IgAV is the most common systemic vasculitis seen in childhood, characterised by the deposition of IgA with complex and complementing component 3 proteins on arterioles, capillaries, and venules. These mainly invade the skin, joints, kidneys, gastrointestinal mucosa, and serosa. Gastro-intestinal manifestations occur in approximately two-thirds of children during the course of IgAV. Abdominal pain is a common symptom, with the small intestine being the most frequently involved site, usually due to swelling caused by submucosal and subserosal hemorrhages, and edema from vasculitis. Severe gastro-intestinal tract involvement can lead to intussusception, bleeding, bowel infarction, intestinal perforation, and necrosis. Our patient developed severe gastrointestinal complications that eventually led to intussusception and underwent surgery. Unfortunately, details of the procedure are not available as it occurred prior to the patient's admission to our hospital.
Acute pancreatitis (AP) is a rare gastrointestinal complication of IgAV. IgAV patients with severe abdominal pain should be evaluated for pancreatitis. Tests for elevated pancreatic enzymes levels are useful tools for early diagnosis of IgAV-associated pancreatitis[5]. The imaging changes in pancreatitis can be atypical. Ultrasonography or radiological signs, such as a swollen pancreas, necrosis, or pseudocysts, can confirm the diagnosis only if the pancreatitis is complicated. Diagnosis of AP in our case was confirmed based on the presence of abdominal pain, elevated serum lipase levels (three times more than the upper limit of the normal range) and swelling of the pancreas observed on ultrasound. There was no prominent cause, such as biliary stones, overeating, drinking, hyperlipidemia, infection, toxins or drugs. The pathogenesis of AP remains unclear. It may be associated with small blood vessel thrombosis and vasculitis, which activate digestive enzymes and lead to inflammation, edema, vascular damage, and even cellular death.
In addition to the symptomatic and supportive treatment provided, intravenous methylprednisolone was also administered as soon as the diagnosis was established in our case. A recent review of IgAV related pancreatitis cases highlighted the importance of timely steroid therapy in order to obtain a good outcome[6]. Methylprednisolone pulse therapy can be used and is effective in alleviating symptoms of AP[7].When the clinical manifestation is steroid-resistant, other immunosuppressive therapies are required. A single high dose of cyclophosphamide may be beneficial in IgAV cases with severe pancreatic involvement that are non-responsive to steroids[8]. Somatostatin can inhibit the secretion of stomach and pancreas, thus reducing the enzyme activity. It also reduces capillary permeability, opens the oddi sphincter, and promotes pancreatic enzyme excretion. Somatostatin may be applied after the diagnosis of AP[6]. Our patient’s symptoms of pancreatitis resolved after using intravenous methylprednisolone plus pulse methylprednisolone.
Our patient experienced two convulsions during the course of the disease. The most likely diagnosis in this case was IgAV-associated encephalopathy. This was deduced after excluding systemic lupus erythematosus, other connective tissue diseases, systemic vasculitides, metabolic diseases, head traumas, and neurological diseases such as intracranial infections. The pathogenesis of IgAV-associated encephalopathy is not thoroughly understood. It may be a result of central nervous system vasculitis, or related to arterial hypertension in cases of IgAV nephritis[9]. Murakam, et al.[10] reported a brain biopsy of a fatal case of IgAV, and demonstrated leukocytoclastic vasculitides that had IgA deposits in the vessel walls. However, such histological confirmations are very rare, the diagnosis usually depends upon imaging examination.
MRI is more sensitive than computed tomography for diagnosis of cerebral vasculitis. The most commonly reported lesions were ischemic, followed by hemorrhagic[11]. Typically, 14% of neuroimaging results are normal. The diagnosis of cerebral vasculitis may be difficult since neurological abnormalities can be caused by multiple factors. Pulsed methylprednisolone is used as first-line treatment for IgAV encephalopathy[12]. Other immunosuppressive drugs, such as cyclosporine A, cyclophosphamide, or mycophenolate mofetil, may be selected for patients who exhibit corticosteroid dependence or who do not respond to treatment. IVIG might be a safe method to treat the cerebral manifestations of IgAV[13]. Another treatment is plasmapheresis, which is believed to regulate the immune response by eliminating and reducing the plasma immune mediators that are responsible for IgAV[14]. Our patient was treated with methylprednisolone and cyclophosphamide pulse therapy for his first convulsive, but the disease progressed rapidly. Less than a month later, he had another convulsive with a combination of pulmonary hemorrhage.
The occurrence of pulmonary hemorrhage is an unusual and fatal manifestation. The pulmonary hemorrhage symptoms vary greatly, ranging from mild cough, epistaxis, hemoptysis, fatigue, and altered activity tolerance to tachypnea, chest pain, dyspnea, and respiratory failure. A chest X-ray is the first step in the diagnosis of pulmonary hemorrhage, and the common imaging findings are fluffy, diffuse, patchy opacities or opacities with a ground-glass appearance. A bronchoalveolar lavage can be performed to confirm diagnosis and start treatment simultaneously. Pulmonary hemorrhage is likely due to diffuse vasculitis. The deposition and fragmentation of IgA immune complexes, as well as the adhesion of masses of white blood cells are the main causes of pulmonary hemorrhage[15]. Lung biopsy reported by W K Wright[16] revealed intra-alveolar hemorrhage with vasculitis of the small blood vessels.
Guidelines regarding the treatment of pulmonary hemorrhage associated with IgAV have not been established, and current recommendations are based on retrospective studies. High dose intravenous pulse methylprednisolone has been recommended as a first-line treatment. Immunosuppressive therapy such as pulsed cyclophosphamide should be considered during respiratory failure. Our patient had been treated with pulsed methylprednisolone and cyclophosphamide prior to the pulmonary hemorrhage, but this did not prevent the development of pulmonary involvement. Considering the possibility of pulmonary infection, we opted for a safe IVIG therapy. However, his pulmonary symptoms did not improve. The optimal treatment for pulmonary involvement in IgAV is still controversial and needs further study.
Renal function is impaired in approximately 50% of patients with IgAV, and may manifest in many ways, from asymptomatic hematuria and proteinuria, to nephritic syndrome, rapidly progressive glomerulonephritis, and even renal failure[17]. A renal biopsy is recommended if severe proteinuria occurs in children with IgAV. Renal histopathology is the most reliable standard to identify the stage of the disease and predict prognosis. Severe IgAV nephritis is treated usually with highdose corticosteroid and intravenous cyclophosphamide to induce remission, and lower doses of corticosteroid combined with azathioprine or mycophenolate mofetil as maintenance treatment[18]. In the present case, the patient's massive proteinuria and intermittent oliguria suggested a serious condition. The lack of renal biopsy made it impossible to determine the pathological changes in the kidney, which was a drawback of our case. The rapid progression of the patient's disease might be a function of vasculitis or might be due to severe infection. A total of seventeen CRRT treatments, two methylprednisolone pulse and one cyclophosphamide pulse therapy failed to alleviate the patient’s symptoms.
IgAV can and often involves vasculitis in many organs at one time, which can lead to numerous complications. Our patient's clinical manifestations were complex and difficult to control. The coexistence of skin lesions, abdominal pain, severe nephritis and IgA deposits on skin and ileocecum biopsy confirmed the diagnosis of IgAV. Pancreatic, pulmonary and CNS involvement were also seen in our case. The SHARE group7 recommends that corticosteroid application should be considered for complications of IgAV including nephritis, orchitis, cerebral vasculitis, pulmonary hemorrhage and severe gastrointestinal involvement. In severe cases (e.g., severe cerebral, pulmonary or gastrointestinal involvement), pulsed intravenous methylprednisolone over three consecutive days may be considered. Corticosteroids were our main treatment, including methylprednisolone pulse therapy. Cytotoxic immunosuppressants or even plasma exchange may be added when the condition is complicated or when there are life-threatening involvement. However, there is no standard treatment.
In our case, cyclophosphamide was used for the patient's first convulsive because he also had severe nephritis at that time. This treatment was also seen in other cases and was successful[14]. However, our patient was not in remission and subsequently developed pulmonary hemorrhage and pulmonary infection. IVIG might be a safe method. The exact mechanism of IVIG is complex and not fully understood. The interaction between IgG-Fc fragments and Fcγ receptors on target cells seems to be the key to anti-inflammatory effects[19]. Unfortunately, a second methylprednisolone pulse after IVIG still failed to relieve the condition of our patient.
In summary, we report a case of IgAV with multisystemic involvement. IgAV is a multisystem disorder and usually runs a benign course. However, the severe cases are critical, with a high mortality rate. The available data suggest an aggressive treatment with pulse methylprednisolone, especially for severe cases. Various immunosuppressive agents have been used in the treatment of multiorgan involvement in IgAV, but there is no definitive evidence to support a single drug or multi-drug regimen. Further studies need to analyse the clinical course and the response to different protocols of treatment in patients with multisystemic involvement associated with IgAV.