ANCA-associated Vasculitic Neuropathy Following Anti-SARS-CoV-2 Vaccination: An Epiphenomenon or Causal Association? : Annals of Indian Academy of Neurology

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ANCA-associated Vasculitic Neuropathy Following Anti-SARS-CoV-2 Vaccination: An Epiphenomenon or Causal Association?

Jha, Shreyashi; Hema, A. V.1; Padmanabha, Hansashree; Mahadevan, Anitha1; Mailankody, Pooja; Mathuranath, P. S.; Mahale, Rohan R.

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Annals of Indian Academy of Neurology 26(2):p 187-189, Mar–Apr 2023. | DOI: 10.4103/aian.aian_848_22
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Dear Sir,

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were introduced to enhance host immunity against coronavirus disease 2019 (COVID-19). ChAdOx1-S (Covishield™/Vaxzervria, AstraZeneca) was one of the vaccines widely utilized in the vaccination campaign in India. They were proven to be safe and effective in randomized controlled trials, but neurological adverse events following immunization (AEFI) have been reported.[1] Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis characterized by the presence of antibodies against antigens in cytoplasmic granules of neutrophils (myeloperoxidase (MPO) or proteinase 3 (PR3) antigens).[2] There are various reports of AAV post-anti-SARS-CoV-2 vaccination causing glomerulonephritis, but ANCA-associated vasculitic neuropathy has not been reported. Hereby we report a patient of new-onset ANCA-associated vasculitic neuropathy following anti-SARS-CoV-2 vaccination.

A 51-year-old male patient presented with weakness in distal lower limbs in the form of foot drop followed by proximal lower limbs and both upper limbs of 3-day duration. He was bed-bound by sixth day of onset of symptoms. On the second day of symptoms, he developed erythematous maculopapular skin lesions over the dorsal aspect of both his legs [Figure 1]. He had distal tingling paraesthesia in both lower limbs on second day of illness. He received the first dose of the ChAdOx1-S (Covishield™/Vaxzervria, AstraZeneca) 10 days before the onset of weakness. There was no bladder, bowel involvement, no dysphagia, or neck weakness. There were no systemic symptoms. There was palpable purpura over dorsal aspect of both legs. Neurological examination showed normal cranial nerves, hypotonia of all limbs, Medical Research Council (MRC) grade 0 power of both lower limbs and distal upper limbs, and grade 2/5 power in proximal upper limbs with generalized areflexia. Sensory examination showed complete loss of sensation to touch, pain, and temperature from below knee in lower limbs and in hands. Proprioception was impaired in both medial malleoli. Complete blood counts showed eosinophilia with raised erythrocyte sedimentation rate of 46 mm/hour, C-reactive protein of 36 mg/dl, and positive rheumatoid factor (RF) of 60 IU/ML. Urine routine examination, renal, hepatic functions were normal. Vasculitis profile showed positive anti-nuclear antibody (ANA) and c-ANCA by indirect immunofluorescence (IF) method [Figure 1]. Cerebrospinal fluid analysis was normal. Nerve conduction study showed low compound muscle action potential (CMAP) in bilateral median, ulnar, and radial nerves with preserved distal motor latencies and conduction velocities, absent CMAPs in bilateral common peroneal and posterior tibial nerves, absent sensory nerve action potentials in bilateral median, ulnar, sural, and superficial peroneal nerves. Sural nerve and skin lesion biopsy showed lymphohistiocytic infiltration, hemosiderin deposition, and vessel damage consistent with probable vasculitis [Figure 2]. A diagnosis of ANCA-associated vasculitic neuropathy was made and was started on intravenous methylprednisolone (1 gram/day for 5 days). He did not have improvement and was subsequently started on intravenous cyclophosphamide (1 gram over 3 days). At 12 weeks of follow-up, he was ambulant with one-stick support with persistent distal upper and lower limb weakness. At 6-month follow-up, he was self-ambulant with persistent distal upper and lower limb weakness.

Figure 1:
Indirect immunofluorescence shows characteristic pattern of cANCA with granular cytoplasmic fluorescence in both ethanol (a) and formalin-fixed neutrophils (b); Hep2 cells do not show fluorescence (internal negative control) (c). (d) Palpable purpura over both legs
Figure 2:
Microphotographs from nerve biopsy shows (a) acute axonal breakdown and myelin ovoid formation (H and E) (a and b) severe loss of myelinated fibers and acute myelin breakdown seen on myelin stains (Kulchitsky pal stain); (c) perivascular lymphocytic infiltrates around nutrient artery and epineurial arterioles are present (LCA immunohistochemistry); (d and e) nutrient artery shows periadventitial capillary proliferation and epineurial neovascularization (Masson’s trichrome stain); (f) Perl’s stain highlights the hemosiderin deposits around the inflamed nutrient artery. Scale bar represents 20 microns

ChAdOX1-S is a recombinant vaccine developed by AstraZeneca and the University of Oxford utilizing the non-replicating viral vector in form of replication-deficient simian adenovirus containing genes for full-length structural spike protein of SARS-CoV2. ChAdOX1-S use a modified Chimpanzee virus itself to generate a protective immune response, by offering a sufficient antigenic stimulus that can drive the host B- and T-cell responses without causing the disease.[3] ANCA-associated vasculitis (AAV) due to anti-SARS-CoV-2 vaccines was noted to be more frequent with mRNA vaccines, and pANCA was most frequently identified autoantibody.[4] New-onset autoimmune manifestations following SARS-CoV-2 vaccination may be due to the molecular mimicry, production of auto-antibodies or due to the immune adjuvants in the vaccine preparations that enhances the immune responses. This phenomenon has been described as “autoimmune or inflammatory syndrome induced by adjuvants (ASIA).” However, the association between the autoimmune manifestations and SARS-CoV-2 vaccine is coincidental or causal remains to be elucidated.[5]

ANCA is associated with vasculitis characterized by inflammatory cell infiltration of the walls of small- and medium-sized vessels leading to vascular destruction and tissue necrosis. The antigen associated with c-ANCA pattern on the indirect IF is the leukocyte PR3 seen in granulomatosis with polyangiitis (GPA), and p-ANCA pattern is MPO seen in microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). GPA is a necrotizing granulomatous inflammation of the upper and lower respiratory tracts with necrotizing vasculitis of small- and medium-size vessels with antibodies directed against PR3 antigen.[2] Our patient did not have systemic features of GPA in the form of respiratory tract, renal or pulmonary involvement. The nerve biopsy did not show granulomatous vasculitis. There are reports of AAV-associated glomerulonephritis following anti-SARS-CoV-2 vaccination, but the ANCA-associated vasculitic neuropathy has not been reported so far. Our patient had good response with cyclophosphamide.

To conclude, neurological AEFI has been reported following anti-SARS-CoV-2 vaccines. This case adds to the list of neurological AEFI following anti-SARS-CoV-2 vaccination. However, ANCA-associated vasculitic neuropathy is a very rare post-vaccinial neurological disorder and should not preclude the mass vaccination campaign to combat the COVID-19 pandemic.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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2. Marzano AV, Raimondo MG, Berti E, Meroni PL, Ingegnoli F. Cutaneous manifestations of ANCA-associated small vessels vasculitis. Clin Rev Allergy Immunol 2017;53:428–38.
3. Mascellino MT, Di Timoteo F, De Angelis M, Oliva A. Overview of the main anti-SARS-CoV-2 vaccines:Mechanism of action, efficacy and safety. Infect Drug Resist 2021;14:3459–76.
4. Prabhahar A, Naidu GSRSNK, Chauhan P, Sekar A, Sharma A, Sharma A, et al. ANCA-associated vasculitis following ChAdOx1 nCoV19 vaccination:Case-based review. Rheumatol Int 2022;42:749–58.
5. Irure-Ventura J, Belmar-Vega L, Fernández-Fresnedo G, González-López E, Castro-Hernández C, Rodrigo-Calabia E, et al. Increased induction of de novo serum ANCA and ANCA-associated vasculitis after mass vaccination against SARS-CoV-2. iScience 2022;25:104847 doi:10.1016/j.isci.2022.104847.
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