Version May 2024
INTRODUCTION — Immunoglobulin A vasculitis (IgAV; formerly called Henoch-Schönlein purpura [HSP]) [1,2], is the most common form of systemic vasculitis in children, with an incidence range of 3 to 27 per 100,000 [3]. Ninety percent of cases occur in the pediatric age group. In contrast to many other forms of systemic vasculitis, IgAV is typically self-limited. The disease is characterized by a tetrad of clinical manifestations:
●Palpable purpura in patients with neither thrombocytopenia nor coagulopathy
●Arthritis/arthralgia
●Abdominal pain
●Kidney disease
The clinical manifestations, pathogenesis, diagnosis, and differential diagnosis of IgAV are presented here. The management of IgAV and a more complete discussion of the kidney manifestations of IgAV are found elsewhere. (See "IgA vasculitis (Henoch-Schönlein purpura): Management" and "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)
EPIDEMIOLOGY — IgAV is primarily a childhood disease that occurs between the ages of 3 and 15 years [3,4]. In a population-based study from the United Kingdom, the annual incidence was approximately 20 per 100,000 in children <17 years of age, with a peak incidence of 70 per 100,000 in children between the ages of four and six years [5]. In reports from Taiwan and the Czech Republic, there was a lower incidence of 10 per 100,000 in children <17 years of age, with a peak incidence at five to seven years of age [6,7]. A subsequent population-based study from France showed an incidence relatively similar to previously reported numbers (approximately 19 per 100,000 children), suggesting general stability of the incidence [8]. A higher incidence has been reported in several Asian studies, including a South Korean study that found an incidence of approximately 56 per 100,000 children [9]. Another South Korean observational study comparing two time periods (1987 to 1996 versus 2006 to 2015) found that the peak incidence was five years of age and also reported longer hospitalization and higher rate of proteinuria and recurrence in the earlier time period [10].
IgAV is less common in adults [11], with an estimated annual incidence of 5 per 100,000 adults in Slovenia [12]. In several retrospective studies, 20 to 30 percent of patients with IgAV were adults. In these cohorts, adults had significantly worse kidney outcomes compared with children [13-15].
Most studies show a male predominance, with reported male-to-female ratios of 1.2:1 to 1.8:1 [3,5,6,12,16,17], although two Korean studies have shown a slight female predominance [9,18]. IgAV is seen less frequently in Black British children compared with White or South Asian British children [2,5].
IgAV occurs primarily in the fall, winter, and spring but rarely in the summer months [2,8,16-19], possibly explained by the association of IgAV with infections. Approximately one-half of the cases of IgAV are preceded by an upper respiratory tract infection [20], especially those caused by Streptococcus [21]. Other infectious agents, vaccinations, and insect bites also have been implicated as possible triggers for IgAV [20]. A large epidemiologic study of 16,000 children from South Korea demonstrated a temporal relationship with respiratory syncytial virus (RSV), influenza, and norovirus [18]. In a systematic literature review, it was noted that a majority of the studies had failed to show causal association between vaccinations and vasculitides including IgAV [22-24]. The rate of IgAV is significantly higher (approximately 5 percent) in patients with familial Mediterranean fever [25,26]. In addition, MEFV innate immunity regular, pyrin (MEFV) pathogenic variants may affect clinical presentation of IgAV. Abdominal pain and intussusception were more common in patients with MEFV pathogenic variants [27].
CLASSIFICATION CRITERIA — A variety of classification criteria for IgAV have been proposed, primarily for use in research protocols and outcome studies. They have not been validated for the diagnosis of individual cases.
In 1990, a committee of the American College of Rheumatology (ACR) established criteria to classify seven types of vasculitides including IgAV [28,29]. The ACR criteria for the diagnosis of IgAV are as follows:
●Palpable purpura
●Age at onset ≤20 years
●Acute abdominal pain
●Biopsy showing granulocytes in the walls of small arterioles and/or venules
These criteria were based upon a comparison between 85 patients with IgAV and 722 adult patients with other forms of vasculitis. Two or more of the criteria had a sensitivity and specificity of approximately 90 percent in separating adult patients with IgAV from those with other causes of vasculitis.
In 2005, pediatric consensus criteria were developed by the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) and the Paediatric Rheumatology European Society (PRES) [30] and were subsequently validated in conjunction with the Paediatric Rheumatology International Trials Organisation (PRINTO) [31]. These criteria, which have a 93 percent sensitivity and 89 percent specificity, are more appropriate for pediatric settings in which a clinician is most likely seeking features to distinguish IgAV from gastroenteritis or appendicitis rather than from granulomatosis with polyangiitis. The mandatory criterion is purpura (usually palpable and in clusters) or petechiae, with lower limb predominance and without thrombocytopenia or coagulopathy. Patients also must have one or more of the following:
●Abdominal pain (usually diffuse, with acute onset)
●Arthritis or arthralgia (acute onset)
●Kidney involvement (proteinuria, hematuria)
●Leukocytoclastic vasculitis or proliferative glomerulonephritis, with predominant IgA deposition
However, IgAV is not the only disease that may have these manifestations. (See 'Differential diagnosis' below.)
PATHOGENESIS — IgAV is an immune-mediated vasculitis associated with IgA deposition accompanied with complement deposition and neutrophil recruitment. Although a variety of infectious and chemical triggers are recognized, the underlying cause of IgAV remains unknown. Immunologic, genetic, and environmental factors all seem to play a role [32-34]. The human leukocyte antigen (HLA) region as well as polymorphisms in other immune-related genes are associated with IgAV, sometimes with conflicting results, which could be due to differences in ethnic and environmental factors [35,36]. Susceptibility polymorphisms in genes that are associated with vascular response, such as the genes encoding endothelial nitric oxide synthase (eNOS), interleukin (IL) 18, and angiotensin-converting enzyme (ACE), have also been shown [2,37]. There are numerous case reports of IgAV occurring after vaccination, and a case-control study found an increased risk of IgAV within 12 weeks after vaccination with the measles-mumps-rubella (MMR) vaccine (odds ratio [OR] 3.4, 95% CI 1.2–10.0) but not with other vaccines [38]. The absolute risk was low, though (2.8 percent of cases had MMR within 12 weeks of developing IgAV compared with 1 percent of controls). A case-crossover study of 167 children found no increased risk of IgAV within three months of receiving a vaccine compared with the three months prior to that (OR 1.6, 95% CI 0.8-3.0) [24]. Similar results were seen for IgAV risk within 1, 1.5, or 2 months of vaccination. These results suggest that vaccinations are not a major etiologic factor in IgAV and therefore should not be avoided. A temporal relationship of IgAV with administration of many classes of drugs including biologics has been reported [39,40].
The characteristic finding of IgAV is leukocytoclastic vasculitis accompanied by IgA immune complexes within affected organs (image 1A-B). Skin biopsies of purpuric lesions demonstrate the involvement of small vessels (primarily postcapillary venules) within the papillary dermis. The predominant cell types within the inflammatory infiltrate are neutrophils and monocytes. (See 'Biopsy' below.)
Immunofluorescence studies show IgA, complement component 3 (C3), and fibrin deposition within the walls of involved vessels. IgA, C3, fibrin, immunoglobulin G (IgG), and, less commonly, immunoglobulin M (IgM) also are deposited within the endothelial and mesangial cells of the kidney (picture 1).
Attention has focused on the potential role of increased serum levels of IgA and IgA immune complexes in the pathogenesis of IgAV, which contributed the current name change. In addition, several studies report alterations in the glycosylation of IgA, elevated levels of IgA anticardiolipin antibodies, and increased levels of transforming growth factor (TGF) beta in patients with IgAV [17,41-45]. The fact that only one of the two IgA subtypes (galactose-deficient IgA1, but not IgA2) is found in the inflammatory infiltrates of this disease remains unexplained [46,47]. Galactose-deficient IgA1 containing immune complexes may deposit more easily [3]. Similarly, the precise role of IgA and the specific involvement of IgA1 in the pathogenesis of IgAV remain unclear. Some research suggests that IgA anticardiolipin antibodies may play a role [41,48,49]. Results from one study suggest that beta-2-glycoprotein I (beta-2GPI) is an antigenic target for IgA [50]. Despite the increased presence of these antibodies, there are few reports of thrombosis. Activated neutrophils and increased production of IL-8, as well as activated cytotoxic T cells and natural killer (NK) cells, may also play a role [51,52].
CLINICAL MANIFESTATIONS IN CHILDREN — The classic tetrad of IgAV includes:
●Palpable purpura without thrombocytopenia and coagulopathy
●Arthritis/arthralgia
●Abdominal pain
●Kidney disease
These clinical manifestations may develop over the course of days to weeks and may vary in their order of presentation. Purpura and joint pain are usually the presenting symptoms, but this is not always the case. In the absence of the classic purpuric rash, the diagnosis of IgAV may not be obvious. Patients who present with significant joint or abdominal symptoms without the skin manifestations may be thought to have an infectious or surgical process. (See 'Differential diagnosis' below.)
The mean age of onset of IgAV is between six and seven years. Based upon retrospective reviews from several different countries, the major clinical manifestations develop with the following frequencies [5,6,13,14,16,17,53-57]:
●Purpura – Purpura is the presenting symptom in approximately three-quarters of patients, preceding other symptoms by a mean of four days in one series [58].
●Arthralgia/arthritis – In most of the series, joint symptoms were the second most common manifestation, occurring in slightly over one-half to three-quarters of the patients.
●Abdominal pain – Colicky pain occurred in approximately one-half of patients and gastrointestinal bleeding in approximately 20 to 30 percent of patients.
●Kidney disease – The frequency of kidney involvement ranged from 21 to 54 percent.
Skin manifestations — Rash is the presenting sign in approximately three-quarters of patients. The rash often begins with erythematous, macular, or urticarial wheals but also can have less typical presentations including targetoid lesions. The rash may be itchy but is rarely painful. The initial rash may coalesce and evolve into the typical ecchymoses, petechiae, and palpable purpura (picture 2A-E). The rash typically appears in crops, symmetrically distributed, and located primarily in gravity/pressure-dependent areas, such as the lower extremities. The buttocks are often involved in toddlers and the face, trunk, and upper extremities in nonambulatory children [2,3].
Localized subcutaneous edema is a common feature that may be found in dependent and periorbital areas, especially in younger children (less than three years of age) (picture 3 and picture 4). Even adult patients, however, may also have this manifestation of IgAV, particularly involving the dorsal aspect of the hands. Blistering eruptions may also occur [59].
Arthritis/arthralgia — Arthritis/arthralgia occur in up to 84 percent of patients [16,56]. However, joint complaints are uncommon as the sole symptom at presentation and are the presenting symptom in approximately 15 percent of patients.
The arthritis is usually transient or migratory, typically oligoarticular (one to four joints), and nondeforming. It usually affects the lower-extremity large joints (hips, knees, and ankles) or less commonly the upper extremities (elbows, wrists, and hands) [2,3,16,17,53]. There is often prominent periarticular swelling and tenderness but usually without joint effusion, erythema, or warmth. Patients may have considerable pain and limitation of motion. Younger children with lower-extremity involvement may refuse to ambulate. The arthritis does not cause any chronic damage or sequelae. It may precede the appearance of purpura, though usually by no more than one or two days.
Gastrointestinal symptoms — Gastrointestinal symptoms occur in approximately one-half of children with IgAV and range from mild (nausea, vomiting, abdominal pain, and transient paralytic ileus) to more significant findings (gastrointestinal hemorrhage, bowel ischemia and necrosis, intussusception, and bowel perforation). Guaiac-positive stool is found in up to 56 percent of patients, but massive gastrointestinal hemorrhage is rare [60]. The frequent presence of fecal occult blood, increased stool alpha-1-antitrypsin, and hypoalbuminemia without proteinuria, even in patients without gastrointestinal symptoms, suggests that gastrointestinal involvement and mucosal injury are more common than the clinical history indicates [58].
Gastrointestinal symptoms typically develop within eight days of the appearance of the rash, although much longer intervals (weeks to months) have been described [61]. Gastrointestinal complaints precede the rash in approximately 15 to 35 percent of cases. In such patients, the diagnosis of IgAV is significantly more difficult. Gastrointestinal symptoms without the appearance of cutaneous purpura at any time also have been described in case reports [62-64]. In one small, retrospective review of children who had skin biopsies, edema and rash above the waist were most common in patients who presented with gastrointestinal involvement [65]. The reason for such a putative association is not clear, since the rash of IgAV is typically found in gravity/pressure-dependent areas. This finding will require confirmation in a larger cohort before it can be relied upon. In a meta-analysis, high neutrophil-to-lymphocyte ratio (NLR) and low mean platelet volume (MPV) were predictors of severe gastrointestinal involvement, though there was significant heterogeneity among studies that were from only a few regions (China, Turkey, and South Korea), limiting the generalizability of these findings [66].
Gastrointestinal pain associated with IgAV is caused by submucosal hemorrhage and edema. Purpuric lesions may be seen on endoscopy, commonly in the descending duodenum, stomach, and colon. The terminal ileum also may be involved. Submucosal edema, ulceration, and spasm of the ileum and jejunum may be seen in small bowel series. (See "Overview of gastrointestinal manifestations of vasculitis".)
Intussusception is the most common gastrointestinal complication of IgAV. Rarer gastrointestinal manifestations include acute pancreatitis, gall bladder involvement, bowel perforation, and, in children, protein-losing enteropathy [60,67-72].
Edema and hemorrhage can act as a pathologic lead point, contributing to the development of intussusception. Intussusception is limited to the small bowel in approximately 60 percent of cases, in contrast to idiopathic intussusception, which is typically ileocolic [73]. Intussusception in IgAV has a reported overall incidence of 2.3 to 3.5 percent, although some retrospective series reported an incidence of only 0.4 to 0.6 percent [16,53,60]. This discrepancy may be due to differences in the population studied. Children demonstrating severe gastrointestinal pain and/or requiring hospitalization are presumably at greater risk.
In a retrospective review of 149 hospitalized children with IgAV from two centers in Chicago, 63 patients (42 percent) presented with severe abdominal pain [74]. Four patients were diagnosed with intussusception, two of which were ileoileal intussusceptions. All four patients required surgical correction. Intussusception is discussed in greater detail separately. (See "Intussusception in children".)
Kidney disease — The kidney manifestations of IgAV, including prognosis and treatment, are discussed in detail elsewhere. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)
Kidney involvement has been reported in 20 to 54 percent of children with IgAV. It is more prevalent in older children and adults [53,55]. The most common presentation is hematuria with or without red blood cell casts and mild or no proteinuria. Nephrotic-range proteinuria, an elevated serum creatinine, and/or hypertension are present in a minority of patients. These findings, as well as the coexistence of hematuria and proteinuria, are associated with an increased risk of progressive disease, which occurs more frequently in adults. The findings on kidney biopsy are identical to those in IgA nephropathy. The presence of microscopic papillary dermal edema and perivascular deposition of C3 on direct immunofluorescence of skin biopsy samples may be associated with development of kidney involvement [65].
Risk factors predicting kidney involvement are not well known, but several clinical and laboratory features have been reported as kidney disease risk factors. In one meta-analysis, older age at onset; gastrointestinal symptoms; relapse; elevated white blood cell count, platelet count, and antistreptolysin O (ASLO) titer; and low C3 were reported as kidney disease risk factors, and a scoring system for risk of kidney disease development was suggested [75]. Other findings associated with development of severe kidney disease include delay in diagnosis, angioedema, central nervous system (CNS) involvement, and persistent purpura [76,77]. Long-term follow-up of these patients is important to determine which patients go on to develop end-stage kidney disease (ESKD), thus identifying which of the kidney risk factors are actually associated with ESKD.
Other organ involvement — Other organ systems occasionally are involved in IgAV.
Urologic — Urologic involvement, most commonly of the scrotum, but also the ureter, bladder, prostate, testicle, and penis, is reported [78]. The rate of scrotal involvement in boys with IgAV ranges from 2 to 38 percent [79-82]. Rarely, scrotal pain may be the presenting symptom. Clinical findings include pain, tenderness, and swelling of the involved testicle and/or scrotum.
The presentation may mimic testicular torsion [83]. Evaluation including ultrasonography and technetium Tc99m radionuclide scanning can differentiate the two entities. In testicular torsion, these studies demonstrate decreased blood flow to the testicle, in contrast to the normal or increased flow seen in boys with IgAV.
The clinical presentation of scrotal involvement in IgAV was reviewed in a retrospective study of 120 Korean boys diagnosed with IgAV between 1992 and 2004 [84]. Twenty-six patients (22 percent) had scrotal involvement, which presented as scrotal swelling (23 patients) or scrotal pain or tenderness (18 patients). Unilateral involvement was more common, with seven patients demonstrating inflammation of the scrotum bilaterally (27 percent). Scrotal pain was the initial manifestation of IgAV in two of the patients. Imaging (ultrasonography and/or radionuclide scan) was performed in 15 patients and demonstrated epididymitis in 13 and orchitis in 2 patients. One patient underwent surgical exploration, but there was no evidence of testicular torsion.
Central and peripheral nervous system — Single reports and case series document neurologic manifestations in children with IgAV including headaches, seizures, encephalopathy (both hypertensive encephalopathy and posterior reversible encephalopathy syndrome [PRES]), focal neurologic deficits, ataxia, intracerebral hemorrhage, and central and peripheral neuropathy [85-88]. Most of the CNS findings are transient except for occasional permanent sequelae associated with hemorrhagic stroke.
Respiratory tract — In a cohort of French patients hospitalized for IgAV, impaired lung diffusion capacity and mild interstitial changes on chest radiographs were found in the majority of patients (97 and 69 percent, respectively), despite the absence of significant respiratory symptoms [89]. Similarly, another study found impaired lung diffusion capacity in IgAV patients who did not have clinical or radiologic evidence of lung involvement compared with age-matched control patients [90]. On the other hand, severe lung involvement, such as pulmonary hemorrhage, is rare in patients with IgAV and is primarily reported in adults and adolescents [91-94]. A comprehensive, 40-year review of lung involvement in IgAV found diffuse alveolar hemorrhage was the most frequent presentation [95].
Eyes — Keratitis and uveitis are rare sequelae of IgAV and usually suggest other diseases [96]. (See "The red eye: Evaluation and management" and "Uveitis: Etiology, clinical manifestations, and diagnosis".)
CLINICAL MANIFESTATIONS IN ADULTS — Adult patients with IgAV present with clinical manifestations similar to those that occur in children [97]. There are two main differences between adults and children with IgAV:
●Intussusception is rare in adults.
●Adults are at increased risk for developing significant kidney involvement including end-stage kidney disease (ESKD) [11,14,98-102]. (See 'Kidney disease' above.)
These characteristics of IgAV in adults were best illustrated in a retrospective review of 250 French patients whose median age was 50 years. At presentation, clinical findings included palpable purpura (96 percent), arthritis (61 percent), and gastrointestinal symptoms (48 percent) [98]. Almost one-third of patients had kidney insufficiency (creatinine clearance <50 mL/minute per m2) within four months of presentation. At a median follow-up of 14.8 years, persistent kidney impairment was seen in 80 patients (32 percent of the original cohort), including ESKD in 27 patients and severe kidney impairment (creatinine clearance <30 mL/minute) in another 32 patients. Potential explanations for the high prevalence of substantial kidney impairment in this study include the possibility of selection bias (all patients in the study had kidney disease severe enough to require kidney biopsy), the long period of follow-up compared with other studies, and the possible role of comorbidities (eg, hypertension) contributing to the progression of kidney disease. An updated report on this cohort that included an additional 10 patients revealed similar results [99]. However, a smaller case series of adult patients from Northern India showed greater rates of arthritis (90 percent) and abdominal pain in only 10 percent of adults at presentation [103], which may suggest differences related to genetic and environmental exposures between these countries. Reported outcomes are worse in adult patients >65 years of age compared with other adults: Older patients achieved clinical remission less often (23.9 versus 46.2 percent) and developed a 50 percent increase in their serum creatinine more often during the period of observation (21.7 versus 4.7 percent) [101]. Another retrospective cohort study comparing 35 adults to 159 children with IgAV also found kidney involvement to be more common in adults. Upper respiratory infections were a frequent trigger for both groups. Nonsteroidal antiinflammatory drugs (NSAIDs) were used more often in children, while adults were typically treated with glucocorticoids and azathioprine. Persistent hematuria was found to be independent risk factor for relapse in both groups and was more common in adults [15].
Another retrospective series reviewed 68 adults with IgAV who had a skin biopsy with leukocytoclastic vasculitis on histopathologic evaluation and IgA on direct immunofluorescence. Notable findings in this patient group included a higher rate of kidney involvement in patients older than 40 years whose skin biopsies showed an absence of eosinophils and a higher rate of gastrointestinal involvement in patients whose biopsies showed an absence of histiocytes [104].
Adults with no known trigger for the development of IgAV should have additional evaluation for solid-organ cancers, especially if the disease is prolonged or recalcitrant to treatment [105].
A more complete discussion of the kidney manifestations and the management of kidney disease in patients with IgAV is found separately. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)
LABORATORY FINDINGS — Serum IgA levels have been reported to be elevated in 50 to 70 percent of patients with IgAV, and higher levels are associated with kidney involvement [17,42,106].
Findings on routine blood tests (eg, complete blood cell count, serum chemistries, and urinalysis) are nonspecific. Patients may have a normochromic anemia because of occult or overt gastrointestinal bleeding. Other results, such as markers of inflammation, generally reflect the triggering condition. IgAV following bacterial infections is more likely to be characterized by leukocytosis (white blood cell count >20,000 cells/mm3) and an elevated erythrocyte sedimentation rate (ESR). IgAV after viral illnesses, on the other hand, often fails to demonstrate elevation of acute-phase reactants. Nevertheless, IgAV generally does not cause systemic inflammation; as such, when present, other etiologies mimicking IgAV should be considered (see 'Differential diagnosis' below). Prothrombin time (PT), partial thromboplastin time (PTT), bleeding time, and platelet count are usually all normal. The initial urinalysis is also typically normal, although proteinuria and/or hematuria may develop over time.
Hypocomplementemia is reported in a significant percentage of children with IgAV, and these patients are more likely to have evidence of a recent streptococcal infection [107]. A case series of 338 children hospitalized at one center in China during a six-month period in 2010 to 2011 found that 53 children (15.7 percent) had decreased levels of complement component 3 (C3) and/or complement component 4 (C4). Complement levels normalized within three months in all patients, and they did not correlate with disease severity or presence of nephritis in this cohort. As noted previously, several reports and a meta-analysis suggest neutrophil-to-lymphocyte ratio (NLR) and mean platelet volume (MPV) may be predictors of severe gastrointestinal involvement [66]. Additional studies with larger cohorts are needed to confirm these findings.
DIAGNOSIS — The diagnosis of IgAV is typically based upon clinical manifestations of the disease (palpable purpura without thrombocytopenia or coagulopathy and two or three of the remaining clinical features: arthritis/arthralgia, abdominal pain, and kidney disease) [2,3,108,109]. The diagnosis is straightforward when patients present with the classic signs and symptoms (palpable purpura of the lower extremities and buttocks in combination with two or more of the other typical disease manifestations). However, the classic rash of IgAV is not the initial presenting sign in approximately one-quarter of affected persons. It may be difficult to make the diagnosis of IgAV prior to the appearance of a rash in patients who present with other clinical manifestations, such as abdominal pain or arthritis, particularly in isolation. In patients with incomplete or unusual presentations, a biopsy of an affected organ (eg, skin or kidney) that demonstrates leukocytoclastic vasculitis with a predominance of IgA deposition confirms the diagnosis of IgAV. The diagnostic approach is reviewed in the algorithm (algorithm 1).
Biopsy — In pediatric patients, biopsy is reserved for patients with an unusual presentation of IgAV (ie, no rash, or an atypical rash) or those with significant kidney disease.
Confirmation of the diagnosis by biopsy is more important in adult patients because of the lower incidence of IgAV beyond the pediatric age group and the comparatively higher incidence of other forms of vasculitis that may be clinically similar to IgAV.
Skin — Biopsies of the skin, which sample the small blood vessels of the superficial dermis, are usually adequate to make the diagnosis of IgAV. Light microscopy studies (hematoxylin and eosin stains) demonstrate the classical leukocytoclastic vasculitis in postcapillary venules with IgA deposition that is pathognomonic of IgAV (image 1A-B) [110]. The biopsy should contain skin lesions that are less than 24 hours old because, in more chronic lesions, vessel damage leads to nonspecific leakage of all isotypes of immunoglobulin. Immunofluorescence studies, essential to confirming the diagnosis of IgAV, generally require biopsy of a second skin site.
Kidney — Kidney biopsy is reserved for patients in whom the diagnosis is uncertain or if there is clinical evidence of severe kidney involvement. IgAV is characterized by IgA deposition in the mesangium on immunofluorescence microscopy that is identical to that in IgA nephropathy (picture 1). Light microscopy changes range from isolated mesangial proliferation to severe crescentic glomerulonephritis. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)
Laboratory tests — No laboratory test is diagnostic for IgAV. However, confirmation of a normal platelet count and coagulation studies (prothrombin time [PT], partial thromboplastin time [PTT], and bleeding time) are necessary when clinical features do not allow conclusive distinction of IgAV from other diseases that present with purpura due to thrombocytopenia or coagulopathy. Other studies may be performed as part of the evaluation for disorders in the differential diagnosis. Some laboratory studies, such as urinalysis, are obtained once the diagnosis of IgAV is made but are not required for diagnosis. (See 'Differential diagnosis' below and "Purpuric skin lesions (petechiae, purpura, and ecchymoses) in children: Evaluation" and 'Additional evaluation' below.)
In patients who have an atypical presentation, such as abdominal pain before or without the rash, endoscopy (EGD) or video capsule endoscopy (VCE) may be needed to confirm the diagnosis. One study of 30 children in whom the diagnosis was still under question even after standard EGD described VCE findings of IgAV (eg, mucosal erosion, erythema, and/or petechia) in most patients [111].
DIFFERENTIAL DIAGNOSIS — In children presenting with the classic signs of palpable purpura plus some combination of abdominal pain, arthritis/arthralgia, and/or kidney involvement, the diagnosis of IgAV is generally straightforward [30]. However, the diagnosis is more difficult if there is an incomplete presentation of IgAV, particularly if the skin manifestations are initially absent. In these circumstances, other causes for purpura, arthritis, abdominal pain, and kidney disease need to be considered [2].
Purpura — Petechiae and purpuric rashes may be associated with septicemia, immune thrombocytopenia (ITP), hemolytic uremic syndrome, leukemia, and coagulopathies (eg, hemophilia). Normal platelet count and coagulation studies differentiate IgAV from these entities.
However, there are several other conditions that may present with purpura with normal platelet counts and coagulation studies:
●Acute hemorrhagic edema of infancy (AHEI) – AHEI (also known as Finkelstein or Seidlmayer disease) is a leukocytoclastic vasculitis described in children between the ages of four months to two years [112-116]. It is a self-limited disease that presents with fever, purpura, ecchymosis, and inflammatory edema of the limbs and resolves in one to three weeks (picture 5). Involvement of the kidney and the gastrointestinal tract is uncommon, but, when it occurs, it is very similar to that seen in IgAV [117,118]. Biopsy of the skin demonstrates a leukocytoclastic vasculitis with occasional IgA deposition. It is unclear whether this condition is truly a separate entity from IgAV or actually overlaps with it.
●Hypersensitivity vasculitis – Hypersensitivity vasculitis is an inflammation of the small vessels that occurs after exposure to drugs or infection or without an identifiable trigger [29]. Patients present with fever, urticaria, lymphadenopathy, and arthralgias but not usually glomerulonephritis. Histopathology shows a leukocytoclastic vasculitis primarily of the postcapillary venules, but IgA deposition is absent. (See "Hypersensitivity vasculitis in children".)
●Other small vessel vasculitides – There are a number of causes of small vessel vasculitis (including IgAV) that may present with asymmetric polyneuropathy, palpable purpura, and/or pulmonary or kidney involvement. These diseases include primary vasculitides (eg, granulomatosis with polyangiitis), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and vascular inflammation secondary to a connective tissue disorder (eg, systemic lupus erythematosus [SLE]) or to an infectious disease (eg, hepatitis B or C). In general, these diseases are uncommon in children. (See "Overview of and approach to the vasculitides in adults" and "Vasculitis in children: Incidence and classification".)
Laboratory evaluation of autoantibodies, including antinuclear antibodies, anti-double-stranded DNA (anti-dsDNA), and antineutrophil cytoplasmic antibodies (ANCAs), is typically negative in IgAV. Abnormal results for any of these studies may differentiate IgAV from the other causes of small vessel vasculitis. The majority of patients have normal complement levels, but hypocomplementemia has been reported both in IgAV and in AHEI [117]. Light microscopic examination of a purpuric lesion demonstrates leukocytoclasis in many small vessel vasculitides, but it is the predominance of IgA deposition that distinctively characterizes IgAV. (See "Vasculitis in children: Incidence and classification" and "Overview of and approach to the vasculitides in adults", section on 'Small-vessel vasculitis'.)
Arthritis and arthralgia — In approximately 15 percent of patients with IgAV, arthritis or arthralgia may be the presenting manifestation, usually preceding the skin manifestations by only one day. Until a patient develops the classical purpura of IgAV, other causes of joint complaints must be considered including autoimmune diseases, septic or reactive arthritis, and toxic synovitis (also called transient synovitis).
Autoimmune diseases, such as SLE, juvenile idiopathic arthritis (JIA), and rheumatic fever, may present with joint symptoms similar to IgAV. Assays for serum complement, antinuclear and anti-dsDNA antibodies, and rheumatoid factor are typically normal in patients with IgAV. Abnormal results for any of these studies may help to differentiate IgAV from SLE and JIA, although at least 15 percent of patients with IgAV may also have transient hypocomplementemia [107].
Evidence of a recent group A beta-hemolytic streptococci infection (eg, positive throat culture, positive rapid streptococcal antigen test, or elevated anti-streptolysin O [ASLO] titers) and the clinical course distinguish acute rheumatic fever from IgAV, with the caveat that a significant proportion of cases of IgAV are triggered by streptococcal infections. Reactive arthritis may be triggered by a variety of genitourinary and gastrointestinal pathogens including beta-hemolytic streptococcal infections. Reactive arthritis may cause a painful polyarthritis and high fevers, but the characteristic rash of IgAV should allow distinction between these conditions. Similarly, when considering toxic synovitis, another self-limited disease with transient joint findings that resolve without long-term sequelae, evolution of the other manifestations of IgAV will help differentiate the two conditions. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications" and "Oligoarticular juvenile idiopathic arthritis" and "Acute rheumatic fever: Clinical manifestations and diagnosis".)
Septic arthritis and toxic synovitis also may present with joint symptoms similar to those seen in patients with IgAV. Septic arthritis and toxic synovitis also may present with joint symptoms similar to those seen in patients with IgAV. These typically involve only one joint, unlike the oligoarthritis involving several joints seen in IgAV. Additionally, affected joints are warm and erythematous in septic arthritis, unlike those in IgAV. In most circumstances, these conditions are easily distinguished from IgAV by an experienced clinician. However, joint aspiration may be needed to differentiate the two. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Clinical features' and "Approach to hip pain in childhood", section on 'Common causes of hip pain in children' and "Overview of the causes of limp in children".)
Abdominal pain — Distinguishing acute abdominal emergencies, such as appendicitis, from IgAV may be difficult before purpura develops. Although the rash of IgAV usually precedes gastrointestinal manifestations and seldom lags by more than a few days, evaluation for potential acute abdomen cannot be delayed. In addition, the IgAV rash may be a nonspecific erythematous or urticarial exanthem or limited to lesions on the buttocks or lower extremities early in the disease course. Thus, careful serial examinations of the entire child are essential when considering the diagnosis. Radiologic studies used to screen for surgical causes of abdominal pain are also used in patients with IgAV who develop gastrointestinal complications, such as intussusception, bowel infarction, or perforation. (See "Causes of acute abdominal pain in children and adolescents" and 'Imaging studies' below.)
Kidney disease — Patients with IgA nephropathy present with immunologic and histopathologic findings similar to those of patients with IgAV. As is true of patients with IgAV, manifestations of IgA nephropathy vary from microscopic hematuria to acute kidney injury. Although patients with IgA nephropathy do not have the other clinical characteristics of IgAV, these two entities may share a similar pathogenesis. (See "IgA nephropathy: Clinical features and diagnosis".)
ADDITIONAL EVALUATION — Additional studies that are frequently performed upon diagnosis as part of the initial evaluation include urinalysis in all patients and imaging studies in those with significant gastrointestinal symptoms.
Kidney studies — Urinalysis should be performed in all patients with IgAV to screen for evidence of kidney involvement. In general, findings on urinalysis reflect the degree of kidney injury and may include the presence of red or white blood cells, cellular casts, and proteinuria. Serum creatinine should be obtained in all adult patients with IgAV because of the increased risk of significant kidney disease. Kidney disease is less prevalent in children, so serum creatinine need not be obtained unless the patient is hypertensive or has abnormalities on the urinalysis. Kidney involvement often becomes detectable after other manifestations of IgAV, so urinary screening should be continued beyond the acute presentation. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)
Imaging studies — Imaging studies generally are performed in patients with significant abdominal symptoms. Plain abdominal radiography may demonstrate dilated loops of bowel consistent with decreased intestinal motility. Abdominal ultrasonography can detect increased bowel wall thickness, hematomas, peritoneal fluid, and intussusception [17,73,74].
If intussusception is considered, ultrasonography rather than contrast enemas should be the initial screening test. Ileoileal intussusception is seen in more than one-half of the cases of intussusception in patients with IgAV. Contrast enemas, usually indicated in children with signs of an intussusception, neither detect nor help reduce ileoileal intussusception. (See "Intussusception in children".)
In males who present with scrotal symptoms, Doppler flow studies and/or radionuclide scans can distinguish scrotal pain caused by IgAV from testicular torsion. These studies demonstrate decreased blood flow to the testicle in testicular torsion, but testicular blood flow is normal or increased in males with IgAV. (See 'Urologic' above and "Causes of scrotal pain in children and adolescents", section on 'Testicular torsion'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: IgA vasculitis (Henoch-Schönlein purpura) (The Basics)")
●Beyond the Basics topic (see "Patient education: Vasculitis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Immunoglobulin A vasculitis (IgAV), formerly called Henoch-Schönlein purpura (HSP), is the most common systemic vasculitis of childhood. IgAV occurs primarily between the ages of 3 and 15 years. The annual incidence is 10 to 20 per 100,000 in children <17 years of age, with a peak incidence in children between four to six years of age. Approximately 10 percent of IgAV cases occur in adults. (See 'Epidemiology' above.)
●Pathogenesis – The underlying cause of IgAV is unknown. It is thought that IgAV represents an immune-mediated vasculitis that may be triggered by a variety of antigens, which may include various infections or other environmental exposures. (See 'Pathogenesis' above.)
●Clinical manifestations – IgAV is a self-limited disease and is characterized by a tetrad of clinical manifestations that vary in their occurrence and order of presentation (see 'Clinical manifestations in children' above):
•Palpable purpura without thrombocytopenia and coagulopathy (picture 2A-E)
•Arthralgia and/or arthritis
•Abdominal pain
•Kidney disease
●Diagnosis – The diagnosis of IgAV is usually based upon clinical manifestations of the disease (algorithm 1). There are no diagnostic laboratory tests for IgAV. In patients with an incomplete or unusual presentation, biopsy of the affected organ (eg, skin or kidney) demonstrating predominantly IgA deposition supports the diagnosis of IgAV. (See 'Diagnosis' above.)
●Differential diagnosis – The diagnosis is more difficult if there is an incomplete presentation of IgAV or if the skin manifestations are absent at disease onset. In these circumstances, other causes for purpura, arthritis, abdominal pain, and kidney disease must be considered. Patients in whom the diagnosis is at all in doubt should have a complete blood count, prothrombin time (PT), and urinalysis. The presence of thrombocytopenia or a coagulopathy largely excludes the diagnosis of IgAV. (See 'Differential diagnosis' above and 'Laboratory tests' above.)
●Additional evaluation – A urinalysis is performed in all patients diagnosed with IgAV. A serum creatinine level should be obtained in children with hypertension or an abnormal urinalysis. Serum creatinine should be assayed in all adult patients with IgAV because of the increased risk of significant kidney disease. Imaging studies are performed in those with significant gastrointestinal symptoms. Abdominal ultrasonography is indicated in patients with severe abdominal pain. It can detect increased bowel wall thickness, hematomas, peritoneal fluid, and intussusception. Contrast studies may miss intussusception in patients with IgAV. (See 'Additional evaluation' above.)
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