS, though adenoviral vaccines should be avoided in those with history of thrombotic events.

Magen E., Mukherjee S., Bhattacharya M., Detroja R., Merzon E., Blum I., Livoff A., Shlapobersky M., Baum G., Talisman R., Cherniavsky E., Dori A., Frenkel-Morgenstern M.

Initial clinical trials and surveillance data have shown that the most commonly administered BNT162b2 COVID-19 mRNA vaccine is effective and safe. However, several cases of mRNA vaccine-induced mild to moderate adverse events were recently reported. Here, we report a rare case of myositis after injection of the first dose of BNT162b2 COVID-19 mRNA vaccine into the left deltoid muscle of a 34-year-old, previously healthy woman who presented progressive proximal muscle weakness, progressive dysphagia, and dyspnea with respiratory failure. One month after vaccination, BNT162b2 vaccine mRNA expression was detected in a tissue biopsy of the right deltoid and quadriceps muscles. We propose this case as a rare example of COVID-19 mRNA vaccine-induced myositis. This study comprehensively characterizes the clinical and molecular features of BNT162b2 mRNA vaccine-associated myositis in which the patient was severely affected.

Bakali-Khan K., Grace-Abraham N., Chen-Joea C., Velez-Dalla Tor M., LaScala N., Ronquillo D.

BACKGROUND Background: COVID-19 is an international public health emergency. In the United States, vaccination rates remain modest. Vaccine-mediated immunity is unlikely in the face of emerging variants and surging cases in vaccinated patients give pause to consider the underlying cause. OBJECTIVE To shed light on how COVID effects the public health, especially in an underserved community. Despite development of promising vaccines, surges in COVID cases gives pause to consider affects on age, gender, comorbidities, length of stay, intensive care unit admission, mechanical ventilation, as well as waning immunity METHODS Methods: Retrospective cohort analysis of Emanate Health hospital system from March - September 2021. Demographic and clinical factors for adult inpatient COVID-19 admissions were analyzed using Meditech software. These included age, gender, comorbidities, date of admission, and immunization status. Immunization status was confirmed via the California Immunization Registry. RESULTS Results: Of 475 COVID+ admissions, 28% were vaccinated. Admissions decreased from March to June, but steeply increased from June to August, driven predominately by unvaccinated patients. Length of stay (LOS) was higher for patients 60-79 years and with four and six comorbidities. Mortality was 1.5 times higher in patients 60-79 years and 1.3 times higher in patients with four and six comorbidities. Incompletely vaccinated patients were more likely to require ICU admission and ventilation, causing increased mortality. CONCLUSIONS Conclusions: Poor outcomes in unvaccinated, older patients and those with comorbidities corroborate national data. Among fully vaccinated, LOS did not vary significantly by vaccine type. Mortality increased with age, peaking at 60-79 years. Hypertension, diabetes mellitus, and obesity conferred higher admission and mortality in vaccinated patients, elaborating foci for risk assessment. Our data builds on existing research, demonstrating the protective effects of vaccination, which may decrease vaccine hesitancy. Administration of a booster may be needed earlier than previous federal guidelines recommended to combat waning immunity.