|CASE BASED REVIEW
|Ahead of print publication
Two cases of adult-onset de novo immunoglobulin A vasculitis with nephritis: Post-Covishield (ChAdOx1 nCoV-19; Oxford–Astra Zeneca) vaccination
Vijoy Kumar Jha1, Ramanjit Singh Akal1, Debasish Mahapatra1, S Harikrishnan2, Gurpreet Kaur Walia3
1 Department of Nephrology, Command Hospital Air Force, Bengaluru, Karnataka, India
2 Department of Medical Division, Command Hospital Air Force, Bengaluru, Karnataka, India
3 Department of Pathology, Command Hospital Air Force, Bengaluru, Karnataka, India
|Date of Submission||25-Apr-2022|
|Date of Acceptance||27-Jun-2022|
|Date of Web Publication||26-Jul-2022|
Vijoy Kumar Jha,
Department of Nephrology, Command Hospital Air Force, Post-Agram, Old Airport Road, Bengaluru - 560 007, Karnataka
Source of Support: None, Conflict of Interest: None
With the ongoing worldwide COVID-19 vaccination programs, new-onset glomerular disease and relapse of the preexisting glomerular disease have been reported after COVID-19 vaccines administration. These incidences are overall very rare and had just temporal association with vaccination. It is, therefore, the causal link with the COVID 19 vaccine is not firmly established. In this case-based review, we present two cases, who presented with purpuric rashes and joint pain between 2 and 3 weeks of 2nd dose of Covishield (ChAdOx1 nCoV-19; Oxford–Astra Zeneca) vaccination. Routine evaluation in both these cases revealed significant proteinuria and microscopic hematuria. The diagnosis of immunoglobulin A (IgA) vasculitis with nephritis was established with renal biopsy suggestive of IgA nephropathy and skin biopsy findings of leukocytoclastic vasculitis. Both these cases had severe renal involvement and responded to oral glucocorticoids after 8–16 weeks of treatment. Close observation and careful monitoring of these cases are required to determine the incidence of de novo or recurrence of glomerular disease postvaccination, the need for immunosuppressive therapy, response to aggressive treatment, and long-term clinical outcomes.
Keywords: COVID-19 vaccine, glomerulonephritis, glucocorticoid, immuanoglobulin A vasculitis, purpura
|How to cite this URL:|
Jha VK, Akal RS, Mahapatra D, Harikrishnan S, Walia GK. Two cases of adult-onset de novo immunoglobulin A vasculitis with nephritis: Post-Covishield (ChAdOx1 nCoV-19; Oxford–Astra Zeneca) vaccination. Indian J Rheumatol [Epub ahead of print] [cited 2022 Aug 20]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=352109
| Introduction|| |
Immunoglobulin A vasculitis (IgAV), the most common vasculitis in children is a systemic immune complex-mediated, small vessel leukocytoclastic vasculitis characterized by nonthrombocytopenic palpable purpura and/or arthritis and abdominal pain. In adults, it has a more severe course due to the high frequency of associated glomerulonephritis-IgAV with nephritis (IgAVN). Recently, with the worldwide spread of the COVID-19 vaccination programs, new-onset and relapses of primary glomerular diseases/vasculitis with renal involvement have been reported. In this case-based review, we present two cases of IgAVN who presented with different complaints 2–3 weeks after receiving the second dose of Oxford–Astra Zeneca vaccine.
| Case Reports|| |
A 45-year-old male presented with abdominal pain of 4 days duration which was intermittent, gradually progressive moderate to severe intensity interfering with his routine activities. It initially started in the epigastric region and spread gradually all over the abdomen. He had a history of 2nd dose of Covishield (ChAdOx1 nCoV-19; Oxford–Astra Zeneca) vaccination 12 days before the onset of abdominal pain. He developed polyarthralgia involving bilateral knees and ankle associated with early morning stiffness about 1 week after the onset of pain. He also developed purpuric rashes over lower limbs and dorsum of hands along with polyarthralgia. He had a subjective feeling of fever, but the documented temperature was always normal. His vital parameters were normal at the time of admission. Skin examination revealed multiple well-defined discrete to coalescing erythematous nonpalpable purpura of variable sizes over the medial, lateral, and dorsal aspects of the bilateral feet and dorsum of both hands [Figure 1]a. His initial laboratory evaluation revealed – Complete blood count, liver and renal function tests including serum electrolytes-normal, autoimmune markers (ANA, anti-dsDNA, ANCA)-negative, urine routine examination/microscopic examination-normal, C3-normal, and viral markers (HIV, HBsAg, Anti HCV)-Negative. His skin biopsy was suggestive of leukocytoclastic vasculitis [Figure 1]b and direct immunofluorescence (DIF) was negative for IgA, IgG, IgM, C3. Ultrasonography (USG) abdomen and Upper Gastrointestinal Endoscopy were normal. In view of the persistent abdominal pain despite symptomatic treatment with opioid analgesics computed tomography (CT) angiography was done, which was normal. His routine investigations were repeated after 2 weeks which remain unchanged except for the proteinuria/microscopic hematuria findings (Urine – albumin 2+, 8–10 red blood cells per high power field [RBCs/HPF]). 24-h urinary protein and creatinine were 2100 mg and 1200 mg respectively. He underwent renal biopsy thereafter in view of microscopic hematuria and subnephrotic proteinuria which was suggestive of IgA nephropathy. Total 18 glomeruli-none sclerosed, one glomerulus with a cellular crescent. All glomeruli showed mild to moderate increase in mesangial matrix/cellularity and few show endocapillary cellularity with intracapillary neutrophil and mononuclear cell margination [Figure 2]a, [Figure 2]b, [Figure 2]c and [Figure 2]e. Interstitial fibrosis and tubular atrophy were 10%–15% of the sampled cortex. DIF revealed-IgA-2+/3+ mesangial, granular, kappa light chain-2+, lambda light chain-2+ mesangial: granular/confluent. Mesangial and endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and presence of crescents (MEST-C) Score was M1E1S0T0C1. He was put on telmisartan 40 mg/day, oral prednisolone (30 mg/day), and other supportive measures. His symptoms improved within 7–10 days of starting the glucocorticoids. During follow-up, his proteinuria subsided after 8 weeks of glucocorticoids and it was tapered after 3 months. Low-dose glucocorticoids was given for a total duration of 6 months. This patient is on routine monthly follow-up with nil albuminuria and normal renal function.
|Figure 1: (a) Multiple well-defined discrete to coalescing erythematous nonpalpable purpura of variable size over medial, lateral, and dorsal aspects of the bilateral feet. (b) Skin biopsy- Light microscopy suggestive of perivascular and periadnexial inflammatory infiltration predominantly lymphocytes in the dermis with few areas of polymorphonuclear cells infiltrating the vessel wall. Foci of RBC extravasation in the papillary dermis seen- suggestive of leukocytoclastic vasculitis. (H and E, ×40)|
Click here to view
|Figure 2: (a) Light microscopy reveals mesangial proliferation (PAS, ×20) -Case 1. (b) Light microscopy reveals focal endocapillary proliferation. (PAS, ×20)-Case 1. (c) Light microscopy reveals mesangial proliferation and active cellular crescent (PAS, ×20)- Case 1. (d) Glomerulus reveals endocapillary hypercellularity (9 o clock) obliterating the capillary lumen apart from mesangial proliferation in the rest of the region. (PAS, ×20)- Case 2. (e) Renal Biopsy-IF reveals granular deposits in the mesangial region with IgA antisera -Case 1. (f) IF reveals granular deposits in the mesangial region with IgA antisera-Case 2. PAS: Periodic acid-Schiff, IF: Immunofluorescence, IgA: Immunoglobulin A|
Click here to view
A 30-year-old male presented with complaints of red cutaneous lesions over both legs and hands of 1-week duration. He had 2nd dose of the Covishield vaccine 18 days prior to the onset of these rashes. About a week after the onset of rashes, he developed pain in metacarpophalangeal joints, proximal interphalangeal joints, and wrist of both the hands with early morning stiffness lasting for more than 40–50 min. His vital parameters were normal. Skin examination revealed multiple well-defined noncoalescing palpable purpuric rashes over both legs. He was treated as a case of viral exanthem initially with paracetamol and nonsteroidal anti-inflammatory drug for symptomatic relief of joint pain. His laboratory evaluation revealed-a normal complete blood count, normal liver and renal function tests including serum electrolytes, C-reactive protein-43.9 ng/ml, total cholesterol-242 mg/dl, triglyceride-113 mg/dl, urine routine/microscopic examination-protein 3+, 10–15 RBCs/HPF, 24-h urinary protein and creatinine-2920 mg and 1280 mg respectively, negative viral markers and autoimmune markers. His skin biopsy was suggestive of leukocytoclastic vasculitis and DIF was negative for all immunoreactants. USG abdomen revealed normal-sized kidneys with left distal ureteric calculus with Grade 1 hydroureteronephrosis (HDUN). Noncontrast CT abdomen revealed nonobstructing left renal calculi, two mm sized calculi (average HU = 360) noted in middle and lower polar calyces, left ureter (in its entire course), and pelvicalyceal system was dilated (Grade II HDUN). Urology consultation was sought and was advised to manage himself conservatively. He was referred to us in view of significant proteinuria and microscopic hematuria. He underwent renal biopsy thereafter which revealed-18 glomeruli. 2 were globally sclerosed. The remaining glomeruli revealed mesangial expansion with cellular proliferation with focal endocapillary proliferation in a few glomeruli [Figure 2]d and [Figure 2]f. There were no crescents. DIF revealed– IgA 3+-mesangial granular, kappa light chain-2+, lambda light chain-3+, C3-1+, remaining immunoreactants-negative. MEST-C score was M1E1S0T0C0. He was put on tab telmisartan 40 mg/day, oral prednisolone 30 mg/day, and other supportive measures. He had significant improvement in his symptoms after 1 week of starting immunosuppression. His proteinuria started improving after 10 weeks and had no proteinuria after 4 months of presentation. The patient stopped all drugs after 4 months on his own. He is normotensive at present and there is no proteinuria 2 months after stopping the drugs.
The timeline of both clinical presentations is depicted in [Figure 3].
| Discussion|| |
Different types of COVID-19 vaccines are being used around the world. The Pfizer BNT162b2 (Pfizer-BioNTech) and Moderna (mRNA-1273) are mRNA vaccines use a lipid nanoparticle nucleoside-modified mRNA encoding the SARS-CoV-2 spike (S) protein that is involved in the host attachment and viral entry. India has three available vaccines as of now (Covishield [ChAdOx1 nCoV-19; Oxford–AstraZeneca; manufactured by Serum Institute of India], Covaxin [BBV152; Bharat Biotech], and Sputnik V [Gam-COVID-Vac; Gamaleya Research Institute of Epidemiology and Microbiology]) approved for emergency use in adults. The Astra-Zeneca vaccine is a chimpanzee adenovirus vector that is deficient in replication and contains the SARS-CoV-2 spike (S) protein. mRNA vaccines have minimal risk of infection and insertion induced mutagenesis, produce antiviral neutralizing immunoglobulins, and stimulate strong immune responses by activating both CD8+ and CD4+ T cells. It was also proposed that mRNA COVID-19 vaccine results in antibody production, activation of virus-specific CD4+ and CD8+ T cells, and release of cytokines such as interferon-γ (IFN-γ). IFN-γ along with Type I INFs inhibits the replication of the SARS-CoV2 virus. In patients with a relapse of preexisting IgAV following COVID-19 vaccination, it is unclear whether the activation of autoreactive B-cells is due to the previous or new autoreactive B-cells producing IgA, or a combination of both of these., The development of IgAV has also been reported following various vaccinations such as influenza, hepatitis A, and meningococcal vaccines. There is a structural similarity between influenza antigens and vaccine proteins suggesting the link between vaccines and autoimmunity. The exact pathogenesis of IgAV following COVID-19 vaccination is still unknown. Cytokines triggered by the mRNA vaccine may activate IgA1-producing B cells as well. The trigger in predisposed individuals may be an immune response to the spike protein or the mRNA of the mRNA-1273 COVID-19 vaccine. A link between an increase in anti-SARS-CoV-2 spike IgA and relapse of preexisting IgAV has also been suggested after receiving the mRNA-1273 COVID-19 vaccine. The Covishield vaccine contains recombinant adenoviral vectors encoding the spike protein of SARS-CoV-2, stabilizers, and immune adjuvants. It has been proposed that molecular mimicry might develop between peptides of the viral spike protein and host endothelial cells.,
With millions of COVID-19 vaccinations administered globally, side effects are being reported. Many adverse effects may remain unreported as the causal link is difficult to establish on the basis of temporal association. COVID-19 vaccines might cause immunologic events, such as autoimmunity or exacerbation of preexisting autoimmune disorders. There are only two cases of IgAV post-Covishield vaccination in the published literature., Out of these two, one case had evidence of renal involvement, and the patient responded to oral glucocorticoid [Table 1]. No renal histopathological information regarding new-onset IgAV with kidney involvement after receiving the Covishield vaccine has been made available as both of the cases had not undergone biopsy. The available literature related to IgAV post COVID vaccination other than Covishield is demonstrated in [Table 2]. Out of these 6 cases, 4 had evidence of renal involvement and only two underwent renal biopsy.,,,,, One of these cases also received intravenous cyclophosphamide in view of severe disease with cellular crescents.
|Table 1: IgA vasculitis cases (New onset) including present case after Covishield (ChAdOx1 nCoV-19; Oxford–Astra Zeneca) vaccine|
Click here to view
|Table 2: IgA vasculitis cases (new onset) after COVID-19 vaccination (other than Covishield vaccine)|
Click here to view
IgA is the leading immunoglobulin against COVID-19 infection which provides mucosal immunity. After the COVID-19 vaccination, both IgG and IgA are elevated, with IgG lasting longer. The period of IgA elevation after COVID-19 vaccination is transient and shorter. Hence, the onsets of IgAVN after vaccination may be earlier than that of another primary glomerular disease.,, This finding also suggests that these onsets occur during IgA elevation. The clinical course of glomerulonephritis in both our cases was severe, and persistent despite putting on an oral steroid for about 8–16 weeks. There is also a difference in mechanisms between severe/persistent and mild/transient cases of IgAVN, which has not been fully elucidated. IgAVN patients were detected to have higher production and circulation of galactose-deficient (GD) IgA1 and GD IgA1-specific IgG autoantibodies compared to healthy subjects and IgAV patients without nephritis. It is possible that both of our patients had large amounts of GD IgA1 and GDIgA1-specific IgG autoantibodies that were necessary to develop severe IgAVN. More studies will be needed to precisely elucidate the exact pathogenesis of IgAVN following COVID 19 vaccination/other vaccination. Renal biopsy postvaccination in IgAN patients developing gross hematuria has revealed active endocapillary hypercellularity, leukocyte infiltration, fibrinoid necrosis, and crescents, although these lesions can involve a few glomeruli. Hematuria and purpura typically resolved rapidly within a few days in most of these cases.,,,,,,, In the present case, though palpable purpura and polyarthralgia subsided within a few days of steroid initiation, it took a few weeks to resolve proteinuria and hematuria. The worse prognosis of IgAVN in most studies in adults than in children justifies the use of aggressive treatment to preserve renal function. Poor prognosis may be due in part to concurrent chronic kidney disease or a longer duration between disease onset and clinical presentation.
| Conclusion|| |
In this case-based review, there is only a temporal relationship between the onset of symptoms suggestive of IgAVN and COVID 19 vaccination, causality is unclear. It may be possible that immunization did not trigger the onset of glomerular disease. Although there are many reported cases of glomerular disease including IgAVN in temporal association with vaccination, the true incidence or prevalence of the disease is not known as many cases may have remained unreported. More research studies are required to determine the incidence of de novo or recurrence of glomerular disease postvaccination, response to treatment, and long-term clinical outcomes.
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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lai L, Liu S, Azrad M, Hall S, Hao C, Novak J, et al.
IgA vasculitis with nephritis in adults: Histological and clinical assessment. J Clin Med 2021;10:4851.
Izzedine H, Bonilla M, Jhaveri KD. Nephrotic syndrome and vasculitis following SARS-CoV-2 vaccine: True association or circumstantial? Nephrol Dial Transplant 2021;36:1565-9.
Wang F, Kream RM, Stefano GB. An evidence based perspective on mRNA-SARS-CoV-2 vaccine development. Med Sci Monit 2020;26:e924700.
Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, et al.
COVID-19 vaccine BNT162b1 elicits human antibody and TH
1 T cell responses. Nature 2020;586:594-9.
Obeid M, Fenwick C, Pantaleo G. Reactivation of IgA vasculitis after COVID-19 vaccination. Lancet Rheumatol 2021;3:e617.
Heineke MH, Ballering AV, Jamin A, Ben Mkaddem S, Monteiro RC, Van Egmond M. New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schönlein purpura). Autoimmun Rev 2017;16:1246-53.
Zafrir Y, Agmon-Levin N, Shoenfeld Y. Post-influenza vaccination vasculitides: A possible new entity. J Clin Rheumatol 2009;15:269-70.
Anderegg MA, Liu M, Saganas C, Montani M, Vogt B, Huynh-Do U, et al.
De novo vasculitis after mRNA-1273 (Moderna) vaccination. Kidney Int 2021;100:474-6.
Badier L, Toledano A, Porel T, Dumond S, Jouglen J, Sailler L, et al.
IgA vasculitis in adult patient following vaccination by ChadO×1 nCoV-19. Autoimmun Rev 2021;20:102951.
Sirufo MM, Raggiunti M, Magnanimi LM, Ginaldi L, De Martinis M. Henoch-Schönlein purpura following the first dose of COVID-19 viral vector vaccine: A case report. Vaccines (Basel) 2021;9:1078.
Grossman ME, Appel G, Little AJ, Ko CJ. Post-COVID-19 vaccination IgA vasculitis in an adult. J Cutan Pathol 2022;49:385-7.
Iwata H, Kamiya K, Kado S, Nakaya T, Kawata H, Komine M, et al.
Case of immunoglobulin A vasculitis following coronavirus disease 2019 vaccination. J Dermatol 2021;48:e598-9.
Hines AM, Murphy N, Mullin C, Barillas J, Barrientos JC. Henoch-Schönlein purpura presenting post COVID-19 vaccination. Vaccine 2021;39:4571-2.
Mohamed MM, Wickman TJ, Fogo AB, Velez JC. De novo
immunoglobulin A vasculitis following exposure to SARS-CoV-2 immunization. Ochsner J 2021;21:395-401.
Nakatani S, Mori K, Morioka F, Hirata C, Tsuda A, Uedono H, et al.
New-onset kidney biopsy-proven IgA vasculitis after receiving mRNA-1273 COVID-19 vaccine: Case report. CEN Case Rep 2022:1-5.
Sugita K, Kaneko S, Hisada R, Harano M, Anno E, Hagiwara S, et al.
Development of IgA vasculitis with severe glomerulonephritis after COVID-19 vaccination: A case report and literature review. CEN Case Rep. 2022:1-6.
Bruel T, Schwartz O, Lacorte JM, Yssel H, Parizot C, Dorgham K, et al
. IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med 2021;13:eabd2223.
Wisnewski AV, Campillo Luna J, Redlich CA. Human IgG and IgA responses to COVID-19 mRNA vaccines. PLoS One 2021;16:e0249499.
Wu HH, Kalra PA, Chinnadurai R. New-onset and relapsed kidney histopathology following COVID-19 vaccination: A systematic review. Vaccines (Basel) 2021;9:1252.
Suzuki H, Moldoveanu Z, Julian BA, Wyatt RJ, Novak J. Autoantibodies specific for Galactose-Deficient IgA1 in IgA vasculitis with nephritis. Kidney Int Rep 2019;4:1717-24.
Kudose S, Friedmann P, Albajrami O, D'Agati VD. Histologic correlates of gross hematuria following Moderna COVID-19 vaccine in patients with IgA nephropathy. Kidney Int 2021;100:468-9.
Blanco R, Martínez-Taboada VM, Rodríguez-Valverde V, García-Fuentes M, González-Gay MA. Henoch-Schönlein purpura in adulthood and childhood: Two different expressions of the same syndrome. Arthritis Rheum 1997;40:859-64.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]