IgA vasculitis with terminal ileitis and giant duodenum ulceration and review of the literatures


 BackgroundImmunoglobulin A vasculitis (IgA V), formerly Henoch–Schönlein purpura, is one of the most common self-limiting vasculitis in children. In 15-20% IgA V cases, gastrointestinal symptoms precede the rashes,they no specific gastrointestinal symptoms and often present as acute abdomen, making the diagnosis difficult.Case presentationWe present two female patients, ages 8 years old and 5 years old, who presented to vomiting and abdominal pain, rashes appeared on the lower limbs a few days later, they were subsequently diagnosed with IgA V. Both patients were given IV methylprednisolone, achieved benign clinical results.ConclusionsWhen gastrointestinal symptoms precede the rashes, it is difficult to diagnose IgA vasculitis, resulting in unnecessary surgery. Early recognition and treatment will promote the remission of the children and avoid unnecessary surgery.


Background
Immunoglobulin A vasculitis (IgA V), formerly Henoch-Schönlein purpura, is one of the most common self-limiting vasculitis in children. It can affect the skin, kidneys, gastrointestinal tract, and joints. The peak age of onset is 4-6 years, and 90% occur within 10 years old. Most occur in winter and spring, with the least in summer, and the population distribution is the highest among Asians. There is a gender difference, the ratio of male to female is about 1.2:1.0. Gastrointestinal symptoms occurred in 85% of patients, including abdominal pain (86%), bleeding (20%), fecal occult blood (66%), diarrhea (20%), 3-5% of patients with gastrointestinal perforation, intussusception [1]. According to the European League Against Rheumatism (EULAR), Pediatric Rheumatology International Trials Organization (PRINTO) and Pediatric Rheumatology European Society (PRES)(2010), the criteria of IgA V include :the presence of purpura, with at least one of four features including (1)diffuse abdominal pain, (2) histopathological evidence of leucocytoclastic vasculitis with predominant IgA deposition or proliferative glomerulonephritis with predominant IgA deposition, (3) acute arthralgia or arthritis and/or (4) renal involvement either in the form of proteinuria or hematuria. These criteria were found to achieve a sensitivity of 100% and speci city of 87% for de ning IgA V [2]. The criteria is more meaningful in the diagnosis of IgA vasculitis in children than in adults [3]. Rashes are mandatory, but in 15-20% cases gastrointestinal symptoms precede the rashes [4], and even in some cases the rashes do not appear [5].
IgA V without rashes has no speci c gastrointestinal symptoms and often present as acute abdomen, making the diagnosis more di cult. We report 2 cases of IgA V terminal ileitis accompanied by duodenum ulcers in our department, one with a 3cm giant ulcer in duodenum and mimic appendicitis.
Both children were treated conservatively and achieved benign clinical results.

Case 1
An otherwise healthy 7-year-old girl was hospitalized to our department, with complaints of vomiting and abdominal pain for 3 days, her abdominal pain worsened after eating. Her blood pressure, body temperature, heart rate, and respiratory rate were normal. Her pharynx was congested, tonsils were swollen, with a little white secretion. Abdominal examination revealed tenderness, epigastric and right lower quadrant pain upon palpation. The rest of his physical examination was normal. Laboratory examinations showed a white blood cell count of 20,760/µl,with Lymphocyte count 5.4% and neutrophil count 90.9% ; a platelet count was 320,000/µl and a C-reactive protein of 31 mg/L (normal, 0-10 mg/L).
Erythrocyte sedimentation rate (ESR) was 47.00mm/h. Liver and kidney functions were within normal limits. Urinalysis was normal. Immunoglobulin M of Mycoplasma pneumoniae was positive (titer 1:640). Helicobacter Pylori was negative. Hepatitis B, Hepatitis C antigen were negative; Coagulation function was within normal limits. Computed tomography with intravenous contrast of the abdomen revealed enlarged appendix, fecal residues in appendix cavity and enlarged lymph nodes behind the peritoneum and around the mesentery [ Fig. 1]. The patient was referred to surgery for appendicitis but did not undergo surgery. She was given Metronidazole for 2 days, and still complained severe abdominal pain. Abdominal sonography showed the small intestine in the upper abdomen was obviously swollen and thickened, the omentum and mesenteric were obviously edema and thickened, and the appendix showed a slight enlargement, the wall thickens slightly, fecal residues were in appendix cavity [ Fig. 1]. The surgeon considered the patient with other problems, she was returned to Department of Digestion. The patient underwent esophagogastroduodenoscopy and ileocolonoscopy, which revealed diffuse erosions at the antral mucosa, an ulcer of about 3 cm at the second part of the duodenum (Fig. 2a) and scattered about 0.5-1.0 cm of polymorphic ulcers at terminal ileum (Fig. 2b). There was no obvious abnormality in the colon. Other tests were done to for diagnosis. D-dimer was 8.89ug/mL, Complement C 4, Complement C 3, Immunoglobulin M, Immunoglobulin G, Immunoglobulin A were within normal limits. Fecal culture and Tuberculosis were negative; Anti-nuclear antibody and anti-neutrophil cytoplasmic antibody (ANCA) were negative; Stool analysis showed occult blood positive, duodenum biopsies showed in ammatory cells (mainly neutrophils and lymphocytes) in mucosa and submucosa, and some dilated and congested blood vessels (Fig. 2c). Several red non-palpable rashes appeared on the lower limbs 5 days after hospitalization. Diagnosis of Henoch-Schönlein Purpura, reexamination of the urine was normal, urine micro-albumin was normal. The patient fasted, She was given methylprednisolone 2mg/ (kg. d) intravenously for 1 day without improvement, and then 4mg/ (kg. d) for 1 day until 10mg/(kg. d) methylprednisolone was administered for 3 days, the abdominal pain resolved, Her skin lesions also gradually regressed. Then the methylprednisolone was reduced to 2 mg/ (kg. d), followed by oral prednisolone (2 mg/kg/day) for 1 month, by tapering to 0.5 mg/kg/day per week. Before she was discharged, Abdominal sonography was reexamined, and appendix was normal. She underwent esophagogastroduodenoscopy and ileocolonoscopy 1month after discharge, ulcers at the second part of Discussion IgA vasculitis is one of the most common vasculitis in children. The pathogenesis is unclear. Previous studies believe that it is related to IgA, especially IgA1. Antigens and IgA form immune complexes, which are deposited on the walls of small blood vessels, causing vasculitis [6]. The causes of IgA vasculitis are mostly related to infection, vaccination, tumor, and drugs. Previous studies have shown that among the infections associated with IgA vasculitis, respiratory tract infections are the main one, accounting for 42%-53.5%, followed by gastrointestinal tract (2.2%-5%). A study on HSP-related infections in Anhui, duodenum and terminal ileum disappeared (Fig. 2d, e). She was symptom-free during a follow-up period of 6 months.

Case 2
A 5-year-old girl was hospitalized to our department, with complaints of vomiting and abdominal pain for 3 days. Abdominal examination revealed tenderness, mid abdomen pain upon palpation. The rest of his physical examination was normal. On the second day of admission, She passed about 100 ml of blood in her stool, with severe abdominal pain. Laboratory examinations showed a white blood cell count of 17,520/µL,with Lymphocyte count 13.1% and neutrophil count 76.2% ; a platelet count was 404,000/µL and a C-reactive protein of 20.34 mg/L. Liver and kidney functions were within normal limits. blood amylase was normal. Urinalysis was normal. Mycoplasma pneumoniae and Helicobacter Pylori were negative; Coagulation function was within normal limits, hepatitis B, Hepatitis C antigen was negative. Erythrocyte sedimentation rate was 6.00mm/h. Complement C 4, Complement C 3, Immunoglobulin M, Immunoglobulin G, Immunoglobulin A were within normal limits. Fecal culture and test for tuberculosis were negative; D-dimer was 19.33ug/mL, coagulation was normal. Anti-streptolysin "O" test and Antinuclear antibody were negative. Rheumatoid factor and EB virus were negative. ANCA was negative.
Abdominal ultrasound showed edema and thickening of the intestinal wall of the small intestine, thickening of the mesentery. Emergency gastroscopy and colonoscopy showed multiple ulcers in the duodenum and mucosal congestion. There are multiple ulcers in the terminal ileum, the larger one is about 1 cm (Fig. 3a). There was no obvious abnormality in the colon. Histopathological examination of the small intestine revealed non-speci c in ammation (Fig. 3b). She was given fasting, antibacterial, and intravenous omeprazole. Then bloody stools turned into jam-like stools. Three days later, a scattered palpable rash appeared on the lower limbs, which did not fade under pressure. She was diagnosed with Henoch-Schönlein Purpura and given methylprednisolone intravenous infusion 2 mg/kg/day for 1 day.
The patient still had obvious abdominal pain and jam-like stools. The methylprednisolone was increased to "10 mg/kg/day, then the abdominal pain improved, she had a black stool, and methylprednisolone was instilled intravenously for 3 days, the skin lesions gradually regressed. Methylprednisolone was reduced to 2 mg/kg/day, followed by oral prednisolone (2 mg/kg/day) for 1 month, by tapering to 0.5 mg/kg/day per week. Re-examination of urine routine and urine microalbumin were normal. She underwent ileocolonoscopy 1month after discharge, ulcers at terminal ileum healed (Fig. 3c). She was normal during follow-up for half a year.
China showed that streptococcal infections are the most (17.08%), followed by Helicobacter pylori (5.92%) and Mycoplasma pneumoniae (4.83%), and anti-infective treatment can speed up the remission of patients [7]. Studies have also shown that throat swabs in IgA vasculitis test positive for group A streptococci as high as 75% [8]. We reported the rst case with Mycoplasma pneumoniae IgM positive, and she had pharyngeal congestion and tonsil secretions, which may have caused respiratory infections, inducing IgA vasculitis. In the second case, no obvious pathogen was detected, but the white blood cells and CRP were elevated, suggesting that there may be a bacterial infection, which may be related to antibiotics after admission. Gastrointestinal symptoms secondary to gastrointestinal vasculitis, causing blood components to penetrate into the interstices of the intestinal wall, intestinal wall edema and hemorrhage, tissue ischemia, necrosis, and ulcer formation. Intestinal wall edema and thickening cause intestinal obstruction and intussusception. It has been reported that the most commonly affected site is the small intestine, of which the descending duodenum is the most susceptible [9] . The study of Eon Jeong Nam et al stated that the terminal ileum is the most vulnerable, but this is based on adult reports [10] . So far, we reviewed the literatures published by PUBMED, 14 of which are IgA vasculitis with terminal ileitis (not including our 2 cases), of which only 3 literatures reported that 5 children had terminal ileitis [4,11,12]. A Chinese study on childhood IgA vasculitis showed that capsule endoscopy revealed that the jejunum was the most affected site, accounting for 96.7%, followed by the descending duodenum (33.3%), and no colon involvement was found [13]. The common manifestations are erosions and ulcers. The cause of terminal ileitis may be because the patch nodules in the terminal ileum are rich in IgA, which causes the deposition of immune complexes [11]. Moreover, the ileocolonic branch of the superior mesenteric artery is the longest branch and is prone to under perfusion [14]. We reported two cases of children with duodenal ulcer and multiple ulcers in the terminal ileum. Duodenal ulcer is not uncommon in the gastrointestinal manifestations of IgA vasculitis, but the rst case of giant ulcer in a child has not been reported, and it needs to be differentiated from malignancy. Terminal ileitis is rarely reported in children with IgA vasculitis. It needs to be differentiated from other diseases, especially Crohn. More and more studies have shown that IgA vasculitis may be related to Crohn. There are reports in the literature that Crohn's disease is diagnosed 3 years after the diagnosis of IgA vasculitis [15]. Moreover, IBD patients developed IgA vasculitis after being treated with adalimumab [16]. There are also 2 literature reports that 3 cases of children with Crohn's disease were diagnosed with IgA vasculitis [4,12 ] . Another study showed that the incidence of IgA nephritis in IBD patients was signi cantly higher than that in non-IBD patients. Among 83 patients with IBD, renal biopsy from 20 patients showed IgA nephritis [15]. These indicate that there may be a relationship between IgA vasculitis and in ammatory bowel disease. Other differential diagnosis includes infections, such as Yersinia, cytomegalovirus, Salmonella, Mycobacterium tuberculosis, malignant diseases, such as lymphoma, drug-induced vasculitis, common drugs include NSAIDs, contraceptives, and digoxin, Eosinophilic gastroenteritis [14].
Diagnosis of atypical IgA vasculitis is di cult, especially when gastrointestinal symptoms appear before the rash, IgA vasculitis is easily confused with acute abdomen. There were reports of 2 cases of children with acute abdomen symptoms, and terminal ileitis was found during abdominal exploration. There are also reports of adults with appendicitis-like manifestations undergoing abdominal exploration, and terminal ileitis was detected. These patients all developed rashes on their lower limbs after abdominal exploration, and were therefore diagnosed with IgA vasculitis [6,11]. Our rst case had symptoms similar to appendicitis: tenderness in the right lower abdomen, and abdominal ultrasound and CT showed thickened appendix. Fortunately, our patient did not undergo surgery. Abdominal ultrasound of these two cases showed mesenteric thickening, edema and thickening of the intestinal wall. Atypical IgA vasculitis requires biopsy and histological examination to identify other diseases. The histopathological manifestations of typical IgA vasculitis are leucocytoclastic vasculitis. IgA deposits can be seen on the blood vessel wall, which requires immunohistochemistry. However, not all biopsy specimens can detect vasculitis. Studies have reported that few duodenal specimens can detect IgA deposits [17], and upper gastrointestinal endoscopy is less sensitive in diagnosing vasculitis. This may be due to the localization of the biopsy to the mucosal layer [18]. Typical cases do not require biopsy, and atypical cases require IgA detection in the skin and gastrointestinal tract when other diseases need to be ruled out. In our rst case, the histology of the duodenum found vasodilation and congestion, suggesting the possibility of vasculitis. However, both children had obvious lower extremity rashes later. Although upper gastrointestinal endoscopy and histology cannot directly diagnose IgA vasculitis, it plays an important role in assessing the location and severity of the lesion, including differential diagnosis. Although upper gastrointestinal endoscopy and histology cannot directly diagnose IgA vasculitis, it plays an important role in assessing the location and severity of the lesion, including differential diagnosis, especially when those cases who show duodenitis and terminal ileitis need to be differentiated from other diseases, such as Crohn. In addition to the symptomatic treatment of IgA vasculitis, oral prednisone 1-2 mg/kg/d is recommended, but when serious complications (such as severe brain, lung, gastrointestinal involvement) occur, high-dose methylprednisolone(10-30mg/kg/d) can be used the maximum is 1g/kg, and the dose will be gradually reduced after 3 days [19]. However, it should be noted that steroid therapy may reduce the follicles of the intestinal mucosa, affect mucosal regeneration and healing, and increase the risk of intestinal perforation [3]. Since the renal of the two cases reported in this report were not involved, we did not discuss IgA nephritis involvement did not occur in the two cases reported in this report, we did not discuss IgA nephritis.

Conclusion
When gastrointestinal symptoms precede the rashes, it is di cult to diagnose IgA vasculitis, which is easily confused with abdominal pain-related acute abdomen, resulting in unnecessary surgery. Although duodenitis is common in children with IgA vasculitis, the giant duodenal ulcer we reported has not been reported before, and terminal ileitis is predominant in adults, and there are not many cases reported in children. When mesenteric edema and thickening, duodenitis and terminal ileitis occur, the possibility of IgA V should be considered. Gastrointestinal endoscopy and histological biopsy are helpful for differential diagnosis and avoid misdiagnosis as surgical diseases and related operations Abbreviations IgA V Immunoglobulin A vasculitis ESR Erythrocyte sedimentation rate ANCA anti-neutrophil cytoplasmic antibody Declarations Figure 1 CT showing enlarged appendix and fecal in appendix cavity Figure 2 The appearance of giant ulcer at the second part of the duodenum, terminal ileitis, and histology of the rst case Figure 3 The appearance of terminal ileitis and histology of the second case