The pathogenesis of COVID-19-induced IgA nephropathy and IgA vasculitis: A systematic review

Objective IgA nephropathy (IgAN) and IgA vasculitis (IgAV) are part of a similar clinical spectrum. Both clinical conditions occur with the coronavirus disease 2019 (COVID-19). This review aims to recognize the novel association of IgAN and IgAV with COVID-19 and describe its underlying pathogenesis. Methods We conducted a systematic literature search and data extraction from PubMed, Cochrane, ScienceDirect, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Our search identified 13 cases reporting IgAV and IgAN associated with COVID-19 infection and 4 cases of IgAN following COVID-19 vaccination. The mean, mode, and median ages of patients were 23.8, 4, and 8 years, respectively. Most cases associated with COVID-19 infection were reported in males (77%). Rash and purpura (85%) were the most common clinical features, followed by gastrointestinal symptoms (62%). In symptomatic cases, skin or renal biopsy and immunofluorescence confirmed the diagnosis of IgAN or IgAV. Most patients were treated with steroids and reported recovery or improvement; however, death was reported in two patients. Conclusion There is a paucity of scientific evidence on the pathogenesis of the association of IgAN and IgAV with COVID-19, which thus needs further study. Current research suggests the role of IgA-mediated immune response, evidenced by early seroconversion to IgA in COVID-19 patients and the role of IgA in immune hyperactivation as the predominant mediator of the disease process. Clinicians, especially nephrologists and paediatricians, need to recognize this association, as this disease is usually self-limited and can lead to complete recovery if prompt diagnosis and treatment are provided.

. This review aims to recognize the novel association of IgAN and IgAV with COVID-19 and describe its underlying pathogenesis.

Methods:
We conducted a systematic literature search and data extraction from PubMed, Cochrane, Science-Direct, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Results: Our search identified 13 cases reporting IgAV and IgAN associated with COVID-19 infection and 4 cases of IgAN following COVID-19 vaccination. The mean, mode, and median ages of patients were 23.8, 4, and 8 years, respectively. Most cases associated with COVID-19 infection were reported in males (77%). Rash and purpura (85%) were the most common clinical features, followed by gastrointestinal symptoms (62%). In symptomatic cases, skin or renal biopsy and immunofluorescence confirmed the diagnosis of IgAN or IgAV. Most patients were treated with steroids and reported recovery or improvement; however, death was reported in two patients.
Conclusion: There is a paucity of scientific evidence on the pathogenesis of the association of IgAN and IgAV with COVID-19, which thus needs further study. Current research suggests the role of IgA-mediated immune response, evidenced by early seroconversion to IgA in COVID-19 patients and the role of IgA in immune hyperactivation as the predominant mediator of the disease process. Clinicians, especially nephrologists and paediatricians, need to recognize this association, as this disease is usually self-limited and can lead to complete recovery if prompt diagnosis and treatment are provided.

Introduction
With an incidence of 3e16% in healthy individuals, IgA nephropathy (or Berger's disease) is the most common type of glomerulonephritis across the world. 1e5 It can be seen more frequently in the second and third decades of life, and the name originates from predominant IgA immune complex deposition in the glomerular mesangium on biopsy. 6 The classic clinical picture is a child or young adult who develops episode(s) of gross or microscopic haematuria resulting from an upper respiratory tract infection. 2 It may cause acute renal failure characterized by ankle oedema, facial puffiness, and hypertension. The clinical features are more in line with a nephritic type syndrome, while a nephrotic type rarely occurs in IgA nephropathy. 7 Closely related to IgA nephropathy is another clinical entity called Henoch Schonlein Purpura (HSP), an IgA-mediated systemic small-vessel vasculitis that, in addition to the kidneys, affects the skin (purpura), joints (arthritis), gut (melena, abdominal pain), etc. 8,9 The definitive diagnosis of both can only be made on biopsy and the main distinction between the two is the extra-renal involvement seen in HSP. 2 Many researchers have upheld the view that both diseases are part of the same spectrum and their underlying pathology is almost identical. 10,11 In December 2019, a new viral disease known as COVID-19 was identified. As of May 26, 2021, the World Health Organisation has confirmed more than 167 million cases of this infection on its official website. Although the virus is causing many unknown systemic effects in the human body, it has also been identified as an etiological factor or trigger for some well-recognised clinical entities. Among these conditions, IgA nephropathy and IgA vasculitis (or HSP) are being increasingly described in conjunction with COVID-19. Recent studies have highlighted the role of serum IgA in immune hyperactivation and early seroconversion to IgA in COVID-19 patients. 12,13 This evidence may serve as the most plausible explanation for the rise in reported cases of these IgA-mediated diseases, but a comprehensive review that explores this link has not yet been published. Not only does this systematic review serve to elucidate this research question, but it also intends to review other possible pathogenic mechanisms at play. A detailed account of underlying pathogenesis can guide treatment, as well as expand the scientific understanding of researchers at large. A compilation of all such cases will alert practising physicians about rare manifestations of SARS-CoV-2 infection and enhance their knowledge regarding the likely clinical presentation. Timely diagnosis and prompt treatment will improve morbidity and mortality, and ultimately enhance patient care. Given the recent origination of this virus and the paucity of literature on the topic under discussion, a systematic review of cases remains the only reliable medical evidence for researchers and physicians. It also lays a foundation for future researchers as they expand our understanding of this novel clinical association.

Study selection and data extraction
The articles were searched and screened according to the PRISMA flowchart ( Figure 1). The records identified through the preliminary search were downloaded into Mendeley and duplicates were removed. Two independent reviewers, HF and MAR, performed the screening and concluded that only case reports and letters to the editor have been published on this topic. In total, 16 articles were shortlisted; 13 articles discussed cases of COVID-19infection-associated IgAN/IgAV, while another 3 reported COVID-19-vaccine-triggered IgAN. These articles' bibliographies were sieved to identify any missed cases. All the selected articles were reviewed thoroughly and essential data (e.g. demographics, clinical course, laboratory investigations, and outcome) were extracted and summarised in the form of three tables. Continuous variables are presented as mean, mode, and median, whereas the categorical variables are presented as absolute values and percentages. Microsoft Excel was used for data extraction as well as the calculation of these variables. The references were added through Zotero.

Quality assessment
The quality of case reports was assessed by Joanna Briggs Institute Critical Appraisal Tool. 14 Three reviewers (SA, AM, MAQ) first scored each article independently and then awarded a consensus score to each. The score report is provided in the Supplementary files.

Results
Our search of the four databases identified 2316 articles; 159 were excluded due to duplication and 2140 were removed due to irrelevance to the subject. One article, even though initially considered due to a similar clinical picture to IgAV, was eventually removed as it ruled out IgAV and concluded with a different diagnosis after histological investigations. Finally, 16 articles were selected for inclusion: 13 articles, 15e 27 including 9 case reports 16e22,26,27 and 4 letters to the editor, 15,23e25 reported cases of IgAN and IgAV following COVID-19 infection. The data of these 13 cases are summarized in the form of two tables (Tables 1 and 2), one focusing on notable clinical findings and outcomes, the other on major laboratory investigations. Additionally, three articles 28e30 describing a total of four patients with COVID-19-vaccination-triggered IgAN were found. These are also described in our article to broaden the scope of this review, as the underlying pathogenic mechanisms might be closely linked to COVID-19-infection-related IgAN/IgAV (Table 3).
The most commonly reported symptoms of IgAV/IgAN were rash/purpura (n ¼ 11, 85%), gastrointestinal symptoms, like abdominal pain, melena/haematochezia, haematemesis etc. (n ¼ 8, 62%), joint problems/pain (n ¼ 7, 54%) and oedema (n ¼ 4, 31%). Urinalysis reported proteinuria and haematuria in six (46%) and four (31%) patients, respectively. The cornerstone of definitive diagnosis in all    patients was either renal or skin biopsy; abnormal renal biopsy was seen in five cases (39%), whereas skin biopsy abnormalities were reported in six patients (46%). Seven samples (54%) demonstrated positive IgA immunofluorescence: two from kidneys, four from the skin, and one from both the kidneys and the skin. Immunosuppressants and supportive therapy were the mainstays of treatment. Most (n ¼ 9, 69%) patients were treated with steroids, while some patients were also administered antihypertensives, analgesics, and antimicrobials. Among the 12 cases that reported proper outcome/followup, 10 (83%) improved significantly with the treatment, whereas death was reported in 2 patients (17%). Both cases of death were reported in the paediatric age group, one in an infant and the other in a child of six years.
Three articles reporting four cases of IgA nephropathy following COVID-19 vaccination have also been described in the literature. All patients were adult females, and the vaccines responsible for this presentation were Moderna and Pfizer (two cases each). Three of these cases occurred as flareups in known cases of IgA nephropathy; however, one occurred in a patient who had no previous history of IgAN. The details are summarised in Table 3.

Discussion
With COVID-19 cases increasing globally, new manifestations of this virus are unfolding before the medical community. This virus of Chinese origin 31 reportedly affects almost every human organ, thus causing cutaneous, renal, cardiac, psychological, neurological, and even vascular problems. 32e 38 Though various types of vasculitides and kidney injury have been well reported with COVID-19, 39,40 little is known about IgA-mediated systemic vasculitis (Henoch Schonlein Purpura) and nephropathy. With increasing evidence of IgA's role in COVID-19 immune response, 12,13 cases of IgA immune complex deposition diseases, like IgA vasculitis and IgA nephropathy, are also rising. There has been a debate among the medical fraternity on the description of IgAV and IgAN as distinct clinical entities, and various specialists consider them part of the same clinical spectrum. 10,11 IgA vasculitis characteristically presents with a tetrad of symptoms, including palpable purpura (in absence of concurrent thrombocytopenia or coagulation disorder), arthralgia/joint pain, abdominal discomfort/pain, and renal involvement. 41 On the other hand, IgA nephropathy is predominantly a renal disease. 42 The criteria devised by the European League Against Rheumatism (EULAR), Paediatric Rheumatology International Trials Organization (PRINTO), and Paediatric Rheumatology European Society (PRES) are usually employed in the clinical diagnosis of IgAV in children but have limited utility in adult patients. In fact, in order to allow for diagnosis, the presence of purpura along with any of the four features (namely abdominal pain, arthritis, renal disease, or IgA mediated vasculitis/ glomerulonephritis) is required. 43,44 Although these criteria were not described in all cases per se, the clinical approach used was well in line with them. Rash/purpura was the most common presenting complaint in the cases fulfilling the inclusion criteria of our study, which is consistent with larger clinical studies describing rash as the most common finding in IgAV. 8,9 Well in line with the literature, 4,5 most cases of IgAN/IgAV associated with COVID-19 were seen in male children or young adults; however, three cases 16,21,24 in old age have been described with SARS-CoV-2, which is rare but also has been reported previously. 1e5, 45 With regards to pathogenesis, the most widely accepted is the 'multi-hit hypothesis'. Raised levels of Galactose deficient IgA1 (Gd-IgA1) are crucial for the development of both IgA nephropathy and HSP nephritis. Generation of IgG autoantibodies can be seen targeting these IgA1 immunoglobulins, which leads to the immune complex formation and an inflammatory process; however, the role of the same immune complexes for extrarenal components of HSP is not well established. 46e49 For vasculitic/extrarenal components of HSP, a multi-hit model involving IgA1-AECA (antiendothelial cell antibody) is accepted. 50 The exact role of COVID-19 in the development of these IgA-related diseases is still being explored, although several possibilities exist. Mucosal infections are believed to enhance IL-6 production that stimulates poor glycosylation/galactosylation of IgA1, thus forming Gd-IgA1 and contributing towards the disease process of IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN). 50 COVID-19, being a mucosal infection as well, might cause IgAVN and IgAN through this pathway. Studies have revealed that bone marrow is the source of increased IgA1-producing B lymphocytes in patients with IgA nephropathy. The cytokines released in COVID-19 (such as IL-1, IL-6, and TNF) can also potentially lead to the proliferation and maturation of these IgA1producing B cells, hence leading to IgAN. 51e53 Research is being carried out to document the diagnostic significance of detecting humoral response against SARS-Cov2 infection 54 and IgA antibodies are emerging as pivotal markers. 55,56 Early seropositivity of IgA, emerging two days after initial symptomatology in COVID-19 patients, is being reported in comparison to five days for IgG and IgM. 12 This might be one of the factors responsible for the formation of immune complexes involving IgA. A previous systematic review exploring the link of COVID-19 with autoimmune diseases has been conducted, suggesting various mechanisms leading to deleterious effects. 57 The complex genome of this virus and its tendency to mimic molecular machinery enhances its ability to cause autoimmune diseases, 57,58 which might be a possible link of this phenomenon with IgAN and IgAV occurring alongside SARS-Cov2 infection.
Moreover, we know that Henoch Schonlein Purpura can be triggered by a variety of other bacterial and viral infections including coxsackievirus, parvovirus, adenovirus, hepatitis A/ B, Staphylococcus aureus, and group A streptococcus, thus further strengthening our idea of its ominous relationship with coronavirus. 59e61 Evidence also suggests that COVID-19 is capable of inducing endothelial injury as a result of viral components directly affecting endothelial cells via ACE2 receptors, as well as indirectly through inflammation occurring due to defence mechanisms of the host. 62 COVID-19 infection has also been observed to exacerbate pre-existing IgA nephropathy, as per one of the case reports 21 included in our study, but the underlying mechanism is debatable. Interestingly, cases of IgA nephropathy also appeared following COVID-19 vaccination in a few individuals. 28e30 Three cases have described flare-ups or worsening of already existing IgA nephropathy following SARS-CoV-2 vaccination, while one case reported appearance of IgAN in a previously healthy patient (although the authors suspected that this patient might have had undiagnosed IgAN). Excessive production of IgA1 monomers in IgAN patients in response to influenza vaccine has been described previously 63 ; hence, the possibility that a similar process occurs after COVID-19 vaccination exists. Some scientists are still looking for a plausible explanation regarding the development of IgA nephropathy despite the non-mucosal injection of the vaccine. It has been postulated that in susceptible patients with pre-existing under-galactosylated IgA1 antibodies, the vaccine triggers the production of anti-glycan antibodies that combine with the former and lead to IgAN. 64 The significance of steroids in treating IgAV and IgAN has been interrogated by various scientists and is said to be controversial. 65,66 In our study, most of the patients suffering from COVID-related IgAN and IgAV were subjected to treatment with steroids along with other options available, particularly antibiotics and antihypertensives. As per our results, a favourable outcome was observed in most cases. This is consistent with the understanding that IgAV is a selflimited disease, but it is hard to conclude whether this favourable outcome was due to the self-limiting nature of the disease itself or the efficacy of steroids in treating IgAV.
Based on the evaluation and discussion of the few case reports published so far, the authors would like to emphasize that there are chances of IgAN and IgAV being reported in connection with COVID-19 in the future. Various case reports and reviews have described other forms of vasculitis in COVID-19 too, most commonly Kawasaki disease and some types of leukocytoclastic vasculitis. 67e69 The herculean task of managing this virus is already imposing a burden on healthcare systems worldwide, and associated conditions like IgAV and IgAN can make it all the more challenging. We believe that physicians should take this association into account when examining patients with ongoing or resolved COVID-19 infection who present with symptoms depicting renal pathology, especially patients with a history of hypertension or kidney disease. Timely inspection and treatment would pave the way to improved prognosis of such patients. Furthermore, a focus on more clinical research in this area is needed in order to better understand its incidence and underlying mechanism, as well as providing reliable information in this regard.
The authors would like to acknowledge some limitations as well. We realize that the sample size in our study is small owing to the lack of published articles related to our research question. Since most of the relevant literature includes case reports, it is harder to extrapolate results from the entire population. Serum IgA/Creatinine ratio was not reported in most of the cases, despite its well-known utility in diagnosing IgAN and predicting its outcome. 70e72 The authors independently scored case reports using the Critical Appraisal Tool, so there is a possibility of subjectivity in quality assessment. Lastly, we suspect publication bias, as clinicians are more likely to report clinically significant, unique, and challenging cases.

Conclusion
IgA-mediated diseases like IgA vasculitis and IgA nephropathy are increasingly occurring in connection with COVID-19. The evidence for the role of IgA in the immune response against COVID-19 is also increasing. The enhancement of IL-6 levels as a result of a mucosal infection like SARS-Cov2 leads to aberrant glycosylation of IgA1 antibodies, forming immune complexes with IgG autoantibodies and depositing in the tissues. Flare-ups/worsening of pre-existing IgAN and new-onset IgAN have also been reported following SARS-CoV-2 vaccination. Special attention must be given by the clinicians to COVID-19 patients belonging to the paediatric age group who present characteristic features of these diseases; however, the possibility of these infections in old age must not be ignored if clinical suspicion exists. Patients may suffer from IgA vasculitis or IgA nephropathy during or even after the resolution of COVID-19 infection, and cases following vaccination have also been reported. Since the vaccination drive and the pandemic are still ongoing, physicians should take common complaints like rash, abdominal pain, and haematuria very seriously. Although most cases are self-limited, timely diagnosis and supportive treatment are still beneficial to prevent long-term consequences to the patient's health.

Source of funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.