In the last years, the ability of SARS-CoV2 to affect almost every human organ became always clearer, thus causing renal, cardiac, cutaneous, psychological, neurological and vascular diseases [50,51,52,53]. Various types of vasculitides have been reported with COVID-19 infection [54]. In the case we presented above, the clinical presentation, the personal history of autoimmune disease, like celiac disease, and the pathologic findings suggested that Sars-Cov2 vaccine may have been the trigger for the unmasking of an autoimmunological trait that led to the development of Henoch–Schonlein purpura.

In this review, we discussed 23 cases of de novo HSP occurring after infection by COVID-19 and 20 after SARS-CoV2 vaccination. In the first group reported cases were mostly male, with a middle age of 21.9 years; these data oppose with the usual mild prevalence of HSP in males and with the usual prediction of IgA vasculitis for children between 5 and 7 years old. Globally, these patients presented less articular involvement compared with typical HSP patients who show arthritis/arthralgia in up 84% of cases. On the contrary they showed similar gastrointestinal (57%) and renal involvement (39%); indeed, gastrointestinal symptoms usually are present in approximately one-half of HSP patients, ranging from mild (nausea, abdominal pain, vomiting) to severe findings, such as gastrointestinal hemorrhage, bowel ischemia and necrosis, intussusception and bowel perforation [49]; while kidney involvement had been reported in 20 to 54% of children with IgAV. In the second group, we observed the same incidence rate of HSP between men and women; and the middle age of patients was significantly higher than that of I group. It could probably be explained by the low vaccination rate for SARS-CoV2 observed among infants. Percentage of articular and kidney involvement were almost the same, while the one of gastrointestinal involvement was lower than that of the first group. Overall, most common laboratory findings were increased CRP, mild leukocytosis, especially neutrophilia and elevated D-dimer. These nonspecific findings may reflect inflammation triggered by COVID-19 rather than the vasculitis itself. Despite common cases of IgAV, where serum IgA levels are elevated in 50 to 70 percent of patients [55], in our cases only few patients showed this laboratory findings, but maybe only because in many cases IgA had not been dosed at all.

However, little is known about the possible pathogenetic mechanism responsible of the association between COVID-19 and IgA-mediated systemic vasculitis (Henoch–Schonlein Purpura).

COVID-19 infection is notoriously associated with vascular endothelial injury and organ vasculitis. This could derive both from endothelial cells’ invasion by SARS-CoV2 and from inflammatory reaction derived by the infection. Some mechanisms for viral cells invasion have been hypothesized, such as the role of angiotensin-converting enzyme 2 (ACE2) receptors, scavengers receptor B type 1 (SR-B1) and other cellular wall receptors that allow the entry of the virus into the endothelial cells, thus determining endothelial dysfunction and endothelialitis. Those vascular alterations generate a prothrombotic and proinflammatory milieu leading to excessive thrombin production, inhibition of fibrinolysis and activation of complement pathways. The thrombo-inflammatory state can finally provoke the deposition of microthrombi in small vessels and a microvascular dysfunction [56]. Interestingly, the case reported by Gómez et al. which described the insurgence of HSP one month after symptomatic COVID-19 infection in a 29-year-old man, was characterized by the presence of a positive SARS-CoV2 PCR from a skin biopsy of the patient [29].

Moreover, infection by SARS-CoV2 determines a dysregulation of the immune system response and the consequent cytokine-release syndrome, due to the overactivation of innate immunity in the setting of T-lymphocytes depletion. During the infection an important increase of cytokines like IL-6, interferon γ (IFN-γ) and Tumor Necrosis Factor alpha (TNF α) had been documented. TNF-α, in turn, induces the production of reactive oxygen species which determines further damage to the endothelial cells, causing endothelial dysfunction and inflammation. Indeed, cytokines levels, especially IL-6 levels differ according to the severity of the disease, with higher values in patients with worse prognosis; therefore, they could even be used as biomarker for the prediction of morbidity duration and mortality in infected patients [56].

The critical role of mucosal and systemic IgA in the immunological response to SARS-CoV2 is getting attention only recently. In the case of respiratory infection, the seroconversion day of IgA is 2 days after onset of initial symptoms, while the first seroconversion of IgM and IgG is 5 days after onset. Secretory IgA (sIgA) induce strong mucosal immunity; indeed, it is in part the result of IgA-mediated interactions with pathogenic microorganisms that prevent pathogens adhesion to the cell surface. Moreover, it seems that sIgA are able to induce interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 and granulocyte–macrophage colony stimulating factor production through normal human lung fibroblasts [57]; besides, they have a synergistic effect with IgG in promoting antibody-dependent cellular cytotoxicity (ADCC) [58]. On the contrary, the role of serum IgA is relatively unexplored. Several studies revealed a both proinflammatory and anti-inflammatory effect of serum IgA in innate immune response and suggested a plausible role of IgA as a trigger for autoimmune disease and immune hyperactivation [59]. Indeed, with COVID-19 cases increasing worldwide, cases of IgA vasculitis are also rising. The most widely accepted possible pathogenesis of IgA vasculitis involves Galactose deficient IgA1 (Gd-IgA1). The mucosal SARS-CoV2 infection may enhance IL-6, IL-1 and TNF production, leading to aberrant glycosylation of IgA1; the increase of Gd-IgA1, together with IgG autoantibodies generation, may result in the immune complex formation and precipitation, with consequent activation of complement cascade and inflammatory processes. In the case reports we selected, the one by Allez M. et al. [15] described the insurgence of HSP in a young patient associated with high levels of serum IgA and with only weak and transitory IgA shown on COVID-19 serologic testing. Similar results have been found by M. El Hachem et al. [60] in children who developed chilblain-like lesions during COVID-19 infection: some of them tested positive only for IgA specific for the S1 domain of the spike protein. This case supports the possible role of IgA as a trigger for inflammation at mucosal and non-mucosal sites. Besides, the strong mucosal immunity IgA mediated developed by some people after COVID-19 infection might impair the triggering of an IgG response, causing a dysregulated hyper-immune activation.

Another supposed pathogenetic mechanism of acute IgA-vasculitis associated to COVID-19 regards a form of type 3 hypersensitivity. Recent studies observed that patients requiring intensive care inappropriately mount a Th2 response against SARS-CoV2, with as main effectors: eosinophils, basophils, mastocytes and B cells. The activation of B cells results in the production of antibodies (humoral immunity), and, presumably, given the high antigen load, a type 3 hypersensitivity reaction takes place with consequent accumulation of antigen–antibody complexes in small vessels. The immune complex deposition determines the subsequent activation of the complement cascade, with the release of complement anaphylatoxins (C3a and C5a). In turn, they stimulate the release of histamine from mast cells and the recruitment of phagocytes, resulting in an acute necrotizing vasculitis with neutrophilic infiltrate, fibrinoid necrosis and karyorrhexis, called “leukocytoclastic vasculitis” [61].

In the mRNA 1237 COVID-19 vaccine trial with 30,420 volunteers, only 2 in the placebo group and 11 in the vaccine group had a macro-purpuric eruption, while no one showed glomerulonephritis [62].

After commercialization, with the unprecedented volume of vaccinations against Sars-Cov2 worldwide, several cases of both IgA vasculitis and nephritis had been reported. These clinical observations raise the possibility of a relationship between vaccinations and stimulation of the immune system leading to autoimmune diseases in predisposed subjects. Vaccines aim to induce a host humoral and cellular immune response to exogenous antigens and to elicit a memory T-lymphocytes response through the years. Usually, vaccines use adjuvants to enhance vaccine immunogenicity. The mRNA vaccines, such as Pfizer-BioNTech BNT16B2b2 or Moderna mRNA-1273, do not require an adjuvant since the mRNA itself can stimulate the innate immune response, promoting immune induction, through pattern-recognition receptors such as Toll-like receptor (TLR) 3, TLR7 or retinoid-inducible gene I [63]. These receptors are expressed by immune cells, such as dendritic cells and macrophages. Various TLRs, including TLR3 and TLR7 had been found upregulated in IgA vasculitis; this suggests their possible involvement in the pathogenesis of the vasculitis. Other mechanisms may also be suggested, such as the molecular mimicry of the SARS-CoV2 spike-protein with some autoantigens. mRNA vaccines are composed of lipid nanoparticles containing the mRNA encoding for the viral spike protein. A case report presented by Obeid et al. [64] showed the production of autoreactive IgA anti-HEp-2 cells after mRNA-1273 vaccine administration in a patient with a history of IgA vasculitis, in remission for over 2 years. Serum tests of the patient made before vaccination did not show any autoreactivity, as well as serum taken from two healthy controls after mRNA 1273 vaccine administration. These observations suggest the capability of mRNA SARS-CoV2 vaccine to induce the production of autoreactive antibodies only in susceptible patients.

A study by Jincan Zan et al. of 2022 [65] investigated the safety of COVID-19 vaccine in patients with IgA nephropathy or IgA vasculitis. It finally involved 367 vaccinated patients and 2 patients developed flare-up events, 3 exhibited > 30% estimated glomerular filtration rate decrease and 3 patients progressed to nephrotic proteinuria within 3 months after vaccination. Among 202 patients investigated with urine tests 3 months before and after vaccine administration, there were no significant differences regarding proteinuria and hematuria, while estimated glomerular filtration showed a mild but statistically significant reduction.

Given these findings and results from recent pharmacovigilance studies, we confirm that COVID-19 vaccine-associated HSP is rare [66, 67], and we cannot rule out a fortuitous association in our patient. However, a possible relationship between these two entities, neither confirmed, nor ruled out should be kept in mind. SARS-Cov2 vaccine administration is, thus, globally safe in IgAN and IgA vasculitis patients, with a low absolute incidence of adverse events. However, in patients with a background or an increased susceptibility for the development of autoimmune diseases, clinicians should pay much attention after vaccine administration to detect and treat any adverse event quickly.