Are You Confident of the Diagnosis?
What you should be alert for in the history
Henoch-Schönlein purpura (HSP) is a variant of small-vessel leukocytoclastic vasculitis that classically presents as palpable purpura on the lower extremities and is associated with abdominal pain, joint pain and hematuria. Skin lesions often present 1-3 weeks after an upper respiratory tract infection and are present in all patients with HSP. The majority also have arthritis, most often in the knees and ankles, as well as abdominal pain, which may be colicky in nature and associated with vomiting. Joints may be swollen, warm and tender but symptoms are transient and resolve without sequelae.
Both joint and abdominal pain may precede the development of skin lesions when they occur. Occult or gross gastrointestinal bleeding and nephritis, most often characterized by microscopic hematuria, occur in roughly 30% and 40% of patients, respectively. Patients may also complain of fatigue, fever, headache and swelling of the lower extremities.
Characteristic findings on physical examination
Skin lesions are symmetric and begin as erythematous macules or urticarial papules that progress to purpuric macules and papules (Figure 1). Uriticarial, vesicular and bullous lesions may be seen, as well as areas of necrosis. Lesions chiefly appear on the extensor surfaces of the lower extremities and the buttocks but the trunk, upper extremities and face may also be involved. Individual lesions usually last 10-14 days.
Renal involvement, usually characterized by microscopic hematuria and mild proteinuria, is common and self-limited in most cases. Gross hematuria may also be seen. Proteinuria often accompanies hematuria but is rarely seen alone in HSP. Long-term renal disease occurs in a small percentage of patients and is more likely to develop in patients that present with severe renal dysfunction. A retrospective study found that adults had an increased risk of developing more severe renal involvement and nephrotic syndrome.
There is no definitive diagnostic test for HSP. The American College of Rheumatology published criteria for the diagnosis of HSP in 1990. The presence of at least two of four criteria was required for a diagnosis of HSP: palpable purpura without thrombocytopenia, age of 20 years or younger at disease onset, bowel angina, and histiologic changes showing granulocytes in the walls of arterioles or venules. A new classification criteria was proposed in 2006 which required the presence of palpable purpura in addition to at least one of four additional features: diffuse abdominal pain, predominant IgA deposition on biopsy, arthritis or arthralgias, and renal involvement.
Expected results of diagnostic studies
Pathologic changes found on skin biopsy are those typical of leukocytoclastic vasculitis, demonstrating leukocytes and leukocyte fragments surrounding small blood vessels in the dermis. There is discordance in the literature regarding which vessels in the dermis are preferentially affected in HSP. It has been argued that IgA deposits are typically seen in capillaries on immunofluorescence. Direct immunofluorescence (DIF) of an early lesion demostrates a predominance of IgA, as well as C3 and fibrin deposits in the vessel walls of early lesions.
The differential diagnosis of HSP includes clotting disorders, septic emboli and infections as well as other causes of vasculitis including urticarial vasculitis, acute hemorrhagic edema of infancy, autoimmune connective tissue disorders, drugs, malignancies, cryoglobulinemia, and the ANCA-associated vasculitidies, microscopic polyangitis, Wegner’s granulomatosis, and Churg-Strauss.
Laboratory tests are ordered to exclude other diagnoses and to assess for kidney involvement. A urinalysis may reveal microscopic hematuria and proteinura, confirming renal involvement. Red blood cell casts may be seen on microscopic examination of the urine sediment. An antistreptolysin-O antibody titer may be positive, suggesting a preceding streptococcal infection. Throat or other bacterial cultures may reveal an active infection. Throat cultures positive for group A beta-hemolytic strep have been reported in 10-30% of patients. There are anecdotal reports of other infections such as MRSA and MSSA bacteremia causing HSP.
A complete blood count (CBC) with differential should be ordered to assess for an elevated neutrophil count, suggesting an underlying infection, and for thrombocytopenia, which indicates a diagnosis other than HSP, such as idiopathic (thrombocytopenic purpora) Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often elevated. Serum IgA levels may be increased but is not diagnostic. Serum C3 or C4 may be low. Antinuclear antibody (ANA), rheumatoid factor, serum cryoglobulin, Epstein-Barr virus (EBV), HIV, and hepatitis serologies may be drawn to exclude other causes of vasculitis.
Who is at Risk for Developing this Disease?
HSP is the most common vasculitis in children, with an incidence of 135 to 180 cases per million. It typically affects children younger than 10 years of age after an upper respiratory tract infection. It occurs less frequently in adults with an incidence of 3 to 14 cases per million. It is seen more often in males than in females and is more common in patients with familial Mediterranean fever. Most patients present in the fall, winter and spring.
Many exposures have been associated with HSP, including infections, drugs, vaccines and foods. Several studies have found a positive antistreptolysin O titer or a positive culture for Group A beta-hemolyitc streptococcus, indicating its role as a trigger. Bartonella henselae, Parvovirus B19, Staphylococcus aureus, Helicobacter Pylori, Haemophilus parainfluenza, mycoplasma, Coxsackie virus, adenovirus, Epstein-Barr virus, varicella, campylobactor, hepatitis A virus and hepatitis B virus have all been associated with HSP. In adults, HSP has been associated with both solid and hematologic malignancies. .
What is the Cause of the Disease?
The precise etiology of HSP remains unknown. Immune complexes of IgA are formed and are deposited in the walls of small vessels where they activate complement and neutrophils, leading to inflammation of the vessels. The clinical manifestations of palpable purpura, gastrointestinal bleeding, and glomerulonephritis are due to deposition of IgA and C3 and subsequent inflammation in the vessel walls of the dermis, gastrointestinal tract, and kidney.
Systemic Implications and Complications
The most common long-term complication is kidney disease. The risk of renal insufficiency has been found to be at least 10 times higher if nephritic or nephrotic syndrome is evident at initial presentation. A retrospective study found that adults had an increased risk of developing renal involvement and nephrotic syndrome.
In adult patients, the spread of purpura to the upper parts of the trunk, fever, the presence of inflammatory markers and a recent history of infection have been found to be predictive factors for developing renal dysfunction. In children, severe abdominal pain, age over 8 years at onset of disease, persistent purpura and recurrence of HSP have also been found to be risk factors for renal involvement.
Hypertension may be seen in patients with renal dysfunction. Intestinal bleeding and intussusception can occur. Rarely, cardiac, pulmonary, neurologic, pancreatic, testicular, ocular and other organ involvement has been reported.
Treatment options are summarized in Table I.
|Medical treatment||Surgical procedures||Physical Modalities|
|Supportive treatment: analgesics and hydration|
|Corticosteroids: 1mg/kg/day for 2 weeks followed by 2-week taper|
Optimal Therapeutic Approach for this Disease
The disease is usually self limited and treatment is typically supportive. For patient with mild symptoms, hydration and analgesics such as acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs) may be given. NSAIDs should be used cautiously due to possible renal dysfunction.
For patients with more severe joint and abdominal pain, prednisone, 1mg/kg/day for 2 weeks followed by a 2-week taper may be administered. Prednisone may improve abdominal and joint pain and reduce the duration of skin lesions. Prednisone may hasten the resolution of mild renal abnormalities in the acute phase but it does not prevent recurrences of HSP or the development of long-term renal dysfunction.
Dapsone has been reported to decrease the duration of skin lesions in a small number of patients. In adults, dapsone 50 to 200mg a day or colchicine 0.6mg a day to 1.2mg twice a day may be given to patients with persistent or recurrent disease. In children, dapsone 1.0mg/kg to 1.5mg/kg per day given together or in divided doses may be administered. Cochicine 1.2mg/day has also been reported to be effective in children with prolonged HSP.
For patients with severe renal or other organ involvement, nephrology or the appropriate subspecialty should be consulted. Possible therapies include corticosteroids and/or other immunosuppressive agents such as cyclosporine, azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil. Rituximab, IVIG and plasmapheresis have also been reported to be beneficial in small numbers of patients.
However, a meta-analysis of interventions for preventing and treating kidney disease in children with HSP none of the interventions, including a short course of prednisone early in the disease, cyclophosphamide, and aspirin and dipyridamole, were shown to prevent long-term renal dysfunction. A study of 19 children found no difference between cyclosporine and methylprednisone/prednisone.
A blood pressure measurement should be performed upon diagnosis and at each return visit to assess for hypertension If an active bacterial infection is detected, it should be treated appropriately.
Consider consulting dermatology, nephrology, rheumatology, surgery and/or gastroenterology depending on severity of symptoms and organ involvement. Nephritis is the most serious long-term sequelae of HSP and may not present until weeks or months after the onset of purpura.
For adult patients with a normal urinalysis or isolated hematuria, a urinalysis should be performed monthly for up to 6 months after initial presentation to monitor for the development of renal involvement. In children without renal abnormalities it has been suggested that weekly urine dipsticks be performed for 2 months. Patients with recurrent HSP or the presence of nephritis should be followed for longer than 6 months.
Unusual Clinical Scenarios to Consider in Patient Management
Although characteristically a disease of childhood, HSP has been increasingly recognized in adults. In the adult population, it is essential to assess renal function as a greater number of patients have renal involvement, with a higher incidence of renal insufficiency than seen in children. Addtionally, vigilence is necessary in assessing for associated malignancies, including solid tumors and lymphoproliferative.
What is the Evidence?
Chartapisak, W, Opastirakul, S, Hodson, EM, Willis, NS, Craig, JC. “Interventions for preventing and treating kideny disease in Henoch-Schönlein Purpura (HSP)”. Cochrane Database Syst Rev. 2009. (A meta-analysis of 10 randomized controlled trials (RCTs) or quasi-RCTs of invertentions used to treat children with HSP showed no benefit over placebo for any of the interventions, including a short course of prednisone early in the disease, cyclophosphamide, and aspirin and dipyridamole, to prevent long-term renal dysfunction. A study of 19 children found no difference between cyclosporin and methylprednisone/prednisone.)
Chung, L, Kea, B, Bolognia, JL, Jorizzo, JL, Rapini, RP. Fiorentino D: Cutaneous Vasculitis. 2008. pp. 347-67. (An excellent review of the clinical features and differential diagnosis of cutaneous vasculitis.)
Hung, SP, Yang, YH, Lin, YT, Wang, LC, Lee, JH, Chiang, BL. “Clinical manifestations and outcomes of Henoch-Schönlein Purpura: comparison between adults and children”. Pediatr Neonatol. vol. 50. 2009. pp. 162-8. (A retrospective study of 65 children and 22 adults with HSP treated over a 5-year period at a medical center in Taiwan. Age greater than 20 years, male sex, bloody stools, relapse of purpuric rash and presistent rash for greater than 1 month were poor prognostic factors for HSP nephritis.)
Iqbal, H, Evans, A. “Dapsone therapy for Henoch-Schönlein purpura: a case series”. Arch Dis Child. vol. 90. 2005. pp. 985-86. (A case series of eight pediatric patients treated with dapsone. Doses ranged from 1.0mg/kg to 1.5mg/kg per day given together or in divided doses. All patients demonstrated improvement of skin lesions within 3 days to 1 week of treatment. Treatment duration ranged from 4 days to 4 weeks. Six of eight patients relapsed after the first course but responded to retreatment. Total duration of treatment for all patients varied from 4 days up to 2.5 years.)
Jauhola, O, Ronkainen, J, Koskimies, O, Ala-Houhala, M, Arikoski, P, Hölttä, T. “Renal manifestations of Henoch-Schönlein Purpura in a 6-month prospective study of 223 children”. Arch Dis Child. vol. 95. 2010. pp. 877-82. (A prospective study of 223 children with HSP revealed that nephritis occured an average of 14 days after diagnosis of HSP and within a month in most cases. The risk of developing nephritis after 2 months was 2%. Age greater than 8 years at disease onset, abdominal pain and recurrent disease were risk factors for developing nephritis.)
Ronkainen, J, Koskimes, O, Ala-Houhala, M, Antikainen, M, Merenmies, J, Rajantie, J. “Early prednisone therapy in Henoch-Schönlein purpura: A randomized, double-blind, placebo-controlled trial”. J Pediatr. vol. 149. 2006. pp. 241-7. (A prospective trial of 171 children under the age of 16 in Finland with HSP treated with either a 2-week course of prednisone 1mg/kg/day for 2 weeks followed by a 2-week taper versus placebo. Prednisone did not prevent the development of renal symptoms but was found to hasten resolution of renal dysfunction and to improve abdominal and joint pain .)
Saulsbury, FT. “Clinical Update: Henoch-Schönlein Purpura”. Lancet. vol. 369. 2007. pp. 976-78. (A succinct review of the epidemiology, clinical presentation, and prognosis of HSP as well as recent studies of the use of corticosteroids in HSP. Corticosteroids have been shown to improve the severity and duration of joint and abdominal pain and lead to resolution of mild nephritis. They have not been shown to prevent nephritis or recurrences of HSP.)
Tancrede-Bohin, E, Ochonsiky, S, Vigon-Pennamen, M, Flageul, B, Morel, P, Rybojad, M. “Schönlein-Henoch purpura in adult patients: predicitive factors for IgA glomerulonephritis in a retrospective study of 57 cases”. Arch Dermatol. vol. 133. 1997. pp. 438-42. (A retrospective study of 57 patients older than 15 years of age with HSP at an academic medical center in France. Their comparative analysis demonstrated that IgA glomerulonephritis was significantly associated with purpura above the waist, a recent infectious history, fever and biological markers of inflammation.)
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