Gastrointestinal Involvement in Pediatric Polyarteritis Nodosa

Abstract

INTRODUCTION Systemic polyarteritis nodosa (PAN) is a vasculitis characterized and defined by necrotizing inflammatory changes in medium- and/or small-sized arteries. Vascular lesions may result in thrombosis or aneurysm formation in any organ of the body. Suggested criteria for its classification have a specificity and sensitivity around 80% in adults but have not been validated in pediatric population. Polyarteritis nodosa is a rare vasculitis in childhood, and there are remarkable differences among pediatric patients when compared with adults. The gastrointestinal (GI) tract is involved in more than 50% of adult patients at some time during its course. Gastrointestinal involvement is characterized by abdominal pain, nausea and vomiting. The most feared complications of mesenteric vasculitis are gastrointestinal infarction, bowel perforation and aneurysmal rupture, all of which pose immediate threats to life. However, severe presentation with mesenteric involvement and gastrointestinal ischemia is rare in pediatric patients. Abdominal complications due to mesenteric vasculitis are especially difficult to diagnose because the symptoms often mimic those of more common diseases, including infectious enterocolitis, appendicitis and inflammatory bowel disease (IBD). In addition, confirmation of the diagnosis often requires invasive procedures, such as angiography or even exploratory laparotomy. We report 2 different cases of pediatric systemic PAN that presented with gastrointestinal symptoms. Involvement of other organs was evident later on in the evolution of the disease. One of the patients had severe intestinal ischemia with fatal outcome. CASE REPORT 1 A 15-year-old boy presented initially with fatigue, abdominal pain, episodes of headache accompanied by fever, vomiting and weight loss, these symptoms lasting for 2 months. Blood tests showed mild microcytic anemia (hemoglobin 11.5 g/dL, hematocrit 36.7%, mean corpuscular volume 67.22 fL), thrombocytosis (platelet count 696,000/mm3) and elevated serum levels of inflammatory markers (C-reactive protein 17.6 mg/L, erythrocyte sedimentation rate 86 mm). Occult blood in feces was negative, as well as repeated fecal cultures and parasites. Other laboratory blood test results (liver and renal functions, coagulation, protein, albumin) were normal. An abdominal computerized tomographic scan showed thickening of the wall of the terminal ileum and mesenteric adenopathies. Colonoscopy showed numerous aphthoid ulcers, all along the ascending colon and the cecum, including ileocecal valve. At terminal ileum, deep ulcers were found. Upper endoscopy showed normal oesophagus and stomach and presence of little ulcers on duodenal folds. Histopathologic studies of the biopsies of terminal ileum, colon and duodenum showed moderate inflammatory infiltration in the lamina propria without presence of granulomas. These findings, although unspecific, together with the endoscopic appearance, lead to the diagnosis of active IBD; and because of the anatomical distribution, diagnosis of Crohn disease (CD) was established. Treatment with mesalamine and controlled-release budesonide (9 g/d) was begun. He had an initially good response with amelioration of inflammatory markers, and budesonide was progressively tapered. After steroid withdrawal, he presented with fever and abdominal pain. Inflammatory markers turned out to be elevated. Under suspicion of a new CD flare-up, he started intravenous methylprednisolone (1 mg/kg/d), with good response after 48 hours. He was then changed to oral steroids. Azathioprine was started but was suspended after 2 doses because of the onset of a cutaneous rash thought to be related to it. One month after starting oral prednisone, he presented with tonic-clonic seizures that required admission in the pediatric intensive care unit of our hospital and treatment with antiepileptic drugs. Intense headache preceding the seizures was observed, as well as permanent tendency to arterial hypertension. Elevated serum levels of inflammatory markers without gastrointestinal symptoms were present. Cerebral computerized axial tomographic scan showed ischemic lesions that were confirmed with magnetic resonance imaging to be suggestive of cerebral vasculitis. Cerebral, thoracic and abdominal angiography showed irregularities in the distal branches of the right middle cerebral artery (Fig. 1) and the right posterior cerebellar artery territories (suggestive of cerebral vasculitis), right renal artery stenosis (greater than 70%) (Fig. 2) and irregularities in the distal branches of the inferior mesenteric artery. Although ileocolonic mucosal appearance in a new lower endoscopy was normal, histological lesions (massive mucosal necrosis, granulation tissue and fibrohyalinosis without crypt distortion, granulomas or ulceration) were very suggestive of previous bowel ischemia. Hepatitis B surface antigen and myeloperoxidase–antineutrophil cytoplasmic antibodies (MPO-ANCA) were negative. Under the suspicion of systemic PAN, methylprednisolone and monthly cyclophosphamide boluses were started, with good response. Six months after his admission to the intensive care unit, while remaining on the same treatment, a new angiography was performed, showing disappearance of the lesions of the cerebral arteries and amelioration of right renal artery stenosis (40%). Therefore, cyclophosphamide was stopped and treatment with oral azathioprine (2.5 mg/kg/d) was started. Nine months after the diagnosis, the patient remains asymptomatic on treatment with low-dose steroids (0.2 mg/kg/d) and azathioprine, with good control of his arterial pressure without antihypertensive therapy, without reappearance of seizures after the withdrawal of antiepileptic drugs and with normalization of the acute phase reactants.FIG. 1: Cerebral angiography showing irregularities in the distal branches of the right middle cerebral artery (arrows) in patient 1.FIG. 2: Abdominal angiography of the same patient. Note the important stenosis of the right renal artery (arrow) with reduction of more than 70% of its diameter.CASE REPORT 2 A previously healthy 10-month-old boy was admitted to our hospital with a previous story of fever, bloody diarrhea, vomiting and weight loss lasting for a week. On physical examination, he was unwell, lethargic and moderately dehydrated. The abdomen was distended, tender and painful. Laboratory test showed white blood cell count of 31,800/mm, platelet count of 800,000/mm and elevated acute phase reactants (C-reactive protein 119.3 mg/L, erythrocyte sedimentation rate 90 mm), without any other significant finding. Results of stool examination for bacteria, viruses and parasites and of investigation of Clostridium difficile toxin were repeatedly negative. Abdominal x-ray showed moderately distended intestinal loops without signs of obstruction. Intravenous rehydration was started, and intravenous cephotaxime was begun because of his septic appearance. The results of the cultures taken (blood, urine, feces and cerebrospinal fluid) did not show evidence of infection. Progressive attempts to start enteral feeding were unsuccessful; and 2 days after admission, the abdominal distension increased, accompanied by bilious drainage by the nasogastric tube. A new abdominal x-ray showed a generalized distension of intestinal loops suggestive of mechanical occlusion. Under suspicion of necrotizing enterocolitis, an emergency laparotomy was performed. Isolated necrotic jejunitis with perforation was found. A jejunal resection (1 m) with end-to-end anastomosis was made, with good postoperative evolution and progressive reintroduction of enteral feeding. Histopathologic examination of the resection piece showed mucosal necrosis with evident distortion of medium arteries and small-sized vasculature (capillaries, venules, arterioles). Thrombotic changes in medium arteries, fibrinoid necrosis of vessels' walls and aneurysms formation were also found (Fig. 3). Diagnosis of systemic PAN with selective jejunal involvement was established, and treatment with intravenous methylprednisolone (2 mg/kg/d preceded by one bolus of 30 mg/kg) and with cyclophosphamide boluses was started. On the following days, his general state remained stable, without fever; and there was a progressive amelioration of laboratory tests results, although tendency to moderate hypertension was present. Hepatitis B surface antigen and MPO-ANCA were negative. Abdominal ultrasound reported images suggestive of hypoperfusion of the small bowel, and abdominal angiography showed no alterations of the mesenteric vasculature. Results of cerebral angiography and Doppler flow studies of the main arteries were also normal. Twenty days after initiation of the combined therapy, he presented abruptly with somnolence, septic appearance and painful abdominal distention. An abdominal ultrasound was suggestive of intestinal perforation, and an emergency laparotomy was performed. Surgical findings included perforation of the sigmoid colon with free fecaloid fluid in the abdominal cavity and an encapsulated abscess that involved terminal ileum and rectum. Resection of 5 cm of sigmoid-rectum was done; and a terminal colostomy was placed, with closure of the rectum. A few hours after the laparotomy, cardiopulmonary arrest developed. Advanced resuscitation manoeuvres were not effective and he died. Histopathologic examination of the resection piece showed thrombotic changes in small- and medium-sized arteries in the mucosa, submucosa and serosa, suggestive of vasculitis. Postmortem examination confirmed vasculitic changes affecting medium-sized arteries at different localizations: coronaries, mesenteric, renal, perirenal and pulmonary arteries.FIG. 3: Histopathologic study of the resected jejunum. Thrombosis in a serosal medium-sized artery (arrow). Hematoxylin and eosin, ×400.DISCUSSION Polyarteritis nodosa is a necrotizing inflammatory vasculitis of unknown etiology involving small- and medium-sized arteries associated with immune complex deposition in the vessel walls. Multiple organ systems may be involved, and prognosis depends on the presence and severity of this visceral involvement. In 1990, the American College of Rheumatology developed the criteria for the classification of PAN (Table 1) (1). The Chapel Hill Consensus on the Nomenclature of Systemic Vasculitis (2) differentiated between polyarteritis nodosa or classic polyarteritis nodosa, restricted to disease with arteritis in medium-sized and small arteries, and microscopic polyangiitis or microscopic polyarteritis, which included pauci-immune necrotizing vasculitis affecting small vessels, with or without involvement of medium-sized arteries.TABLE 1: American College of Rheumatology criteria for the classification of PANPolyarteritis nodosa is rare in childhood, occurring with equal frequency in both sexes and with a peak age at onset of 9 to 11 years. Juvenile PAN has different clinical features than those found in adults. The proposed criteria for adult PAN have not been validated in the pediatric population, and specific criteria for children have been recently revised (Table 2) (3). The typical presentation in children is of isolated one- or two-organ involvement, with constitutional symptoms; and the diagnosis is often based on histopathology. Some authors classically considered juvenile PAN as a different entity and classified it in 4 subtypes (Table 3) (4). With the new classification, the term childhood PAN is equivalent to what was previously known as systemic PAN.TABLE 2: Proposed classification criteria for childhood PANTABLE 3: Subtypes of juvenile PANCombined treatment with steroids and immunosuppressants is the first choice in PAN. A commonly accepted schedule for severe disease is prednisone 1 to 2 mg/kg/d, to be tapered after clinical suppression, and cyclophosphamide for the first 6 months, either orally (2 mg/kg/d) or intravenously (monthly boluses of 500–1000 mg/m2). Life-threatening organ involvement can require initial intravenous administration of both methylprednisolone (30 mg/kg) and cyclophosphamide boluses. If remission is achieved after 6 months, substitution of azathioprine for cyclophosphamide is a reasonable option to diminish drug toxicity. Azathioprine must be continued for 1 or 2 years. Studies in adults estimate that systemic PAN involves the GI tract in around 50% of patients at some time during its course (5–7). The commonest complaints are abdominal pain (79%), nausea (63%), vomiting (37%) and diarrhoea (23%) (8); but other severe complications have also been reported. Approximately 6% of patients with PAN develop GI bleeding (9), and 31% present with acute abdominal syndromes (10). Peritonitis, intestinal infarction, pancreatitis, acute cholecystitis, appendix inflammation mimicking appendicitis, duodenal ulcer and severe melena, and hematochezia have been reported, in some cases as the initial manifestations of systemic PAN (11–15). A fulminant and often fatal course due to necrosis of the small or large bowel, gallbladder, appendix and liver has been described (16–21). Some factors defining a possibly poorer prognosis have been postulated: GI haemorrhage, intestinal perforation, digestive tract surgery, intractable abdominal pain and weight loss greater than 20% (22). Upper gastrointestinal involvement in PAN is uncommon, but often fatal (23). There are very few published data about GI involvement in pediatric PAN. A multicenter survey of pediatric PAN patients has been recently published (24). In the patients who suffered from systemic PAN (57.2%), presentation was variable according to the involved organs, but the common features were elevated acute phase reactants and constitutional symptoms. Cutaneous lesions developed in 92%, and 43% had hypertension. Musculoskeletal features and myalgia were described in 71.4% of the cases. Gastrointestinal symptoms at presentation were reported only in 23.8% of the patients and central nervous system involvement in 22.2%. Only 6 of the 47 tested systemic PAN patients had a positive ANCA by indirect immunofluorescence. Some had p-ANCA pattern, some c-ANCA pattern and some not specified; but none had MPO-ANCA enzyme-linked immunosorbent assay titers. The diagnosis was made by angiography in 55.5% of the patients, and through biopsies in the rest. Gastrointestinal biopsies were diagnostic in only 4.8% of these systemic PAN patients. Previous studies had estimated gut involvement in 61% to 80% of childhood PAN, ranging from abdominal pain to severe bleeding (25). Classical findings in juvenile vasculitis (fever, malaise, weight loss, elevated acute phase reactants)—if accompanied by unspecific GI symptoms (abdominal pain, vomiting, nausea, diarrhea or bleeding) and in the absence of other more characteristic hallmarks—can sometimes mimic other diseases, mostly IBD. Thus, previous reports exist of vasculitic patients firstly thought to suffer from IBD (26–29). Endoscopic findings (rectal inflammation, ileitis terminalis, apthoid ulcerations) can even lead to a wrong diagnosis (30), as occurred in our first patient (case 1). Concomitance or posterior appearance of symptoms suggestive of other organs' involvement can help in the differential diagnosis. Our patient presented initially with constitutional symptoms, elevated acute phase reactants and unspecific abdominal pain. Based on endoscopic findings, diagnosis of CD was made. Initiation of steroids and immunosuppressants probably helped the initial control of the disease. Onset of generalized seizures preceded by intense headache, and hypertension were suggestive of a systemic disease with involvement of different organs. Arteriographic findings confirmed the suspicion of systemic PAN. Oral steroids and cyclophosphamide boluses were effective in the disappearance of his symptoms and control of his arterial pressure. Occasional case reports of rarer or more severe GI involvement in pediatric PAN have also been published (31). Massive gastrointestinal necrosis with acute abdomen, perforation, massive bleeding and an often-fatal course has been very scarcely published (32–34). To our knowledge, our case 2 patient is the youngest child described with such a fatal course after massive mesenteric necrosis. Acute abdomen with septic appearance and with hematochezia leads to emergency laparotomy, where segmentary jejunum necrosis was found. Histopathology confirmed intestinal PAN. Although combined treatment with steroids and cyclophosphamide was initially effective in amelioration of the symptoms, complications of the disease seemed to have played an important role in colonic ischemia with sigmoid perforation, secondary intra-abdominal abscess and fatal septic shock.