Henoch-Schönlein PURPURA

Henoch-Schönlein Purpura (HSP) anaphylactoid purpura is a common vasculitis of small vessels with cutaneous and systemic complications. It is the most common cause of nonthrombocytopenic purpura in children.

EPIDEMIOLOGY The etiology is unknown more frequent in children than adults, with most cases occurring between 2 and 8 yr of age, most frequently in the winter months. The overall incidence is estimated to be 9/100,000 population. Males are affected twice as frequently as females.

PATHOGENESIS The pathogenesis of HSP is not known, in specific populations, patients with HSP have a significantly higher frequency of HLA-DRB1*01 and decreased frequency of the *07 haplotype than controls. increased serum concentrations of the cytokines tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. In one study, almost half of the patients had elevated antistreptolysin O (ASO) anti-bodies, implicating group A streptococcus. HSP is an IgA-mediated vasculitis of small vessels. Immunofluorescence techniques show deposition of IgA and C3 in the small vessels of the skin and the renal glomeruli;

CTLA-4 +49 A/G genotype and HLA-DRB1 polymorphisms in Turkish patients with Henoch-Schönlein purpura. Soylemezoglu O, Peru H, presence of Cytotoxic T lymphocyte-associated protein 4( CTLA-4) AG genotype and HLA-DRB1*13 could be a risk factor for developing nephrotic-range proteinuria in these patients. Pediatr Nephrol. 2008 Aug;23(8):1239-44.

The immunobiology of Henoch-Schönlein purpura The immunobiology of Henoch-Schönlein purpura. Yang YH, Chuang YH, Department of Pediatrics, National Taiwan University Hospital, group A beta-hemolytic streptococcus (GAS) has widely studied and found in 20–50% of patients with acute HSP by serological tests or bacterial cultures, Bartonella henselae (12 of 18 HSP patient sera were positive ) Parvovirus B19 (only one of 29 HSP patients ) Other HSP-associated pathogens have been reported Staphylococcus aureus, Helicobacter Pylori, Hemophilus parainfluenza, Coxsackie virus, adenovirus, hepatitis A virus, hepatitis B virus Autoimmun Rev 2008 Jan

CLINICAL MANIFESTATIONS The disease onset may be acute, or insidious, with sequential occurrence of symptoms over a period of weeks or months. Low-grade fever and fatigue are present in more than half of affected children. The typical rash and the clinical symptoms of HSP are a consequence of the usual location of the acute small vessel damage primarily in the skin, gastrointestinal tract, and kidneys.

CLINICAL MANIFESTATIONS Rash (95-100%), especially involving the legs, may not be present on initial presentation Subcutaneous edema (20-50%) Abdominal pain and vomiting (85%) Joint pain (60-80%), especially involving the knees and ankles Scrotal edema (2-35%) Bloody stools

Fifteen-year experience of children with Henoch-Schönlein purpura in southern Taiwan, 1991-2005 Bao-Ren Nong, Yung-Feng Huang, Chih-Ming Chuang, Chia-Chia Liu, Kai-Sheng Hsieh Department of Pediatrics, Veterans General Hospital-Kaohsiung, Kaohsiung, Taiwan No hematuria or proteinuria (n = 77) Hematuria or proteinur (n = 30) No. (%) No. (%) P --------------------------------------------------------------------------------------------------------------------- Skin rash 73 (95) 30 (100) 0.21 GI symptoms 57 (74) 20 (67) 0.45 Arthritis 34 (44) 16 (53) 0.40 J.Microbiol Immunol Infect. 2007;40:371-376

Fifteen-year experience of children with Henoch-Schönlein purpura in southern Taiwan, 1991-2005 Bao-Ren Nong, Yung-Feng Huang, Chih-Ming Chuang, Chia-Chia Liu, Department of Pediatrics, Taiwan Variable Skin rash Gastrointestinal symptoms Arthritis No. (%) No. (%) No. (%) -------------------------------------------------------------------------------------------------------- Fever group (n = 77) 45 (58) 29 (38) 7 (9) Non-fever group (n = 30) 15 (50) 9 (30) 6 (20) P 0.43 0.45 0.12 URI group (n = 64) 33 (52) 29 (45) 6 (9) Non-URI group (n = 43) 27 (63) 9 (21) 7 (16) p 0.25 0.01 0.28 Male (n = 63) 33 (52) 25 (40) 7 (11) Female (n = 44) 26 (59) 13 (30) 6 (14) P 0.60 0.28 0.69

Rash beginning as pinkish maculopapules that initially blanch on pressure and progress to petechiae or purpura, characterized clinically as palpable purpura that evolve from red to purple to rusty brown before they eventually fade last from 3-10 days, and may appear at intervals that vary from a few days to as long as 3-4 mo. In <10% of children, recurrences of the rash may not end until as late as a yr, Damage to cutaneous vessels also results in local angioedema, which may precede the palpable purpura. Edema independent of purpura occurs primarily in dependent areas such as below the waist, over the buttocks (or on the back and posterior scalp in the infant), or in areas of greater tissue distensibility such as the eyelids, lips, scrotum, or dorsum of the hands and feet.

Rash

Arthritis present in more than ⅔ of children with HSP, is usually localized to the knees and ankles and appears to be concomitant with edema. The effusions are serous, not hemorrhagic, resolve after a few days without residual deformity or articular damage. They may recur during a subsequent reactive phase of the disease.

Gastrointestinal tract intermittent abdominal pain that is often colicky in nature. There may be peritoneal exudate, enlarged mesenteric lymph nodes, segmental edema, and hemorrhage into the bowel. More than half of patients have occult heme-positive stools, diarrhea (with or without visible blood), or hematemesis. Intussusception may occur, which may rarely be followed by complete obstruction or infarction with bowel perforation. If not resolved by hydrostatic reduction during a contrast study, surgical intervention is necessary.

Significance of bowel wall abnormalities at ultrasound in Henoch-Schönlein purpura. Nchimi A, Khamis J, Paquot I, Bury F, Magotteaux P. Medical Imaging Department, CHC, Rue de Hesbaye, 75, 4000 Liège, Belgium METHODS: Clinical and ultrasound data from 43 consecutive children with HSP (36 with and 7 without abdominal symptoms) were reviewed. Patients with abdominal symptoms were divided into 4 groups (0-III) The diagnostic value of ultrasound in diagnosing gastrointestinal involvement of HSP (grades I-III) was calculated using as the standard of reference the absence or presence of clinical symptoms. RESULTS: The duration of both symptoms and hospitalization was significantly higher in group III than in the other groups (P < 0.05). J Pediatr Gastroenterol Nutr. 2008 Jan;46(1):48-53.

Renal involvement occurs in 25-50% of children may manifest with: hematuria, proteinuria, or both; nephritis or nephrosis; acute renal failure. Renal involvement at presentation may lead to chronic hypertension or end-stage renal disease in the future

Increased serum levels of insulin-like growth factor (IGF)-1 and IGF-binding protein-3 in Henoch-Schonlein purpura. Yildiz B, Kural N, Aydin B, Colak O. Department of Pediatric Nephrology and Rheumatology,, Faculty of Medicine, Turkey Serum IGF-1 levels were significantly higher in HSP with proteinuria than those without proteinuria and controls (p = 0.001 and p = 0.001, respectively). Also, IGFBP-3 levels were greater in HSP with proteinuria compared to those without proteinuria and controls (p = 0.005 and p = 0.0001). Serum immunoglobulin-A/complement-C3 ratio was higher in HSP than in the controls (p = 0.0001) but this ratio did not change according to proteinuria, hematuria or positive SOB. In conclusion, IGF-1 and IGFBP-3 levels could be new markers for determination of renal involvement in HSP. Tohoku J Exp Med. 2008 Apr

What is the difference between IgA nephropathy and Henoch-Schönlein purpura nephritis? Davin JC, Ten Berge IJ, Weening JJ. Department of Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands Kidney Int. 2001 Oct;60(4):1611-2.

What is the difference between IgA nephropathy and Henoch-Schönlein purpura nephritis HSPN IgAN Clinical features + - Extra-renal symptoms >15 y <15 y Age at onset +++ +/- Nephritic/nephrotic syndrome ++ Risk of chronic renal failure (CRF) Hypersensitivity Secondary forms Endocapillary proliferation Epithelial crescents Perivascular glomerular IgA Subepithelial/subendothelial dense deposits Fibrin deposits <19S 7S-19S IgA-containing complexes size

Relationship between initial clinical signs and risk of chronic renal failure in Henoch-Schönlein purpura nephritis

Complications of Henoch-Schönlein Purpura Hepatosplenomegaly Myocardial infarction Pulmonary hemorrhage Pleural effusion Unnecessary abdominal surgery Intussusception Hemorrhage Shock Gastrointestinal bleeding Bowel infarction Renal failure Hematuria Proteinuria Seizures Mononeuropathies Testicular torsion

Masked severe stenosing ureteritis: a rare complication of Henoch-Schönlein purpura. Siomou E, Serbis A, Salakos C, Papadopoulou F, Stefanidis CJ, Department of Pediatrics, University Hospital of Ioannina, Stavros Niarchos Avenue, Ioannina, Greece. This article reports on a 3.5-year-old boy with HSP and severe nephritis who developed a unilateral stenosing ureteritis with atypical manifestations, resulting in a nonfunctional kidney and consequent nephrectomy. Pediatr Nephrol. 2008 May;23(5):821-5

DIAGNOSIS Diagnostic uncertainty arises when the symptom complex of edema, rash, arthritis with abdominal complaints, and renal findings occurs for a prolonged period.

DIAGNOSIS Routine laboratory tests are neither specific nor diagnostic. Affected children often have a moderate thrombocytosis and leukocytosis. The erythrocyte sedimentation rate (ESR) may be elevated. Anemia may result from chronic or acute gastrointestinal blood loss. Immune complexes are often present, and 50% of patients have elevated concentrations of IgA as well as IgM usually negative for antinuclear antibodies (ANAs), antibodies to nuclear cytoplasmic antigens (ANCAs), and rheumatoid factor (even in the presence of rheumatoid nodules). Anticardiolipin or antiphospholipid antibodies may be present and contribute to the intravascular coagulopathy. Intussusception is usually ileoileal in location; Renal involvement manifests in red blood cells, white blood cells, casts, or albumin in the urine and azotemia

Endothelin 1 levels in relation to clinical presentation and outcome of Henoch Schonlein purpura. Fessatou S, Nicolaidou P, Gourgiotis D, Georgouli H, 3rd Department of Pediatrics Attikon University Hospital, Greece. The aim of the present study was to investigate whether ET-1 levels are correlated with the clinical presentation and the outcome of HSP. RESULTS: ET-1 levels in plasma and urine did not differ between patients and controls at three distinct time points. urinary ET-1 levels were a significant predictor of the duration of the acute phase of HSP (HR = 0.98, p = 0.032, CI0.96-0.99). CONCLUSION: Urinary ET-1 levels are a useful marker for the duration of the acute phase of HSP but not for the length of renal involvement. BMC Pediatr. 2008 Sep 2;8:33.

Definitive diagnosis confirmed by biopsy cutaneous site showing leukocytoclastic angiitis. Renal biopsy may show mesangial deposition of IgA and occasionally IgM, C3, and fibrin.

H & E stain of skin biopsy showing leukocytoclastic vasculitis with infiltration of neutrophils.

Henoch-Schönlein purpura. A: Cutaneous purpura; B: Urine sediment red blood cell cast; C: Acute glomerular inflammation and crescent formation; D: Details of basal membrane mesangial proliferation and IgA deposits

Immunofluorescence micrograph of a glomerulus from a patient with HSP nephropathy stained for the presence of IgA.

Differential Diagnosis of Henoch-Schönlein Purpura Acute abdomen Meningococcal meningitis or septicemia Rheumatoid arthritis Rheumatic fever Idiopathic thrombocytopenic purpura Systemic lupus erythematosus poly-arteritis nodosa, Child abuse Drug reactions Bacterial endocarditis Rocky Mountain spotted fever familial Mediterranean fever inflammatory bowel disease. Kawasaki disease.

Acute hemorrhagic edema (AHE) is an acute cutaneous benign leukocytoclastic vasculitis seen in children ≤2 yr of age AHE presents with fever; tender edema of the face, scrotum, hands, and feet; and ecchymosis (usually larger than the purpura of HSP) on the face and extremities petechiae may be seen in mucous membranes. The patient usually appears well except for the rash. The platelet count is normal or elevated; the urinalysis is normal. The younger age, nature of the lesions, absence of other organ involvement, and biopsy may help distinguish AHE from HSP.

Acute hemorrhagic edema (AHE)

TREATMENT Symptomatic treatment adequate hydration, bland diet, pain control with acetaminophen is provided for self-limited complaints of arthritis, edema, fever, and malaise. Avoidance of competitive activities and avoidance of maintaining the lower extremities in a dependent position may decrease local edema. If edema involves the scrotum, elevation of the scrotum and local cooling, as tolerated, may decrease discomfort.

TREATMENT Therapy with oral or intravenous corticosteroids (1-2 mg/kg/day) is often associated with dramatic improvement of both gastrointestinal and CNS complications. the effects of corticosteroids on renal manifestations are not clear. intussusception may be life-threatening and managed with cortico-steroids and, when necessary, hydrostatic reduction (by air or with contrast) or resection of the intussusception.

TREATMENT is the same as for other forms of acute glomerulonephritis If anti-cardiolipin or antiphospholipid antibodies are identified and thrombotic events have occurred, aspirin (81 mg) given once may decrease the risks associated with a hypercoagulable state. Rheumatoid nodules may respond to alternate-day colchicine (0.6 mg every other day).

Leukocytapheresis for the treatment of refractory Henoch-Schönlein purpura resistant to both prednisolone and intravenous immunoglobulin therapy. Oki E, Tsugawa K, Suzuki K, Ito E, Tanaka H. A 5-year-old Japanese girl was admitted to a regional hospital with a generalized purpuric rash associated with severe abdominal pain administration of oral PDN at 30 mg daily additional treatment was initiated with IVIG at the dose of 1 g kg¡1 per day. While transient clinical improvement was noted following Leukocytapheresis may be attempted as an effective treatment option in selected patients with steroid-resistant refractory HSP combined with severe abdominal symptoms. Rheumatol Int. 2008 Jun;28(8):

Prognosis HSP is generally a benign disease with an excellent prognosis. More than 80% of patients have a single isolated episode lasting a few weeks. Approximately 10-20% of patients have recurrences. Fewer than 5% of patients develop chronic HSP. Abdominal pain resolves spontaneously within 72 hours in most patients

Clinical outcome in children with Henoch-Schönlein nephritis Sevgi Mir1, Onder Yavascan1, Renal involvement was determined in 58.1%. Nephrotic and/or nephritic syndrome were found to be an unfavorable predictor both for short and long-term outcome (P<0.05). However, 35% of these patients and 62% of them showed complete remission after 6 months and long-term course. Overall prognosis of HSN is relatively good and long-term morbidity is predominantly associated with initial presentation and renal involvement. Pediatric Nephrology 21 September 2006

Outcome of Henoch-Schönlein purpura nephritis treated with long-term immunosuppression Mohan Shenoy1, Mark G. Bradbury1, Royal Manchester Children's Hospital This retrospective study investigated the outcome of 27 children (19 male) with Henoch-Schönlein purpura nephritis (HSN) of International Study with long-term immunosuppressive therapy single centre over a 10-year period. The treatment protocol comprised daily steroids and cyclophosphamide for 8–12 weeks followed by azathioprine and a reducing regimen of alternate-day steroids for 8–12 months. After a mean follow-up period of 7 years following presentation, 37% made a complete recovery 40.7% had persistent proteinuria, 7.4% had persistent proteinuria and were on antihypertensive therapy 14.8% had progressed to end-stage kidney failure (ESKF). Children with poor outcome were older at presentation (p 0.005), had more crescents (p 0.015) had heavier proteinuria 6 months post initial biopsy (p 0.023). All of the four children with ESKF had nephrotic range proteinuria and greater than 50% crescents on initial biopsy. Pediatr Nephrol. 2007 Oct;22(10):1717-22