Cutaneous vasculitis in children is rare. Causes of cutaneous vasculitis are varied and are typically differentiated by the affected vessel size. A skin biopsy remains the gold standard for diagnosis but other causes for vasculitis, including systemic conditions, should be considered. This article discusses the childhood conditions commonly presenting with cutaneous vasculitis (leukocytoclastic vasculitis, cutaneous polyarteritis nodosa), biopsy recommendations and findings, and management and potential differential diagnoses, and includes a brief summary of other diseases that may include cutaneous symptoms as a constellation of other systemic findings.
Key points
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Cutaneous vasculitis is rare in children.
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Henoch-Schönlein purpura is the most common vasculitis in childhood.
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Leukocytoclastic vasculitis describes the typical histopathologic findings on skin biopsy of most childhood cutaneous vasculitic lesions: small vessel wall inflammation with fibrinoid necrosis and immune complex deposition.
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Differential diagnosis of cutaneous vasculitis includes infectious causes, systemic forms of vasculitis, and other connective tissue diseases.
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Referral to a dermatologist and/or rheumatologist is warranted, particularly when the rash and/or presentation is atypical.
Introduction
Vasculitis is an inflammatory cell-mediated process involving cellular infiltration, necrosis, and destruction of blood vessels. Cutaneous vasculitis (CV) can be seen among a spectrum of heterogeneous conditions. Although it can be limited to cutaneous deposition only, it can also be associated with other inflammatory and autoimmune conditions such as systemic vasculitides and connective tissue diseases, and has also been associated with certain medications, infections, and malignancy (although malignancy is more commonly seen among adults). This article focuses on the childhood conditions most commonly associated with CV and the varying histopathology, clinical presentation, and treatment, including leukocytoclastic vasculitis (Henoch-Schönlein purpura [HSP], urticarial vasculitis [UV], acute hemorrhagic edema of infancy [AHEI]) and cutaneous polyarteritis nodosa (cPAN). There is also a brief discussion of systemic conditions and other causes or mimickers of CV.
Introduction
Vasculitis is an inflammatory cell-mediated process involving cellular infiltration, necrosis, and destruction of blood vessels. Cutaneous vasculitis (CV) can be seen among a spectrum of heterogeneous conditions. Although it can be limited to cutaneous deposition only, it can also be associated with other inflammatory and autoimmune conditions such as systemic vasculitides and connective tissue diseases, and has also been associated with certain medications, infections, and malignancy (although malignancy is more commonly seen among adults). This article focuses on the childhood conditions most commonly associated with CV and the varying histopathology, clinical presentation, and treatment, including leukocytoclastic vasculitis (Henoch-Schönlein purpura [HSP], urticarial vasculitis [UV], acute hemorrhagic edema of infancy [AHEI]) and cutaneous polyarteritis nodosa (cPAN). There is also a brief discussion of systemic conditions and other causes or mimickers of CV.
Pathophysiology
The exact mechanism leading to vasculitis remains uncertain. It is presumed that CV is an immune complex–mediated condition with the majority of lesions having immunoglobulin and/or complement deposition on direct immunofluorescence. For example, in leukocytoclastic vasculitis (LCV), immunoglobulin (Ig) A, IgG, IgM, fibrin, and activated third component of complement (C3) deposition is noted. Endothelial cell factors, inflammatory mediators, and adhesion molecules are also presumed to play a role in the damage seen in vasculitis. Following immune complex deposition, complement (C3a, C5a) is activated triggering the recruitment of inflammatory cells including neutrophils and mast cells. Adhesion molecules, including intracellular adhesion molecule-1, P-selectin, and E-selectin, have been found to be expressed within vasculitic lesions. Activated lymphocytes and macrophages trigger further complement activation and cytokine production, including production of tumor necrosis factor (TNF) alpha and interferon gamma, which serve to induce and upregulate adhesion molecules, thus perpetuating the vascular destruction. Other autoantibodies, including antineutrophil cytoplasmic antibodies (ANCA), may play a role in some cases of CV, particularly those cases seen in certain systemic vasculitides.
Epidemiology
Given the rarity of childhood cases of CV, limited information is available for incidence and prevalence. HSP is the most common systemic vasculitis in children, occurring in 1 in 5000 children annually in the United States, with Kawasaki disease being the second most common vasculitis. Although not specific to the pediatric population, causes of CV in adults are typically idiopathic (45%–55%) but can be associated with infection (15%–20%), autoimmune conditions (15%–20%), medications (10%–15%), and malignancy (<5%). Other inflammatory conditions like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren syndrome (SS), Behçet disease (BD), and inflammatory bowel disease can have cutaneous findings of CV as part of the clinical manifestation of disease. Medications associated with CV in children include penicillins, paracetamol, and/or nonsteroidal antiinflammatory drugs (NSAIDs). Multiple infections, primarily upper respiratory infections (viral, bacterial, mycobacterial), and vaccinations including hepatitis A, hepatitis B, influenza, and H1N1 have also been implicated. Other potential triggers seen more frequently in adults include chemical exposures, foods, and illicit drugs. Diagnosing drug-induced vasculitis is difficult given the lack of diagnostic tests; however, eosinophilia has been found in some cases. Therefore, other causes must first be excluded. Some clues to drug-induced vasculitis include the temporal relationship of skin findings to the drug (typically 5–7 days after exposure, although it can be years), effect of withdrawal of the drug, effects of rechallenge with the drug, dose exposure, and the type of drug.
Clinical features
History
To date, classification criteria have been controversial for vasculitic syndromes, in part because of the heterogeneity of the different diseases. Nonetheless, in pediatrics, a revised classification criteria was proposed in 2008 via a consensus panel by the European League against Rheumatism (EULAR), the Pediatric Rheumatology International Trials Organisation (PRINTO), and the Paediatric Rheumatology European Society (PRES) to better define childhood vasculitic syndromes. Additional criteria for systemic disease has been suggested by both the American College of Rheumatology (ACR) and the North Carolina Chapel Hill Consensus Congress, but these have limitations and are unique to the adult population.
At present, when evaluating a child with suspected CV, key criteria to consider include the size of the vessel(s) involved, histopathologic features, as well as extent of disease with or without additional systemic symptoms (limited cutaneous vs systemic). Skin is composed of both small and medium-sized vessels. Small-vessel disease involves inflammation within the superficial dermis of capillaries, postcapillary venules, and nonmuscular arterioles and presents clinically as palpable purpura, petechiae, vesicles, pustules, and/or urticaria. Medium-sized vessels of the skin are arterioles located deep in the junction of dermis and subcutis with medium-vessel vasculitis presenting clinically as subcutaneous nodules, livedo reticularis, cutaneous ulcers or infarcts, and/or necrotic lesions.
Diagnostic recommendations
A thorough history and physical examination helps to guide the need for laboratory and imaging studies. The history should focus on recent illnesses, drug or vaccination exposure, family history, and medical history. Constitutional symptoms including fever, weight loss, anorexia, malaise, arthralgias, and myalgias are helpful to elicit. Additional organ-specific symptoms should be reviewed to evaluate for possible systemic disease.
Laboratory Studies
In general, laboratory studies may not be helpful in making the diagnosis of CV limited only to skin. However, they may be helpful when differentiating isolated cutaneous versus systemic disease. In all cases, there may be evidence of mild to moderate systemic inflammation (increased white blood cell [WBC] count, erythrocyte sedimentation rate [ESR], or c-reactive protein [CRP]); however, in systemic disease, there may be greater increases of inflammatory markers. Additional screening should include a complete metabolic panel (CMP), urinalysis (UA), urine protein/creatinine ratio (an indirect measure of proteinuria), antinuclear antibody (ANA), complement levels (C3, C4, CH50), ANCA, antistreptolysin-O (ASO) antibodies, anti-DNase antibodies, and other bacterial or viral studies as appropriate. Rheumatoid factor (RF), anti-SSA, anti-SSB, cryoglobulins, and hepatitis B/C titers may be considered but are less commonly seen among children.
Histology
A skin biopsy is helpful when performed correctly. It is important to consider both location and timing of the biopsy for optimal diagnostic yield. The type of biopsy (punch of 3–4 mm vs incisional/excisional >6 mm) should be chosen based on vessel size of interest, with larger vessels present in deeper tissue. Lesions of choice should be active (appearing no more than 48 hours before biopsy) and ideally include a tender, reddish, purpuric lesion. In small-vessel (diameter<50 μm) vasculitis, a punch biopsy should be sufficient; however, for cPAN, a deeper biopsy including subcutaneous fat is needed for adequate evaluation of medium-sized (diameter 50–150 μm) vessels, and therefore an incisional or excisional biopsy may be more appropriate.
Timing of the skin biopsy is also critical. Classic lesions less than 24 hours old typically reveal fibrin deposits and neutrophilic infiltration with hemorrhage (caused by extravasation of erythrocytes) and nuclear debris. However, soon thereafter, neutrophils are replaced with infiltration of lymphocytes and macrophages and, by 48 hours, lymphocytes predominate. Thus, it is strongly recommended that the lesion be less than 48 hours old. Furthermore, immunofluorescence deposition declines with time.
In addition to standard hematoxylin and eosin staining, all skin biopsies should undergo direct immunofluorescence (DIF), particularly given the hallmark finding of IgA deposition in HSP. In immune complex–mediated vasculitis, all biopsies should stain for immunoglobulins within the first 48 hours. However, only 70% are present at 48 to 72 hours, and none are detected after 72 hours. In contrast, complement may still be seen in most lesions of vasculitis even after 72 hours. A lesional biopsy is also preferred for DIF, although perilesional (2–3 mm from active lesion) biopsies may reveal positive immunoglobulin deposition. A diagnosis of LCV-type vasculitis was associated with IgA deposition within lesional (sensitivity 87%, specificity 73%) and perilesional (sensitivity 68%, specificity 66.7%) biopsies. Likewise, in LCV, IgM and IgG were also more commonly seen in lesional (56%, 20% respectively) than perilesional (34%, 8%) skin biopsies.
Therapeutic recommendations
Pharmacologic Treatment
Because most isolated cutaneous lesions have a benign course, treatment is mainly supportive with rest, elevation, and NSAIDs. Avoidance or removal of potential triggers (ie, medications) should also occur and appropriate treatment of identified infections should be implemented. Patients who do not respond readily to these supportive measures, or in whom there is significant pain or involvement, may benefit from dapsone, colchicine, or hydroxychloroquine. There is anecdotal evidence that a short course of oral (and possibly topical) steroids may provide rapid relief but should be reserved for severe cases of cutaneous disease and should likely be tapered slowly to prevent rebound. Those cases of CV associated with systemic conditions require more specific immune suppressants including systemic corticosteroids; a discussion of this is beyond the scope of this article.
Leukocytoclastic vasculitis
HSP
Introduction/overview
HSP is the most common small vessel vasculitis of childhood with a classic presentation of palpable purpura. HSP is typically a benign, self-limited condition, although some patients have a protracted course with relapses and renal complications. Skin findings are the absolute criteria for diagnosis; therefore, awareness of the variations of cutaneous presentation can be helpful. Most cases of HSP are diagnosed and managed by the general pediatrician; however, at times, with atypical presentations or unusual skin findings, a dermatologist’s evaluation can be helpful. Additional consultants may include a rheumatologist if there is consideration for an alternate systemic vasculitis or treatment recommendations, a nephrologist for renal disease, and a gastroenterologist or urologist if necessary.
Pathophysiology
HSP is an immune complex–mediated leukocytoclastic vasculitis affecting small blood vessels including arterioles, venules, and capillaries. Polymorphonuclear infiltration of vascular and perivascular tissue is frequently seen. It is an IgA-mediated disease with deposition noted on histopathology. Direct immunofluorescence may further reveal additional IgM and C3 deposition. Other autoantibodies including ANCA, endothelial cell factors like vascular endothelial growth factor (VEGF ), inflammatory mediators, and adhesion molecules are also presumed to play a role in the damage seen in vasculitis. In a 2004 study evaluating the presence of ANCA in HSP, blood samples of IgA ANCA were found with greater prevalence (82.3%) among patients with HSP in the acute stages compared with IgG ANCA (2.8%) and in comparison with healthy controls (0%) and patients without LCV vasculitis (38%). In the resolution phase, IgA ANCA was seen in only 12% of patients with HSP, indicating that ANCA testing could be a useful biomarker of disease, although further studies have yet to be reported. This finding further indicates the potential pathogenic involvement of ANCA.
Epidemiology
The annual incidence of HSP in children has been reported at 14 to 20.4 per 100,000. As one of the most common vasculitides in childhood, it accounts for more than half of all cases of pediatric vasculitis. There may be a slight gender predilection affecting male rather than female patients at a 2:1 ratio. Average age of onset is approximately 2 to 11 years. Although skin disease is always present, vasculitis can also involve the gastrointestinal tract, kidneys, scrotum, and joints. Frequent association with a preceding illness has been reported, in particular with beta-hemolytic streptococcus (20%–50%), parvovirus B19, Bartonella henselae , Staphylococcus aureus , Helicobacter pylori , Haemophilus parainfluenza , Coxsackie virus, mycobacteria, Salmonella , other viral illnesses, immunizations, and medications. The seasonal predilection (primarily fall and winter) for HSP provides further evidence of a strong association with infectious triggers.
Prognosis
In most classic cases of HSP, patients have a short-lived (<1 month), benign course and require little to no treatment (other than supportive care). About one-third of patients tend to have a remitting and relapsing course, particularly with skin findings. Nevertheless, each subsequent episode is less severe and shorter in duration than the one before. Approximately 2% to 20% of all patients with HSP develop permanent renal disease.
Clinical features
History
In children with HSP, classic symptoms of palpable purpura typically occur 5 to 7 days following an upper respiratory infection or other trigger noted earlier. The rash is the presenting symptom in nearly three-quarters of cases.
Physical Examination
Children with HSP classically present with palpable purpura ( Fig. 1 ) located in areas of dependency, including the buttock and lower extremities. A rash can also appear on other sites, including the arms and trunk. Lesions may occur following trauma or under pressure (eg, sites such as the waistband). There can also be mucosal involvement. In addition to classic purpura, papules, vesicles, and urticaria-like lesions can occur. Less common findings include petechiae and necrotic, ulcerated, hemorrhagic, or bullous lesions ( Fig. 2 ). More atypical skin lesions (necrotic, ulcerative) seem to be associated with a longer duration to presentation (2–3 weeks) and worse gastrointestinal (upper gastrointestinal bleed, abdominal pain, or gastritis) and renal (oliguria, hypertension, hematuria) symptoms. However, several case reports of bullous lesions in children with HSP do not seem to be associated with worse prognosis or renal outcomes.
Systemic symptoms may include peripheral edema or periarticular swelling and corresponding arthralgias. True arthritis, typically symmetric involvement of large joints (hips, knees, ankles) may be apparent (66% of patients). Some patients also have gastrointestinal symptoms (56%) of sharp, colicky pain; gastritis; bleeding; and/or intussusception (0.7%–13.6%). Male patients can have scrotal edema. Renal findings (30%) can vary from hypertension, hematuria, oliguria, nephritis/nephrotic range proteinuria, to end-stage renal disease (end-stage renal disease is a late complication). If renal disease is present and severe, consultation with nephrology is appropriate. Typical onset is 4 weeks from initial symptom onset and risk of serious, long-standing renal disease may be related to severity of disease at presentation, with greater risk (19%) associated with nephritic or nephrotic syndromes. Other rare manifestations include serositis, ascites, pancreatitis, cerebral vasculitis, orchitis, and pulmonary hemorrhage.
Differential Diagnosis
Possible differential diagnoses include idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, sepsis, scurvy, other systemic vasculitis, and connective tissue diseases like juvenile idiopathic arthritis or SLE. A thorough history, physical examination, and additional laboratory testing should help identify these conditions.
Diagnostic recommendations
A revised childhood classification criteria for HSP was proposed in 2008 ( Table 1 ), with a sensitivity of 100% and specificity of 87%. Laboratory and radiology recommendations are generally nonspecific in HSP and imaging is not always necessary ( Table 2 ). On histology, the classic leukocytoclastic vasculitis appearance includes disruption of the vasculature with segmental regions of transmural inflammatory infiltration (primarily neutrophils) and fibrinoid necrosis ( Fig. 3 ). Leukocytoclasis, or granulocyte debris, is frequently noted, as is hemorrhage from extravasated erythrocytes. Direct immunofluorescence reveals deposition primarily of IgA ( Fig. 4 ) but also C3 and IgM.
| Criteria | Definition |
|---|---|
| Purpura or petechiae must be present Plus at least one of the following: | Palpable purpura or petechiae a predominantly located on the lower extremities b |
| Abdominal pain | Pain is of acute onset, diffuse, colicky, or GI bleeding, or intussusception |
| Histopathology | |
| Skin | Leukocytoclastic vasculitis with IgA deposition |
| Renal | Proliferative glomerulonephritis with IgA deposition |
| Arthritis or arthralgias | Acute-onset joint swelling or pain with limitation of motion |
| Renal involvement | Proteinuria: >0.3 g/24 h or >30 mmol (urine protein/creatinine ratio c ), or Hematuria: >5 RBC/HPF or RBC casts or ≥2+ on dipstick |
a Not caused by thrombocytopenia.
b If distribution of lesions is atypical, then biopsy must show IgA deposition.
| Laboratory Studies | Laboratory Findings in HSP |
| CBC and differential | Normal to increased platelet count Normal to increased WBC Otherwise normal CBC |
| Inflammatory markers ESR, CRP | Normal to increased |
| Complete metabolic profile | Normal |
| Lipase or amylase (if abdominal pain present) | Normal |
| PT, PTT, INR | Normal |
| UA, urine protein, urine creatinine | Normal or proteinuria, hematuria, RBC casts |
| BUN, creatinine | Normal to mildly increased BUN |
| Imaging Studies Indication | Imaging Modality |
| Suspect intussusception | Abdominal ultrasound, ±barium enema |
| Scrotal edema, concern for torsion | Testicular ultrasound |
Therapeutic recommendations
Pharmacologic Treatment
For most cases of HSP, only supportive care is necessary. NSAIDs are often provided for mild to moderate pain (abdominal, joint, edema). However, there may be instances when more aggressive immune suppression is required. Potential indications for advanced immunotherapy (ie, oral or parenteral corticosteroids) include severe abdominal pain, gastrointestinal bleeding, severe renal disease (proteinuria, hematuria), and/or serious scrotal edema. The use of corticosteroids, the dose, and timing for their use remain controversial. A recent multisite randomized placebo-controlled trial was performed in the United Kingdom assessing potential benefits of early corticosteroid therapy in preventing long-term renal morbidity. The results of this large cohort (180 treatment and 170 controls) did not show benefit in reducing proteinuria 1 year after diagnosis following implementation of oral corticosteroids within 1 week of onset of symptoms. The literature on the benefits of corticosteroids on both renal and gastrointestinal disease remains contradictory. Nonetheless, there seems to be some benefit to corticosteroid use for hospitalized patients with respect to duration of hospitalization, need for abdominal surgery, and hospital readmission. Routine steroid use cannot be recommended based on the evidence to date.
Complications
Morbidity associated with HSP is primarily caused by gastrointestinal (intussusception, bleeding, pancreatitis) and/or renal involvement. Of the ∼2% to 20% of all patients with HSP who develop permanent renal disease, nearly 97% of patients do so by 6 months following disease onset. Therefore, routine blood pressure and urinalysis are recommended for 6–12 months.
AHEI
AHEI is a benign LCV condition affecting children aged 4 months to 2 years with a slight male predilection. There have been approximately 300 cases reported in the literature. It is surmised to be a variant of HSP; however, unlike HSP, the location and histology of skin lesions differ.
Clinical features
History
There is a classic triad of symptoms in AHEI. This triad includes fever (low grade) in an otherwise well-appearing infant; edema; and a classic purpuric rash involving the face, ears, and extremities. There is almost always a preceding trigger or prodrome (60%–75%), frequently an upper respiratory tract infection of viral or bacterial cause (group A streptococcus, Mycoplasma pneumoniae ), certain medications (paracetamol, antibiotics, NSAIDs), or immunizations.
Physical Examination
The classic rash of AHEI includes 1-cm to 5-cm iris-like or targetoid red or purple purpuric lesions with surrounding indurated edema scattered symmetrically in a cockade pattern ( Fig. 5 ). Lesions are located on the face, ears, and eyelids as well as lower and upper extremities and perianal region. Although the rash can be significant in appearance and infants may have a low-grade fever, children appear well. The edema can be painful and nonpitting in extremities, face, and ears. There can be scrotal swelling in boys. There are a few case reports of additional systemic symptoms including transient arthralgias, arthritis, and renal symptoms (glomerulonephritis, hematuria, proteinuria); abdominal pain; gastrointestinal bleeding; and/or intussusception.
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