Iga Vasculitis And COVID-19 In Children: A Systematic Review


 Background: Immunoglobulin A vasculitis is the most common form of vasculitis in children. The diagnosis is made clinically and patients will present with a rash, together with gastrointestinal, musculoskeletal, and renal system involvement. Progress in the classification of the systemic vasculitides has facilitated better understanding of the pathogenesis underlying these inflammatory conditions. Over the past year, several cases of IgA vasculitis have been reported in both children and adults in association with SARS-CoV2 infection, raising the question of whether there is any causal or even a synergistic association.Methods: This systematic review was performed following the guidelines of Meta-analysis of Observational Studies in Epidemiology. A literature search was conducted using MEDLINE, SciELO and Google Scholar using the search terms “COVID-19” or “SARS-CoV-2" in combination with “IgA vasculitis”, or “Henoch-Schonlein Purpura”. We considered articles to be eligible for inclusion if they reported a case report or series of cases of IgA vasculitis associated with proven COVID-19 infection. We excluded cases from further review if the case reported was a patient older than 18 years. WHO causality assessment categories were used to standardize case causality. Results: After reviewing the complete article and applying our exclusion criteria, 12 articles describing 12 cases of COVID-19 associated IgA vasculitis in children were included. In 83% of the cases the diagnosis of COVID-19 was made on presentation of IgA symptoms or on presentation to seek medical care. In 17% of cases the SARS Cov-2 test was positive before IgA vasculitis symptoms presentation. The mean age of the patients was 7.3 years of age (SD ±4.8). Male to female ratio was 3:1. Lower extremity purpura was present in all 12 patients. Gastrointestinal manifestations were present in 7 patients. Oligoarthritis was present in 7 patients. Three patients presented renal involvement with hematuria/proteinuria. Conclusions: During the pandemic, several autoimmune phenomena have been described to co-occur with or following COVID-19. The exact role of COVID-19 in the development of these IgA-related diseases is still being explored. Our review of case series and case reports with standardized causality assessment identified 12 cases of IgA vasculitis associated with COVID-19 infection in children.

care. In 17% of cases the SARS Cov-2 test was positive before IgA vasculitis symptoms presentation. The mean age of the patients was 7.3 years of age (SD ±4.8). Male to female ratio was 3:1. Out of the 12 patients, 6 presented 2/4 criteria for IgA vasculitis and 6 presented 3/4 criteria. None presented 4/4 criteria.
Conclusions: During the pandemic, several autoimmune phenomena have been described to co-occur with or following COVID-19. The exact role of COVID-19 in the development of these IgA-related diseases is still being explored. Our review of case series and case reports with standardized causality assessment identi ed 12 cases of IgA vasculitis associated with and/or in the context of COVID-19 infection in children.

Background
Immunoglobulin A vasculitis (IgAV; formerly Henoch-Schonlein Purpura) is the most common form of vasculitis in children. It can occur in any age and peaks around 4-6 years old. The diagnosis is made clinically and 95% of patients will present with a rash, together with any from a triad of other systems: gastrointestinal, musculoskeletal, and renal (1,2). Progress in the classi cation of the systemic vasculitides has facilitated a better understanding of the pathogenesis underlying these in ammatory conditions, which can be mediated by cells, immune complexes, or anti-neutrophil antibodies. Over the past year, several cases of IgA vasculitis have been reported in both children and adults in association with or in the context of SARS-CoV2 infection, raising the question of whether there is any causal or even a synergistic association, as SARS-CoV-2 has proved to cause endothelial damage via a cytokine mediated in ammatory cascade (3).
The cutaneous manifestations of COVID-19 in children reported in the literature include chilblain-like lesions, erythema multiforme, urticaria, and acute hemorrhagic edema of infancy (4)(5). IgA vasculitis associated with and in the context of COVID-19 has been also described in multiple case reports and case series (6-25).
This systematic review's purpose is to answer the question of possible association between IgA vasculitis and COVID-19 in children.

Methods
This systematic review was performed following the guidelines of Meta-analysis of Observational Studies in Epidemiology (26) Literature Sources A literature search was conducted using MEDLINE, SciELO and the rst 15 pages of Google scholar using the search terms "COVID-19" or "SARS-CoV-2" in combination with "IgA vasculitis", or "Henoch-Schonlein Purpura" to identify case reports published from January 1st, 2020 until August 30th, 2021. In addition, abstracts from the 2020 conferences of the American Society of Nephrology, the American College of Rheumatology and the American Academy of Pediatrics were reviewed for relevant case reports.
Causality criteria of the World Health Organization causality assessment system (27) were applied to each report. Data was subsequently analyzed with descriptive statistics.

Study Selection
We considered articles to be eligible for inclusion if they reported a case report or series of cases of HSP/IgA vasculitis associated with COVID-19 infection. We used the criteria of the Paediatric Rheumatology International Trials Organization and the Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) in 2010 (28), which consists of mandatory and supportive criteria. Mandatory criterion includes palpable purpura in the absence of thrombocytopenia, while the supportive criteria involve at least one or more of the following: acute-onset diffuse abdominal pain, acute-onset arthralgia or arthritis, renal involvement in the form of proteinuria or haematuria, and histopathological evidence of leukocytoclastic vasculitis or proliferative glomerulonephritis with predominant IgA deposits. COVID-19 infection was de ned as: Detection of SARS-CoV-2 ribonucleic acid in a respiratory swab or clinical specimen using a diagnostic molecular ampli cation test or SARS-CoV-2 speci c antigen in a clinical specimen (29). We excluded cases from further review if they ful lled 1 or more of the following criteria: Age older than 18 years, failure to have a positive diagnostic test for COVID-19, missing information that could not be obtained from the authors or causality criteria of unlikely, conditional/unclassi ed, or unassessable/ unclassi able by the WHO-UMC causality assessment.

Data Abstraction
One author (EGL) scanned titles and abstracts for initial selection. Selected articles were reviewed in full and independently assessed for eligibility and causality by two authors (EGL, DAA). Discrepancies were resolved by consensus and involvement of other authors (AP). Data from each included: baseline demographic characteristics (age, gender), comorbid conditions, presenting symptoms and chronological relationship of COVID-19 diagnosis to IgA vasculitis/HSP presentation.
Causality/assessment Criteria Causality criteria of the World Health Organization-Uppsala Monitoring Center (WHO-UMC) causality assessment system were applied to each report to assess the likelihood of a causal relationship between Covid-19 infection and IgA vasculitis. The WHO-UMC scale is a causality assessment system that is validated and widely accepted in pharmacovigilance that uses pre-speci ed criteria to categorize the causal link between a drug and an adverse event into 1 of 6 discrete levels of certainty (certain, probable/likely, possible, unlikely, conditional/unclassi ed, and unassessable/unclassi able) (27) ( Table  1). The mean age of the patients was 7.3 years of age (SD ±4.8) with a bimodal distribution with the rst and larger peak at 3.8 years (SD ±1.24) and the second peak at 13.5 years (SD ±1.5). Out of the 12 patients, there were 9 males and 3 females. In regards to ethnicity, 3 were of Mediterranean origin, 3 were Hispanic, 2 were Caucasian, 1 was black, 1 was Asian and 2 were not speci ed. Out of the 12 patients, 8 were reportedly healthy, 1 did not specify and 3 had a positive medical history: Atopic dermatitis, Hirschsprung disease, and suprasellar germinoma with secondary panhypopituitarism. (Tables 2 and 3

Discussion
During the pandemic, several autoimmune phenomena have been described to co-occur with or following COVID-19 (3)(4)(30)(31) and it seems that the in ammatory response is similar in COVID-19 and autoimmunity. The immunological alterations associated with different stages of COVID-19 have been described since the earliest reports, and include an elevated number of macrophages, hyperactivation of T cells, and the release of increased plasma levels of pro-in ammatory cytokines as well as molecular mimicry, bystander activation and the epitope spreading (32)(33).
Aberrant IgA responses underlie the pathogenesis of IgA vasculitis. The exact role of COVID-19 in the development of these IgA-related diseases is still being explored. 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 (1,(34)(35). COVID-19, being a mucosal infection as well, might cause IgA vasculitis through this pathway.
Our review of case series and case reports with standardized causality assessment identi ed 12 cases of IgA vasculitis associated with or in context of COVID-19 in children.
As in non-COVID-19-associated childhood IgA vasculitis, our research revealed that childhood IgA vasculitis associated with COVID-19 was more prevalent in early childhood. However, we also identi ed a second peak during adolescence. COVID-19 associated HSP was more common in males than in females with a ratio of 3:1, in comparison to non-COVID-19 associated IgA vasculitis, in which the ratio is 1.5:1 (1). In a study by Gardner-Medwin et al (36), in which they studied the incidence of childhood IgA vasculitis per ethnicity, there was a predominance of the disease in white and Asian populations. This study did not include Hispanic or Mediterranean population as study subjects. Our study demonstrated more cases of COVID-19-associated IgA vasculitis in both Hispanic and Mediterranean populations.
The disease presentation of the included studies was matched to the known IgA vasculitis presentation (1), with a purpuric rash needed for diagnosis; along with GI symptoms, including blood in stool in around 70% of patients; musculoskeletal involvement developing as arthritis and arthralgia mostly in the lower extremities in around 60% of patients; and renal involvement in 40-50% of patients.
In spite of criteria being met for IgA vasculitis in the context of Covid-19 in these cases, we need to be aware that these ndings, including such GI symptoms, hematuria, proteinuria and even arthritis can be present during a viral illness regardless of IgA vasculitis. Moreover, there is evidence that since Covid-19 causes direct damage to capillaries, it can manifest with leucocytoclastic vasculitis (4).

Limitations
We acknowledge that the sample size in our study is small owing to the shortage of published articles related to our research question. Moreover, we were not able to concisely establish the time frame between COVID-19 infection and IgA vasculitis. For these reasons, and in the setting of a pandemic of the magnitude of COVID-19, the possibility of incidental co-disease cannot be excluded. More and larger studies should be done for the purpose of clarifying causality.

Conclusions
Several cases of IgA vasculitis have been described in the literature following, or in the setting of SARS-CoV2 infection. Evidence of a role of IgA in the immune response against COVID-19 is increasing. The exact role of COVID-19 in the development of these IgA-related diseases is still being explored. We hope that the future will bring a better understanding of the pathogenesis, correlation, causality and management of this entity. We know of no con icts of interest associated with this manuscript.

Funding
There has not been signi cant nancial support for this work that could have in uenced the outcome Authors' contributions EGL and DAA developed the idea of the study, performed a literature search, generated and lled the tables with data, performed data analysis, scored case reports on critical appraisal, and drafted the manuscript. AP and AH also developed the idea of the study, scored case reports on critical appraisal, and reviewed the manuscript. All authors have critically reviewed and approved the nal draft. Table   Table 2 is available in the Supplemental Files section. Figure 1 Flow diagram of included studies

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. Table2Casereportdescriptions.docx