Henoch-Schönlein purpura (HSP), also known as anaphylactoid purpura, is a systemic vasculitis primarily affecting small blood vessels. It is characterized by leukocytoclastic vasculitis involving immune complexes, particularly those containing IgA. In recent years, with advancements in understanding its pathophysiology, HSP has been renamed IgA vasculitis (IgAV) in the latest classification criteria for vasculitides. Clinically, it is marked by non-thrombocytopenic purpura, often accompanied by joint pain/swelling, abdominal pain, gastrointestinal bleeding, hematuria, and proteinuria. It predominantly affects children aged 2–8 years, with boys being more commonly affected than girls. The disease can occur throughout the year but peaks in spring and autumn.
Etiology
The exact etiology of HSP remains unclear. Reports suggest potential associations with factors such as foods (e.g., eggs, milk, legumes), medications (e.g., aspirin, antibiotics), microorganisms (e.g., bacteria, viruses, parasites), vaccinations, anesthesia, and malignancies. However, definitive evidence is lacking.
Recent studies have highlighted a potential link between streptococcal infections and HSP. Approximately 50% of pediatric HSP cases reportedly have a history of streptococcal respiratory infections. However, subsequent research found no significant difference in the prevalence of such infections between HSP patients and healthy children. In addition, up to 30% of children with HSP-associated nephritis show deposits of nephritis-associated plasmin receptor (NAP1r), an antigen from group A streptococci, in the mesangial regions of their glomeruli, compared to only 3% in non-HSP nephritis. This suggests that group A streptococcal infection may play a significant role in triggering both HSP and HSP-associated nephritis.
Pathogenesis
The disease is characterized by polyclonal B cell activation. Overexpression of CD40 ligand (CD40L) on T lymphocytes and monocytes promotes excessive IgA (particularly IgA1) production by B lymphocytes. Elevated serum IgA levels, an increased number of peripheral blood IgA-secreting B cells during the acute phase, and the deposition of IgA immune complexes have been observed. Additionally, elevated levels of pro-inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) have been noted. Immune complexes containing IgA, complement C3, and fibrin deposit in the mesangium, skin, and intestinal capillaries, suggesting that the condition represents an IgA-mediated immune complex proliferative disease, also known as IgAV.
The disease shows some hereditary predisposition. Siblings in the same family may develop the condition simultaneously or sequentially. Increased expression of genes such as HLA-DRB1*07 and HLA-DW35 has been observed in some patients, while individuals with complement component C2 deficiency have a higher risk of developing HSP.
Thus, the pathogenesis of HSP is believed to involve various factors, including infectious agents or allergens acting on individuals with a genetic predisposition, triggering B cell proliferation and leading to systemic small-vessel vasculitis mediated by IgA immune complexes.
Pathology
The characteristic pathological change in HSP is widespread leukocytoclastic vasculitis, primarily affecting capillaries but also involving small venules and arterioles. Thickening, swelling, and necrosis of the vascular wall are observed, accompanied by infiltration of neutrophils and scattered nuclear debris in the surrounding tissue. Interstitial areas may exhibit edema, serous exudate, and extravasation of red blood cells. Endothelial cells often appear swollen, with occasional thrombus formation. Lesions affect the skin, kidneys, joints, and gastrointestinal tract, with less frequent involvement of the heart, lungs, and other organs.
Skin and kidney biopsies frequently reveal predominant IgA deposition in immune complexes under immunofluorescence microscopy. In HSP nephritis (HSPN), pathological changes range from mild mesangial proliferation or minimal lesions to focal or diffuse proliferative glomerulonephritis with crescent formation. Glomerular IgA complex deposits are also seen in IgA nephropathy, although this condition lacks the cutaneous rash and features of skin vasculitis associated with HSP.
Clinical Manifestations
The onset of HSP is often acute, with the presentation of symptoms varying in order and timing. Skin purpura is the most common initial manifestation, although some patients first experience abdominal pain, joint symptoms, or kidney involvement. A history of upper respiratory tract infection within 1–3 weeks prior to disease onset is common, along with systemic symptoms such as low-grade fever, reduced appetite, and fatigue.
Skin Purpura
Recurrent skin purpura is the hallmark feature of HSP, typically appearing symmetrically on the extremities and buttocks, often more prominent on extensor surfaces. Lesions are rare on the face and trunk. Initially, the purpura present as raised, purplish-red maculopapules that do not blanch under pressure. Over several days, the lesions darken to a dusky purple hue and eventually fade to brown. In severe cases, purpura may coalesce into large blisters with hemorrhagic necrosis. Some patients also develop urticaria and angioedema. Skin lesions usually resolve within 2–4 weeks, but recurrence over weeks, months, or even years is possible.
Gastrointestinal Symptoms
Approximately two-thirds of patients experience these symptoms. Intestinal wall edema, hemorrhage, necrosis, or perforation caused by vasculitis are the primary reasons for gastrointestinal symptoms and complications. Paroxysmal abdominal pain is common, usually localized to the periumbilical or lower abdominal region. Severe pain may accompany vomiting, although hematemesis is rare. Some patients may pass black stools or fresh blood in their stool, and occasional complications such as intussusception, bowel obstruction, or perforation require surgical intervention.
Joint Symptoms
Around one-third of patients develop swelling and pain in large joints, such as the knees, ankles, elbows, or wrists, often limiting movement. These symptoms typically occur alongside pronounced skin lesions. Joint effusion may be present, although it is typically serous without hemorrhage, and symptoms usually resolve within a few days without residual effects.
Renal Symptoms
Between 30% and 60% of patients exhibit signs of kidney involvement, often within the first month of disease onset, though renal symptoms may develop later in the disease course or even after other symptoms have resolved. Renal symptoms vary in severity and are not always proportional to the severity of extrarenal manifestations. Most affected patients present with hematuria, proteinuria, and casts, often accompanied by hypertension and edema, leading to a diagnosis of purpura nephritis (HSPN) or IgA vasculitis-related nephritis (IgAVN). Some exhibit features of nephrotic syndrome. While hematuria and proteinuria may persist for months or years in some cases, most patients recover completely. A small proportion progress to chronic nephritis or succumb to chronic renal failure.
Other Manifestations
Rarely, intracranial bleeding occurs, leading to seizures, paralysis, coma, or aphasia. Bleeding tendencies may also present as nosebleeds, gum bleeding, or hemoptysis. Involvement of the cardiovascular system can manifest as myocarditis or pericarditis. Respiratory involvement may include laryngeal edema, asthma, or pulmonary hemorrhage.
Auxiliary Examinations
There is no specific diagnostic test for this condition. However, the following tests may help assess the severity of the disease and identify complications:
Blood Tests
White blood cell counts may be normal or elevated, with increased proportions of neutrophils and eosinophils. Anemia is uncommon unless there is severe bleeding. Platelet counts are normal or increased. Bleeding time, clotting time, clot retraction, and capillary fragility tests are typically normal, although capillary fragility may occasionally be positive in some cases.
Urinalysis
Red blood cells, proteins, and casts may be present in urine. Severe cases can feature gross hematuria and significant proteinuria.
Fecal Occult Blood Test
This test may be positive in patients with gastrointestinal symptoms. In severe cases, fresh blood may be observed in the stool.
Other Laboratory Tests
Erythrocyte sedimentation rate (ESR) may be mildly elevated.
Serum IgA is increased, while IgG and IgM may be normal or slightly elevated.
Complement components C3 and C4 are normal or sometimes elevated.
Antinuclear antibodies and rheumatoid factor are negative.
Plasma viscosity may be elevated in severe cases.
Imaging and Pathological Examinations
Abdominal ultrasound is useful for detecting early intestinal wall edema and diagnosing or excluding intussusception.
Abdominal X-rays are helpful in diagnosing intestinal obstruction or perforation.
Brain MRI may provide insights in cases with central nervous system symptoms.
For patients with severe or prolonged renal symptoms, biopsy can help identify the pathological type of purpura nephritis and guide appropriate treatment.
Diagnosis and Differential Diagnosis
The diagnosis is usually straightforward in typical cases. According to the 2006 Paediatric Vasculitis Classification for Europe, a diagnosis can be confirmed if characteristic purpura is present along with at least one of the following four criteria:
- Diffuse abdominal pain.
- Arthritis or arthralgia.
- IgA immune complex deposition identified in biopsy from any site.
- Renal involvement.
In atypical presentations, particularly before the appearance of skin purpura, misdiagnosis as other conditions is possible. Differential diagnoses include immune thrombocytopenic purpura (ITP), rheumatoid arthritis, sepsis, other renal diseases, and acute surgical abdominal conditions.
Treatment
General Management
Rest is recommended during active periods with prominent purpura. Identifying and eliminating causative factors, such as treating infections or supplementing vitamins, may be beneficial. Antihistamines and calcium supplements are used for urticaria or angioedema. Antispasmodics can help relieve abdominal pain, and gastrointestinal bleeding is managed with fasting and intravenous cimetidine, 20–40 mg/kg/day. Severe bleeding with anemia may require transfusion.
Corticosteroids and Immunosuppressants
Corticosteroids are effective for alleviating acute abdominal pain and joint symptoms but neither prevent renal damage nor influence long-term prognosis; thus, routine use for preventing skin purpura is not advised. For complications such as gastrointestinal bleeding, angioedema, or severe arthritis, prednisone at 1–2 mg/kg/day (administered orally in divided doses), dexamethasone, or methylprednisolone at 2–10 mg/kg/day (administered intravenously) may be considered. Corticosteroids should be withdrawn once symptoms resolve.
For severe HSP nephritis, immunosuppressive agents such as cyclophosphamide, mycophenolate mofetil, or azathioprine are added to corticosteroids.
Anticoagulant Therapy
Inhibition of Platelet Aggregation and Thrombosis
Aspirin is given at 3–5 mg/kg/day or 25–50 mg once daily. Dipyridamole at 3–5 mg/kg/day in divided doses may also be used.
Heparin
In cases of hypercoagulable states, low-molecular-weight heparin at 0.5–1 mg/kg once a day for seven days may be administered, with coagulation function monitored during treatment.
Other Therapies
Calcium channel blockers such as nifedipine, at 0.5–1.0 mg/kg/day in divided doses, may help address hypertension caused by renal damage.
For significant proteinuria, angiotensin-converting enzyme inhibitors (ACEIs) may be considered.
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen at 10–15 mg/kg/day in divided doses, can alleviate joint symptoms.
Severe gastrointestinal symptoms or nephritis may require blood purification therapy when necessary.
Prognosis
The overall prognosis is favorable, with most patients achieving full recovery. Only a small percentage of severe cases result in death due to gastrointestinal complications such as hemorrhage or intussusception. Rare occurrences of neurological involvement, such as intracranial hemorrhage, may lead to severe outcomes.
The disease duration is typically 1–3 months, although some cases persist for several months to over a year. Regular long-term outpatient follow-ups are recommended. The long-term prognosis depends on the extent of renal involvement. Renal lesions often have a protracted course, lasting months to years. A minority of patients may experience refractory or recurrent disease, progressing to chronic kidney disease or, in severe cases, chronic renal failure.