Pediatric Henoch–Schönlein purpura

Henoch–Schönlein purpura (HSP) is an acute, self-limited, systemic, small-vessel vasculitis usually seen in otherwise healthy children and adults. HSP is the most common necrotizing vasculitis affecting children. Although it most often affects young children, it may develop at any age.1 It represents an immune complex-mediated disease of widespread nature and multisystem involvement. Most HSP occurs between 3 and 5 years of age.2 Ninety per cent of HSP patients are under 10 years of age.3,4 The mean age of patients is approximately 6 years.5,6 HSP is a distinctive self-limited disorder, typically occurring during the autumn and winter months in children.2,6 The disease is present worldwide. The average annual incidence rate of HSP in the population aged 14 years and younger is approximately 135 per million, about 100 times that in adults.4,6 It is thought to occur more often in female children, although some have found a male predominance or both sexes to be equally affected.2,6–9 No racial predominance has been noted, but African-Americans are rarely affected.10 The disease usually lasts for 1–4 weeks, although great variability in this time frame can occur; relapses are possible. The first case of HSP was described by William Heberden (1710–1801) in 1801.11 He described a 5-year-old boy with a purpuric eruption, macroscopic hematuria, abdominal pain, bloody stools, vomiting, arthralgia, and edema. It was not until 1837 that Johann Schönlein recognized a similar constellation of symptoms, and named the arthritic component associated with purpura "peliosis rheumatica" or "purpura rubra."10,12 Schönlein, in addition to the other symptoms, also described renal involvement, citing "frequent precipitates in the urine" of patients.12 It was Eduard Heinrich Henoch, a pupil of Schönlein, who added abdominal colic, bloody diarrhea, and hemorrhagic nephritis to the syndrome's components.5,10,13,14 In 1914, William Osler15 proposed that the disease was the result of anaphylaxis. The term "anaphylactoid purpura" refers to the syndrome known today as "Henoch–Schönlein purpura."16 HSP may still be referred to as anaphylactoid purpura, although it is evident that anaphylaxis is not involved in its pathophysiology. The vasculitic nature of HSP, or anaphylactoid purpura, was described by Gairdner17 in 1948. Subsequently, the role of immunoglobulin A (IgA) in the pathogenesis of HSP was established. HSP, an immune-mediated vasculitis, may be the result of an immune complex reaction to various antigenic stimuli in susceptible persons.18 Increased occurrence among family members supports a genetic predisposition for this vasculitis.19 Increased susceptibility to HSP is found among human leukocyte antigen (HLA)-DRB1*01 patients.19,20 HLA-DRB1*01, however, has not been found to be associated with any specific complication of HSP.19 A decreased frequency of the HLA DRB1*07 allele occurs in patients, implicating it in a protective role.20 Increased susceptibility to nephritis has been observed in HLA-B35-positive patients; this locus seems to independently code for renal complications.21 Although the exact etiology of HSP is unknown, clinical evidence points to an infectious etiology. The peak incidence of pediatric HSP occurs during the autumn and winter months.2 It is often preceded by an upper respiratory tract infection and is found to cluster within families.22,23 Furthermore, the higher incidence of HSP in childhood, a time at which individuals first encounter many microbes, also points to an infectious component as part of its etiology.4 The short and self-limited course of HSP in pediatric patients is consistent with a viral etiology.24 A prodrome consisting of an upper respiratory tract infection 1–3 weeks prior to the onset of symptoms is found in 90% of cases.25 Many cases follow streptococcal infection.26 Intercurrent infection is also more commonly found among younger patients.27 Many organisms have been postulated to be the etiologic agents of HSP; objective evidence consistent with an infectious etiology exists. In children, serologic testing most commonly reveals viral and bacterial pathogens (see Table 1). However, less common viral pathogens have also been isolated in patients (see Table 2). One case of HSP associated with pulmonary tuberculosis (Mycobacterium tuberculosis) has been documented among children.36 In adults, drugs and toxins, including vaccinations, insect bites, and food allergies, may be the primary predisposing factors for HSP.10,18,37 Drug-induced HSP is a common association in adults. The drugs most commonly linked with HSP are angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (losartan), antibiotics (clarithromycin), and nonsteroidal anti-inflammatory drugs.10,38,39 Immunologic evidence indicates that IgA deposition is a key factor in the pathogenesis of HSP. HSP may be initiated by certain microorganisms that share an antigenic determinant with human small-vessel endothelial cells.40 For example, cardiolipin is an autoantigen on endothelial cells, and anticardiolipin antibodies have been found to be elevated in children with acute HSP.41 Under this hypothesis, following the invasion of a pathogen, antigen-specific antibodies of the IgA subtype cross-react with and are deposited on endothelial cells; however, no specific antigen has been consistently associated with HSP. This may suggest that deposition occurs by a mechanism other than the classical antigen–antibody interaction. One possible mechanism involves altered glycosylation of O-linked oligosaccharides in the hinge region of IgA1.25 The abnormal IgA1 is not fully catabolized in the liver. The decrease in IgA1 clearance results in its deposition in various tissues, such as the renal mesangium.42,43 Regardless, once deposited, IgA can activate the complement system via the alternative pathway and cause further damage to the endothelial lining.40 IgA and C3 deposits are typically found within endothelial cell gaps of the skin and kidney mesangium of patients with HSP.44 Although classically associated with IgA, newer evidence suggests that additional factors are associated with the pathogenesis of HSP. Tumor necrosis factor-α (TNF-α), a cytokine produced by macrophages and T cells during an immune response, is found in high levels in tissue and plasma during the acute phase of HSP.45 TNF-α normally induces the expression of adhesion molecules [intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), E-selectin] on endothelial cells and leukocytes, resulting in the localization of the latter to sites of infection; however, studies have found that endothelial cells treated with TNF-α bind IgA with higher affinity.40 The endothelial cell-specific antigenic determinants triggered by TNF-α interact with IgA to cause vascular inflammation. The specific antigens remain to be determined. Cytokines, such as TNF-α, also induce the nitric oxide (NO) pathway in various cell types.37 Serum NO and urinary nitrate excretion, markers of NO production, have been found to be elevated in the acute phase of HSP.37 The elevation of NO was found to be associated with the activation of the disease, but not its severity.37 It is likely that the increase in serum NO levels reflects endothelial injury.37 The levels of NO return to normal with remission. Endothelins (ET-1), vasoconstrictor hormones produced by endothelial cells, are also significantly higher in the acute phase of HSP, but their significance remains to be determined.46 HSP is a syndrome which encompasses nonthrombocytopenic purpura, arthritis, arthralgias, gastrointestinal symptomatology, and nephritis. The predominant cutaneous finding of HSP is painless, palpable purpura. In more than 70% of patients, palpable purpura alone or purpura associated with abdominal and/or joint pain is the first sign.6,27 Early in the course of the disease, the eruption may blanch with pressure, but this feature disappears with time. At onset, the eruption appears as crops of erythematous, raised patches, which progress to palpable purple indurations of up to 1 cm in diameter (Fig. 1).5 The first crop is usually found below the waist, with subsequent crops appearing on the extensor aspect of the forearms, cheeks, and ears. Maculopapular, urticarial, or vesicular lesions may precede or occur together with typical palpable purpura.3,6 With urticarial lesions, pruritus is usually mild or absent. Petechiae and ecchymoses may be scattered among the lesions. The eruption in children is characterized by its polymorphism, whereas, in adults, it is often monomorphic.5 As recovery ensues, the lesions fade, leaving areas of postinflammatory hyperpigmentation. With time, they will disappear completely. These cutaneous manifestations are found to be most commonly localized to the lower extremities. In young children, they are usually localized to the back, buttocks, and upper thighs, whereas, in older children and adults, the eruption is found on the calves and ankles. In addition, skin lesions may be found on the scrotum, penile shaft, and glans penis.47 The trunk, face, palms, soles, and mucous membranes are spared in most patients. Cutaneous necrosis is uncommon and affects fewer than 5% of HSP pediatric cases.27,48 The frequency of necrotic purpura is directly correlated with patient age.27 Blisters or hemorrhagic necrotic lesions have been reported to occur in up to 60% of adult patients with HSP49 (Fig. 2). The reasons for the difference in incidence of hemorrhagic necrotic lesions in children and adults are not known. Up to 35–70% of young children may develop nonpitting subcutaneous edema of the scalp, face, and dorsum of the hands or feet in addition to the exanthem.4 Henoch–Schönlein purpura: thigh with erythematous, violaceous, indurated plaques Bullous Henoch–Schönlein purpura: discrete bullae on the lower extremities In approximately 20–50% of cases, arthritis or abdominal pain precedes the onset of the purpura by 1–14 days.5,27 Gastrointestinal involvement, including colicky abdominal pain, vomiting, hematemesis, and guiac-positive stools, has been reported to occur in approximately 50–75% of all HSP patients.5,6,9,25,50 These symptoms are caused by peritoneal or visceral purpura, leading to the extravasation of blood and interstitial fluid into the intestinal lumen. Abdominal pain is the most common of the gastrointestinal symptoms, affecting two-thirds of children. The pain is usually localized to the periumbilical or epigastric region, and described as blunt in nature.5 HSP begins with arthralgias and/or arthritis as the only initial manifestation in 25% of cases;3,6 however, more than 50% of HSP cases involve auricular manifestations.5,6 The frequency of joint manifestations is inversely correlated with patient age, with more frequent involvement noted among children.27 The arthralgia or arthritis typically involves the large joints of the lower extremities, and usually resolves without any permanent deformities.6 Approximately 20–40% of pediatric HSP patients have renal involvement, a much lower frequency than that seen among adult patients, which is nearly 70%.8,9 The significant risk factors for the development of renal involvement in HSP include severe abdominal pain with gastrointestinal bleeding, an age of more than 4 years at onset, and persistent purpura for more than 1 month.51 Children of less than 2 years of age are less likely to develop renal manifestations.51 Microscopic hematuria, with or without proteinuria, is the most common renal manifestation.52 The onset of renal involvement may follow the appearance of purpura by weeks or months.51 The mean interval from the appearance of purpura to the onset of renal involvement is approximately 1 month. This is in contrast with the situation seen in adults, with over 40% of cases presenting more than 1 month after the onset of HSP.10 Of patients with renal pathology, 97% of the complications arise within 3 months of disease onset.51 Evidence suggests that the prognosis is correlated with the degree of renal pathology, defined as the presence of crescents53,54 or tubulointerstitial changes.55 Although most patients with renal involvement have a good prognosis, some with significant proteinuria may progress to end-stage renal failure.49 Children may develop rapidly progressive glomerulonephritis, a syndrome diagnosed when at least 50–80% of renal glomeruli have circumferential crescents. In the pediatric population, factors predictive of a poor prognosis include nephrotic syndrome, nephritic syndrome, altered renal function at presentation, nonselective proteinuria, and hypertension.9 Approximately 12% of children with HSP will have chronic renal failure 3–4 years after onset.9 Of those children with HSP nephritis, approximately 20% progress to end-stage renal disease.10 The risk of progression to renal insufficiency is much higher, approximately 30%, among adult patients.24,27 Other features of HSP include low-grade fever, malaise, orchitis,47 seizures,56 epistaxis,5 ileoileal intussussception,25 jejunal hemorrhages,57 orbital hematomas,58 central nervous system bleeding, and ischemic strokes.59 Despite these documented cases, HSP in children is usually a mild, acute condition. The course of the illness varies among patients. The individual crops last 5–7 days, although new cutaneous lesions may develop for up to 8 weeks. On average, the disease lasts 2–3 weeks; 15–40% of children have at least one recurrence.5,25 A recurrence is defined as the reappearance of symptoms following the resolution of disease for at least 2 weeks. No association exists between the risk of recurrence and the age of the patient. The mean onset of recurrences is 3 months after initial resolution of symptoms.5 Recurrences are usually limited to cutaneous and gastrointestinal symptomatology. A skin biopsy specimen may help to confirm the diagnosis. The histologic criteria for cutaneous necrotizing vasculitis include fibrinoid necrosis of blood vessel walls, endothelial swelling, and a neutrophilic infiltrate showing nuclear fragmentation (Fig. 3). As defined by the American College of Rheumatology, HSP is a leukocytoclastic vasculitis with IgA-predominant deposits, affecting the capillaries, venules, and arterioles, as well as perivascular infiltration of neutrophils and mononuclear cells (Fig. 4).4,52 Leukocytoclastic vasculitis encompasses inflammation and fibrinoid necrosis of the vessel walls, together with deposition of cellular debris in the surrounding skin. Henoch–Schönlein purpura: leukocytoclastic vasculitis (hematoxylin and eosin, ×100) Henoch–Schönlein purpura: direct immunofluorescence demonstrating immunoglobulin A (IgA) deposition in the papillary dermal blood vessels (×100) The diagnosis of HSP is based on clinical findings. A careful history, including recent infections and medications, should be elicited. The physical examination should reveal the presence of palpable purpura. Edema of the scalp and extremities may also be present;4 however, as cutaneous involvement can occur in any of the primary systemic vasculitic syndromes, the diagnosis of this specific form of vasculitis requires the documentation of organ involvement, as well as histopathologic studies. Direct immunofluorescence (DIF) of skin biopsy specimens will generally show IgA and complement deposition in lesional as well as clinically normal skin; however, it should be noted that sampling of old or necrotic lesions may yield a negative result.52,60,61 This test has been found to have a sensitivity between 92% and 100%.62,63 The DIF test is a useful adjunct to histopathology if performed within 48 h of lesion onset, as the sensitivity of the test is higher in this subgroup. It is likely that immunoreactants deposited in the blood vessels are destroyed and removed after 48 h.64,65 In dark-skinned children, early lesions are harder to identify. This results in delayed recognition by the patient and a decrease in the sensitivity of the DIF test.65 Among dark-skinned individuals, histopathology may be more useful in aiding the diagnosis as it is not influenced by the duration of the lesion. Nailfold capillaroscopy of HSP patients shows tortuous, granular capillaries, edema, and derangement and branching of capillaries with temporary arrests in blood flow (sludging).66 The American College of Rheumatology has defined the diagnostic criteria for HSP as the presence of two or more of the following: palpable purpura, an age of 20 years or less at onset, bowel symptoms suggestive of ischemia, and histologic documentation of leukocytoclastic vasculitis.60 The presence of any two of the four criteria distinguishes HSP from other vasculitic syndromes with a sensitivity of 87.1% and a specificity of 87.7%.60 A urine analysis should be performed at the time of diagnosis. Sequential urinary examinations are recommended for 3–6 months after HSP onset.2,4,51 The incidence of renal disease drops dramatically 3 months after the onset of HSP.4,51 In atypical patients, a complete blood count, platelet count, and coagulation studies may facilitate the diagnosis.4 The laboratory tests should show moderate leukocytosis with a mild elevation of acute phase reactants. An increased serum IgA is found in approximately 50% of patients with HSP.4 The clinical significance of this finding is uncertain, especially as the pathogenesis of HSP is still unclear. Although an elevated serum IgA may be suggestive, it is of limited utility when evaluating a patient for HSP, which is primarily a clinical diagnosis. Sepsis, bacterial endocarditis, rickettsial infections, clotting disorders, and thrombocytopenia may all be associated with cutaneous purpura;67 however, the distribution and morphology of purpura, together with hematologic testing, should differentiate these cases from HSP. The hallmark of leukocytoclastic vasculitis is palpable purpura. Chronic meningococcemia is characterized by the simultaneous appearance of a localized purpura, fever, and joint soreness. As the fever dissipates, normally so does the eruption; however, the periodic nature of the fever and eruption may recur for weeks to months. It is associated with various skin lesions, usually distributed about one or more painful joints. Most crops consist of rose-colored macules and papules. The cutaneous findings of HSP are more symmetric, usually localized to the lower extremities, and do not have the periodicity of the eruption of meningococcemia. Septic vasculitis is usually accompanied by thrombocytopenia and increased clotting times, further distinguishing it from HSP. Acute hemorrhagic edema of childhood (AHEC), or acute infantile hemorrhagic edema (AIHE), is an acute leukocytoclastic vasculitis which affects children under the age of 2 years. AHEC and HSP share features such as the prodrome, seasonal predisposition, cutaneous involvement, and histologic findings on skin biopsy.68 In AHEC, facial edema may be the initial sign. The cutaneous findings are concentrated on the face and distal portions of the extremities, with relative sparing of the trunk. The lesions are larger purpuric plaques than the palpable purpura of HSP. They are target-like in appearance and may develop into bullae. In addition, painful edema of the hands and feet is a common finding. Unlike in HSP, recurrence and gastrointestinal and renal involvement are rare. Histologically, AHEC is found to have IgA deposition within the vessel walls in only a minority of cases.5,68 Leukocytoclastic vasculitis, like that of HSP, can also be associated with leukemia and leukemic lymphoma. Inflicted bruises or vascular purpura caused by intrinsic structural abnormalities of the blood vessels may mimic cutaneous HSP. A careful history helps to distinguish between the two. Traumatic skin injuries, unlike HSP, are usually not associated with systemic symptoms, such as abdominal pain, hematuria, or proteinuria; however, atypical presentations, such as those seen in infants, may mimic physical abuse.69 Infants with HSP may only exhibit edema, erythema, or purpura of the face at onset and lack the classic systemic features. Although the diagnosis depends on the history and clinical a biopsy specimen showing leukocytoclastic vasculitis with IgA deposits as the cause of the purpura. vascular disorders, including tissue disease and may also show a vasculitic Unlike in HSP, and are common in In addition, antibodies are associated with its diagnosis. The hallmark of is In a the initial manifestations are of and an to of childhood can be limited to skin involvement or the may the involvement by years. The eruption is both and symmetric, with over the extensor of the and The diagnosis of is by an abnormal and should be when elevated such as are Other of the vessel walls, such as and hemorrhagic in addition to cutaneous are associated with gastrointestinal These disorders, unlike HSP, are chronic and can be on the of the course of the Acute and may also show In addition, may mimic the joint pain, hematuria, and edema associated with HSP. Unlike HSP, immunofluorescence of kidney tissue typically shows granular deposits of and in which the skin is the are as erythema, or Unlike the and associated with HSP are usually A careful history, including recent and medications, together with clinical will further help to distinguish these from HSP. syndrome, or syndrome, is an uncommon purpuric of The skin lesions consist of painful up to in usually distributed over the of the lower extremities and trunk. As in HSP, including malaise, fever, arthralgias, and gastrointestinal symptoms, may also Unlike HSP, however, the lesions are and usually weeks after or severe examination can differentiate HSP from of patients with the latter show blood cells in the and subcutaneous with no evidence of leukocytoclastic vasculitis or fibrinoid HSP is a syndrome with a clinical The to which individual patients features of the the to The of HSP is generally associated joint and abdominal In patients with normal kidney should on the of and Most that and/or nonsteroidal anti-inflammatory agents should be for the of joint pain and inflammation in In addition, may be in children with painful cutaneous Despite the significant associated with the gastrointestinal manifestations in the short term and the renal complications in the however, no with to their Cutaneous manifestations are usually self-limited without but may The of may be with a of or with The of is and is usually for children with severe systemic manifestations and renal of has many including face, and edema. In many children with HSP, studies have an in the activation of the In these children, and levels high and plasma was In children with high and significantly the rate of the cutaneous lesions when with manifestations in HSP are usually mild and in however, will progress to renal The role of in nephritis remains unclear. have to be that with the onset of renal that with no The of renal disease at the time of is one of the predictive factors for no studies that the to in patients with significant renal involvement. In patients with disease, exists for with alone or in with is and appears to proteinuria which is a known risk factor for the development of renal insufficiency in with and has clinical and the of may be the of and for severe HSP nephritis may be for those patients with risk of progression of their especially if early during the course of the disease the In patients with rapidly progressive HSP nephritis, by a of and seems to be Gastrointestinal involvement has been reported to occur in approximately 50–75% of all HSP Abdominal pain is the most common Although abdominal pain will with or without with will its abdominal pain that is to may dramatically to a of such as or may be in children with gastrointestinal and ischemic bowel as a result of widespread may be as recent evidence has that the ischemic may after As gastrointestinal manifestations may a significant risk factor for renal involvement, early with for at least 1 within the first 3 weeks of disease should be to both the abdominal pain and the risk of renal patients may from A with the symptoms and have been to with no recurrence after of the and In addition, a may be in the clinical symptoms in and and are the most in children with HSP. as HSP is a syndrome with a clinical the to depends on the clinical manifestations of the individual patient.