Corona virus disease-19 vaccine–associated autoimmune disorders

Hepatobiliary Manifestations

New-onset autoimmune hepatitis (AIH) after vaccination is a well-documented phenomenon with vaccines such as influenza^[12] and Hepatitis A virus (HAV) vaccine.^[13] It has also been reported following both infection with SARS CoV2 ^[14] and vaccination against it. It is a form of chronic hepatitis of inflammatory origin, which is triggered by environmental factors in genetically susceptible individuals. It is characterized by derangement of liver functions, development of specific antibodies, elevations of serum immunoglobulin levels, and interface hepatitis on liver histology.^[15]

Bril et al.^[16] published the first probable case of autoimmune hepatitis in a 35-year-old postpartum woman who developed jaundice and pruritus 13 d after getting vaccinated with Pfizer–BioNTech vaccine. She had hyperbilirubinemia and transaminitis, positive antinuclear antibodies (ANA) and anti double stranded deoxyribonucleic acid antibodies (anti-dsDNA) antibodies, and normal immunoglobulins. A liver biopsy showed findings consistent with autoimmune hepatitis. Resolution of symptoms and normalization of the liver profile with glucocorticoid therapy further affirmed the proposition.^[17] This triggered the publication of many similar cases by researchers all over the world suggesting the role of COVID-19 vaccines as a potential trigger for immune-mediated liver injury. Vuille Lessard et al.^[18] reported the development of AIH in a 76-year-old woman after getting mRNA-1273 vaccine. Londono et al.^[19], Tan et al.^[20], and McShane et al.^[21] followed suit and observed the development of autoimmune hepatitis in association with mRNA Moderna vaccine. Clayton-Chubb et al.^[22] and Rela et al.^[23] reported a case of AIH in association with adenoviral vector vaccines.

Palla et al.^[24] and Suzuki et al.^[25] described cases of AIH following administration of BNT162b2 (Pfizer–BioNTech mRNA) vaccine, all of which responded dramatically to steroids.

With the myriad of cases of AIH developing after COVID-19 vaccination, it can be ascertained that it is not a mere casualty but a definitive association, and both mRNA vaccines and adenoviral vector vaccines have been implicated.

Cardiovascular Manifestations

Myocarditis and myopericarditis have been recognized as a rare complication following SARS CoV2 mRNA vaccination. Bozkurt et al.^[26] gathered data from various case reports and case series of myocarditis published in peer-reviewed journals. They reported that for ≈ 300 million vaccines administered through June 2021, 1226 probable cases of myocarditis/myopericarditis were reported. The affected patients were primarily young males who developed myocarditis with typical symptoms and ECG findings, confirmed by increased cardiac troponins within 2–3 d after receiving the second dose of mRNA vaccines. A total of 40% had abnormal echocardiography findings, and cardiac magnetic resonance (MR) was abnormal in all patients showing late gadolinium enhancement and myocardial edema, consistent with the diagnosis. Almost all patients recovered with or without therapy.

Since then, multiple case series have been published documenting myocarditis following vaccination with mRNA vaccines for SARS CoV2, as depicted in Table 1.

Ocular Manifestations

A number of ocular complications have been reported following vaccination with all types of COVID-19 vaccines that are in use, uveitis being the most frequent. Vaccine-induced uveitis, although rare, is a well-documented phenomenon and has sparked considerable interest. Benage and Fraunfelder^[31] studied the incidence of vaccine-related uveitis over a period of 26 years in which 289 cases were reported. Most commonly implicated vaccines in decreasing order of frequency are Hepatitis B virus (HBV), Human papilloma virus (HPV), influenza, bacille Calmette-Guerin (BCG), measles mumps rubella (MMR), and varicella zoster virus (VZV) vaccines.

Cases of acute uveitis have been reported in association with SARS CoV2 vaccines. Rabinovitch et al.^[32] described 21 patients who developed uveitis following the administration of BNT162b2 SARS CoV2 vaccine. The mean age of the patients were 51.3 years, of whom 8 developed uveitis after the administration of the first dose and 13 after the second dose. The mean time from the day of vaccination to the development of uveitis was reported to be 7.5 d. Moreover, ElSheikh et al.^[33] reported development of uveitis in association with inactivated COVID-19 vaccine, whereas Alhamazani et al.^[34] documented uveitis following vaccination with BNT162b2 vaccine.

Other than uveitis, diverse ocular complications have been observed post-COVID-19 vaccination. Some of these complications, as reported by Bolletta et al.^[35] from the ocular immunology unit, Reggio Emilia, Italy, are summarized in Table 2.

Table 3 shows ocular adverse events observed in association with inactivated COVID vaccines reported by Chen et al.^[36] from a tertiary care center in southeast China.

Neurological Manifestations

Bell's palsy and Guillain–Barre syndrome have emerged as the most common neurological complication occurring in temporal association with COVID-19 vaccination. Wan et al.^[37] described a case series including 44 patients who developed Bell's palsy within 42 d of getting vaccinated with either BNT162b2 vaccine (16 patients) or inactivated CoronaVac vaccine (28 patients).

Like with other vaccines, Guillain–Barre syndrome has also been described in association with SARS CoV2 vaccines. Several case reports^[38,39] and case series have since surfaced (Table 4).

Both new-onset myasthenia gravis^[42,43] and exacerbation of existing disease have been reported with COVID vaccines.^[44,45] Although rare, acute transverse myelitis has also been reported in association with COVID vaccine. Hirose et al.^[46] described a case of acute transverse myelitis in a 70-year-old man 7 d after receiving mRNA-1273 SARS CoV2 vaccine. The diagnosis was supported with both radiological and laboratory evidence. The patient recovered after treatment with high-dose steroids.

Shin et al.^[47] and Zuhron et al.^[48] described very rare cases of autoimmune encephalitis developing in young female individuals 5 d after receiving their first dose of ChAdOx1 nCoV19 vaccine.

Fernandes et al.^[49] reported 4 patients who developed neurological sequelae in the form of new-onset seizure and insulin-dependent diabetes mellitus (Pfizer–BioNTech), longitudinally extensive transverse myelitis (Pfizer–BioNTech), Guillian Barre Syndrome (GBS) (ChAdOx1 nCoV19 vaccine), and meningitis retention syndrome (ChAdOx1 nCoV19 vaccine).

Kaulen et al.^[50] described a case series documenting neurological complications in 21 patients occurring in temporal association of either mRNA or ChAdOx1 nCoV19 vaccination. The complications included central nervous system (CNS) demyelinating diseases (n = 8), cerebral venous sinus thrombosis secondary to vaccine-induced thrombotic thrombocytopenia (n = 3), inflammatory peripheral neuropathy (n = 4), myositis (n = 3), and one case each of myasthenia gravis, limbic encephalitis, and giant cell arteritis.

Hematologic Manifestations

COVID-19 vaccines have the potential to initiate autoimmunity in almost all organ systems of the body, and the blood remains no exception. Rare cases of thrombotic thrombocytopenia have been described in association with the adenoviral vector vaccines with the development antibodies to platelet factor 4 as the underlying pathogenesis.^[11] The index case of thrombotic thrombocytopenia was reported in February 2021 when a 49-year-old healthcare worker developed thrombocytopenia leading to portal vein thrombosis and pulmonary embolism after receiving the first dose of ChAdOx1 nCoV-19 vaccine. Despite aggressive treatment, the patient succumbed to complications.^[51] More cases started pouring in, and soon, the term vaccine-induced immune thrombotic thrombocytopenia (VITT) was coined. See et al.^[52] published a case serious reporting 12 cases of VITT leading to cerebral venous sinus thrombosis in association with Ad26.COV2 vaccine, and Schultz et al.^[53] reported 5 cases of VITT from Norway following vaccination with ChAdOx1 nCov19 vaccine.

Acquired hemophilia with hemorrhagic manifestations has been reported after vaccination with adenoviral vector and BNT162b2 Pfizer–BioNTech vaccine.^[54,55] Warm Autoimmune hemolytic anemia (AIHA) after administration of mRNA1273 vaccine^[56] and hemophagocytic lymphohistiocytosis in association with inactivated SARS COV2 vaccine has also been reported.^[57]

Skin Manifestations

Delayed local skin reactions leading to the so-called “COVID arm” have been observed in association with mRNA COVID-19 vaccines. It is a type of benign dermal hypersensitivity reaction manifested as erythema, edema, and induration at the injection site.^[58]

Much dreaded autoimmune bullous skin diseases including both bullous pemphigoid and pemphigus (vulgaris and foliaceous) have been reported in association with Oxford–AstraZeneca and Pfizer–BioNTech vaccines, respectively.^[59] Pérez-López et al.^[60] and Russo et al.^[61] have also reported bullous pemphigoid in association with Pfizer–BioNTech vaccine.

Vasculitic skin rash (AstraZeneca vaccine),^[62] atypical maculopapular eruption after Pfizer–BioNTech vaccine^[63] and cutaneous thrombosis leading to genital necrosis following the administration of the first dose of Pfizer–BioNTech vaccine^[64] has also been described.

Renal Manifestations

Minimal change disease (MCD) is the commonest immune-mediated renal disease developing after vaccination against SARS CoV2. Lebedev et al.^[65] reported the index case in a 50-year-old man 10 d after receiving the first dose of BNT162b2 Pfizer–BioNTech vaccine. He presented with anasarca and nephrotic range proteinuria (6.9 g/d). Renal biopsy findings were consistent with those of MCD. He received high-dose steroids and achieved complete remission. More cases of MCD emerged in association with Pfizer–BioNTech vaccine,^[66,67] making it the most commonly implicated vaccine. Likewise, other vaccines have also been linked to the development of MCD. Holzworth et al.^[68] reported the first case of MCD in association with mRNA1273 Moderna vaccine. Likewise, cases of MCD after ChAdOx1 nCoV19 vaccine,^[67,69] Ad26.CoV2 vaccine,^[70] and the inactivated CoronaVac vaccine^[71] have also been reported.

IgA nephropathy is the second commonest autoimmune renal manifestation following vaccination against COVID-19. Six new cases and 6 flares of pre-exiting IgA nephropathy have been reported until August 2021. Eight of the cases developed following mRNA1273 Moderna vaccines, whereas 4 others were associated with Pfizer–BioNTech vaccine.^[72] Moreover, renal vasculitis,^[72] relapse of membranous nephropathy,^[73] relapse of IgG4-related nephritis,^[74] and acute rejection after renal transplant^[75] have also been reported.

Endocrine Manifestations

Graves’ disease has been reported in association with SARS CoV2 vaccine. Both molecular mimicry and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) have been proposed as the underlying mechanism. Bostan et al.^[76] reviewed the available literature till February 2022 and found 20 reported cases of graves’ disease. Of these, 9 patients (45%) had a previous history of autoimmune thyroid disease, whereas 11 patients (55%) developed new-onset graves’ disease. Most common culprit vaccine was found to be mRNA vaccine (15 patients, 75%), whereas 4 cases occurred with vector COVID-19 vaccine and 1 case with inactivated vaccine. The median time from vaccination till symptom onset was 8.5 d.

Other than Graves’ disease, the thyroid gland can be a target of autoimmunity in the form of subacute thyroiditis. Cases have been reported in association with inactivated vaccines, mRNA vaccines, and adenoviral vector vaccines.^[77,78]

Miscellaneous

antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis has been reported in the literature in association with all COVID-19 vaccines, mRNA vaccines being the most common culprit. Twenty-nine cases have been identified thus far till February 2022. Most of the patients presented with renal involvement (93.1%) and responded favorably to immunosuppressive therapy.^[79] Other forms of vasculitis, notably giant cell arteritis,^[80] leukocytoclastic vasculitis,^[81] and flares of quiescent IgA vasculitis^[82] and cryoglobulinemic vasculitis,^[83] have also surfaced after vaccination.

Reactive arthritis after vaccination is rare and scarcely reported in the literature. An et al.^[84] reported a single case of reactive arthritis in a 23-year-old woman after inoculation with inactivated CoronaVac vaccine. She was treated successfully with intra-articular steroid injection.

Raviv et al.^[85] reported the case of a 24-year-old male patient of Ashkenazi Jewish descent who developed a facial rash akin to a malar rash of systemic lupus erythematosus (SLE) 2 d after he received the first dose of mRNA Pfizer–BioNTech vaccine. A subsequent workup showed positive ANA, while all other lupus-specific antibodies were negative. He was diagnosed with SLE as per the 2019 ACR/EULAR criteria and treated with hydroxychloroquine. It has been postulated that the development of SLE in this patient is merely coincidental, but the temporal relationship between vaccination and disease onset may suggest a dysregulated immune response after vaccination.

Table 5 summarizes the most frequently reported multisystem autoimmune manifestations observed thus far and the associated vaccines.