Association between immunoglobulin A (IgA) vasculitis and coronavirus disease 2019 (COVID-19) in children


Researchers from Nicklaus Children’s Hospital-Florida, USA have uncovered a correlation between Immunoglobulin A (IgA) vasculitis and children with COVID-19.

Immunoglobulin A (IgA) vasculitis, formerly called Henoch-Schönlein purpura or HSP, is a disease that causes the antibody immunoglobulin A to collect in small blood vessels, which then become inflamed and leak blood. Nearly all individuals with IgA vasculitis develop a red or purple rash link.

The study findings were published on a preprint server and are currently being peer reviewed.

The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) have impacted children and younger adults more adversely due to the different virulence of the VOCs.

COVID-19-related cutaneous complications like urticaria, erythema multiforme, chilblain-like lesions in children, and acute hemorrhagic edema in infants of ages between four and five months have been reported. Furthermore, COVID-19-related symptoms of IgA vasculitis have also been observed.

The present study reviewed research articles to assess a possible association between COVID-19 infection and IgA vasculitis manifestation in children.

The review included articles published between 1 January 2020 and 30 August 2021 that reported a case of IgA vasculitis associated with COVID-19 or a series of cases with the association. IgA vasculitis cases were selected based on mandatory criteria including palpable purpura without the presence of thrombocytopenia and supportive criteria inclusive of at least one or more manifestations out of acute-onset diffuse abdominal pain, proteinuria, haematuria, or acute-onset arthralgia, arthritis, presence of predominant IgA deposits in proliferative glomerulonephritis, or leukocytoclastic vasculitis.

Cases of COVID-19 infection were identified based on SARS-CoV-2 ribonucleic acid (RNA) detection in a sample using a SARS-CoV-2 specific antigen test or a diagnostic molecular amplification test.

The team collected data from each article eligible for the study, including age, gender, comorbidities, symptoms, and the sequential correlation of SARS-CoV-2 detection and IgA vasculitis manifestations.

Causality criteria recommended by the causality assessment system of the World Health Organization-Uppsala Monitoring Center (WHO-UMC) were applied to the selected reports to assess the possible causal association of COVID-19 and IgA vasculitis.

The causality assessment system was used to assess any causal link between the two diseases into one to six different levels of certainty, ranging from certain, probable/likely, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable.


The study findings showed that the 12 identified cases provided sufficient evidence of association of IgA vasculitis with or without the presence of SARS-CoV-2 infection in children.

A prevalence of COVID-19-related IgA vasculitis was noted, particularly in early childhood. Furthermore, the increase in association of COVID-19 and IgA vasculitis was observed thrice as many times in males than in females, while non-COVID-19-associated IgA vasculitis was detected five times more in males than females.

The inflammatory responses of COVID-19 are very similar to the manifestations of autoimmunity. Although the exact role of SARS-CoV-2 in the manifestation of IgA vasculitis is still unknown, further research to investigate the specific association can help manage the two conditions more efficiently.

The human body is surrounded by the external environment. The skin is the outermost organ of the human body. It is exposed to various environmental factors, such as microorganisms, and drives the cutaneous immune response to protect the host human body. This self-defense action against the external environment sometimes triggers excessive inflammatory reactions, namely autoimmune reactions.

Immunoglobulin is a key driver of host defense immunity against microorganisms; there are several subtypes, including IgG, IgM, and IgA. Among other immunoglobulin subtypes, IgA has the unique characteristic of broad recognition of microorganisms. IgA sometimes causes autoimmune reactions, causing the immune complex to drive the inflammatory response in the host.

IgA vasculitis, previously called Henoch–Schönlein vasculitis, is a representative autoimmune disease mediated by IgA deposition on the small blood vessels and causes inflammatory reactions in various organs. In this review, we focus on the basic characteristics of IgA, IgA vasculitis symptoms, therapeutic options, biomarkers, and epigenetic modifications.

Triggers of IgA Vasculitis

As IgA is driven in response to external stimuli, especially microorganisms, it is assumed that various microorganisms have the capacity to induce abnormal IgA autoimmune reactions in the host. Consistently, many types of bacteria and viruses are thought to be associated with the pathogenesis of IgA vasculitis.

The representative causative pathogens are Streptococcus [22,23,24], S. aureus [25,26,27,28], Helicobacter pylori [29,30], varicella-zoster virus [31,32], hepatitis virus [33], Parvovirus [34,35], human immunodeficiency virus [36], cytomegalovirus [37], and Clostridium difficile [38]. Therefore, these microorganisms are triggers for the development of IgA vasculitis.

The Difference of IgA between Adults and Pediatrics
It remains unclear whether there is a clear difference in IgA levels between pediatric and adult patients. As IgA vasculitis and nephritis show different clinical courses between adult and pediatric patients, it is assumed that there are some differences in IgA between adult and pediatric patients.

The first difference is the amount of IgA, which contributes to the development of IgA [47]. Consistently, IgA production in adults is much higher than in children [66]. For instance, 2–3-year-old and 5–6-year-old children showed IgA levels of 40.8% and 69.5%, respectively, compared with adults [66].

IgA levels reach adult proportions after the age of 11 years. These findings suggest that IgA levels in children might not be at a sufficient volume to respond to vessels and the kidneys.

Another possibility is that the frequency of memory B cells might be a clue to answering this question. The frequency of memory B cells in the peripheral blood is higher in adults than in children [67]. Schoolchildren showed a decreased frequency of memory B cells compared to adults; however, adolescents showed almost the same level of the frequency of adult memory B cells, without significant differences. These findings suggest that pediatric memory B cells might show less activity in memorized IgA production, leading to continuous pathogenic IgA production.

The difference might also depend on other immune profile differences. In the comparison of IgA nephritis between pediatric and adult patients, CD68+ macrophages were increased in adult glomerular and interstitial sites in the kidney. Macrophage function is decreased in pediatric patients compared with adults, such as cytotoxicity [68] and anti-tumor immunity [69].

In contrast, galactose-deficient IgA in patients with pediatric IgA vasculitis and nephritis is similar to that in adults [70]. This finding suggests that pathogenic IgA1 might not be different between adult and pediatric IgA vasculitis and nephritis. In addition, there is no evidence of the difference in the survival duration of memory B cells between pediatric and adult patients, and the actual impact of the frequency of memory B cells remains unclear. Therefore, further investigation is necessary to clarify this basic question.

The Relationship with Coronavirus Disease 2019 (COVID-19)

Interestingly, several studies have reported COVID-19 associated IgA vasculitis [71,72,73,74,75,76,77]. COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the COVID-19 pandemic is currently an ongoing global problem and is known to cause vasculitislike syndromes [78]. The characteristics of patients with IgA vasculitis following COVID-19 are summarized in Table 2. There were seven cases of IgA vasculitis.

The median age was 23.3 years and the ratio of adults to children was 4:3. Interestingly, all cases were male. Other symptoms excluding cutaneous purpura were observed in three of seven cases with abdominal pain, and three of seven cases with nephritis. Furthermore, all nephritis cases were adults, and 75% of adult cases showed IgA vasculitis following COVID-19 infection, whereas IgA nephritis was not identified in the children.

Table 2

The summary of cases of IgA vasculitis following COVID-19.

AuthorAgeSexDays after COVID-19 Test PositiveInvolvementTreatment
Suso, et al. [71]78Male5 weeks laterSkin
Steroid pulse plus Rituximab
Hoskins, et al. [72]2MaleSame timeSkin
Abdominal pain
Intravenous steroid
Allez et al. [73]24MaleUnknownSkin
Abdominal pain
Methylprednisolone 0.8 mg/day
Sandhu et al. [74]22MaleSame timeSkin
Prednisolone 1 mg/kg
AlGhoozi et al. [75]4Male37 days laterSkinNot described
Jacobi, et al. [76]3MaleSame timeSkin
Abdominal pain
Li et al. [77]30MaleSame timeSkin
Losartan 25 mg following prednisolone 40 mg for 7 days

COVID-19 has the potential to induce a cytokine storm, which might also be involved in the pathogenesis of IgA vasculitis. In addition, as another possibility, the medications for COVID-19 are not completely excluded as a trigger, similar to drug-induced IgA vasculitis.

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