Recurrent Pericarditis Due to Mesalamine Hypersensitivity: A Pediatric Case Report and Review of the Literature

Pericarditis is a life-threatening condition that requires prompt diagnosis and immediate, appropriate therapy. Its occurrence has been reported previously in inflammatory bowel disease, in which it may develop as an extraintestinal manifestation or as an adverse reaction to the medicines used for its therapy. We report the first pediatric patient in the literature in whom pericarditis developed as a hypersensitivity reaction to mesalamine(a 5-aminosalicylate [5-ASA]-containing compound) therapy for inflammatory bowel disease. We also review the literature on pericarditis in inflammatory bowel disease. CASE REPORT Ulcerative colitis was diagnosed in a 16-year-old boy after a 3-month history of malaise, intermittent abdominal pain, and loose stools that later became bloody. He had a 10-lb weight loss and microcytic anemia with an elevated erythrocyte sedimentation rate. The upper gastrointestinal and small bowel series was normal. Pancolitis with crypt abscesses was seen on histologic examination of specimens obtained by colonoscopy. Therapy with 40 mg prednisone and 2.4 g mesalamine per day (Asacol, Procter and Gamble, Norwich, NY, U.S.A.) was begun, and an improvement in the colitis symptoms was observed. Approximately 4 weeks after initiation of therapy, symptoms of dysphagia, odynophagia, and malaise developed with fevers as high as 39.5°C. An upper endoscopy revealed Candida esophagitis, which was attributed to the high steroid dosage, and oral fluconazole was administered. The dosage of prednisone was tapered more rapidly, and the mesalamine dosage was simultaneously increased to 4.8 g per day. The patient was well until 3 weeks later, when he experienced acute onset of shortness of breath, pleuritic chest pain, myalgia, and fever of 39.5°C, which required emergent hospital admission. At the time of admission, his steroid dosage had been reduced to 5 mg prednisone each day. He had marked chest discomfort, with pain during deep inspiration and bilateral wheezes. He was tachycardic to 110 beats per minute, with normal blood pressure and negative findings in an abdominal examination. He had no symptoms of colitis. A radiograph of the chest showed a mildly globular heart and left lower lobe pulmonary infiltrate. Intravenous erythromycin was initiated for presumed atypical pneumonia. Intravenous trimethoprim (Bactrim, Roche Laboratories, Nutley, NJ, U.S.A.) was also administered for possible Pneumocystis carinii pneumonia. During the next 3 days, his shortness of breath worsened, and he required oxygen support. A second chest radiograph showed a globular heart with an increased cardiothoracic ratio and a left-side pleural effusion. He was transferred to our hospital with the diagnosis of pneumonia and pericarditis. His sputum cultures were negative for bacteria including acid-fast bacilli. Hemoglobin was 9.3 g/dl, mean corpuscular volume 71 fl, and erythrocyte sedimentation rate was elevated to 92 mm/hr (determined by the Westergren method). Results of serology for mycoplasma,Legionella, and Coxsackievirus were negative. Antinuclear and peri-antineutrophil cytoplasmic antibody titers were both 1:80. The anti-double-stranded DNA antibody was negative. Echocardiography confirmed the pericardial effusion. The family medical history was negative for lupus erythematosus, and infectious and autoimmune laboratory determinations did not reveal the cause of the pleuropericarditis. He commented that his ill health seemed to have begun at the time his mesalamine dose was increased. A hypersensitivity reaction to mesalamine appearing as pleuropericarditis as an extraintestinal manifestation of inflammatory disease was then considered. The mesalamine was discontinued, and the prednisone increased to 20 mg per day, resulting in a gradual improvement in his shortness of breath and complete resolution of the pleural effusions. A follow-up echocardiogram 8 days later showed complete resolution of the pericardial effusion. During the next 4 weeks, the prednisone dosage was reduced to 10 mg every other day without exacerbation of the pericarditis or colitis symptoms. The erythrocyte sedimentation rate also normalized to less than 20 mm/hr. Antibody tests showed a positive result in an enzyme-linked immunosorbent assay specific for ulcerative colitis. A trial of low-dose sulfasalazine (250 mg three times daily) was initiated, because the delayed onset of the initial pericarditis (7 weeks) still made drug allergy a questionable diagnosis. However, 4 to 6 hours after taking the medication, the patient had an acute recurrence of the pleuritic chest pain and shortness of breath, requiring readmission to the hospital. Echocardiography revealed a new posterior pericardial effusion that responded to a 10-day course of 30 mg prednisone per day that was later reduced to 10 mg every other day. Two months later, he experienced a flare in his colitis symptoms that required intravenous cyclosporine therapy after his condition was observed to be refractory to 2 weeks of intravenous steroids. After the colitis was controlled, azathioprine (Imuran; Glaxo Wellcome, Research Triangle Park, NC, U.S.A.) was administered. Nine months after the flare-up, the colitis remained quiescent. DISCUSSION Mesalamine-induced pericarditis is a life-threatening hypersensitivity reaction that requires prompt diagnosis and immediate discontinuation of the drug. The temporal correlation between development of pleuropericarditis and an increase in the mesalamine dosage while reducing the steroids and recurrence of the pericarditis after re-exposure to another 5-ASA-containing medication (sulfasalazine) confirmed the cause of the pleuropericarditis in this patient. The occurrence of pericarditis with inflammatory bowel disease has been reported, and different causes are apparent. It may occur as an extraintestinal manifestation of ulcerative colitis and Crohn's disease or as an adverse reaction to mesalamine or sulfasalazine. In each one of the three, the pathogenesis appears to be different (seeTable 1).TABLE 1: The multifactorial origin of pericarditis in inflammatory bowel diseaseaUntil the late 1970s, sulfasalazine and steroids were the main therapeutic drugs in the treatment of inflammatory bowel disease. Sulfasalazine is effective in the treatment of mild to moderately active ulcerative colitis or in the maintenance of remission, but it has a high incidence of side effects occurring in as much as 21% of patients (1). Because 5-ASA was determined to be the active component in sulfasalazine, several new active 5-ASA compounds were developed. In a retrospective study to evaluate the clinical safety and efficacy of long-term olsalazine therapy in 76 adults with ulcerative colitis, Sandberg-Gertzen et al. (2) found relapse-preventing effects similar to those of sulfasalazine. However in one patient who was treated with olsalazine, pericarditis developed and resolved after discontinuation of the medication and steroid therapy. In a 56-subject, pediatric, multicenter study comparing olsalazine and sulfasalazine therapy in mild to moderate ulcerative colitis, the latter appeared to be more efficacious but produced more side effects. (Pericarditis was not reported as an adverse reaction to either medication)(3). Habal et al. (1) also reported a patient receiving sulfasalazine therapy, in whom pericarditis and bronchospasm developed and recurred when mesalamine was instituted. Since that report, there have been a series of reports of pericarditis in association with mesalamine use (1,2,4-7), including one case of fatal myocarditis(4), all occurring in adults. Patients with pericarditis caused by 5-ASA hypersensitivity typically experience onset of symptoms within 2 weeks of initiation of therapy and have resolution of their symptoms after discontinuation of the 5-ASA compound(4-6) and treatment with steroids. They then have an immediate reoccurrence of pericarditis when inadvertently rechallenged with a 5-ASA-containing medication (6,7). Jenss et al. (5) carried out serial lymphocyte stimulation tests on the serum of a 22-year-old woman in whom pericardial effusion occurred after initiation of mesalamine therapy. They observed that the patient's lymphocytes had an increased proliferation index when compared to that of control subjects, which showed no stimulation in the presence of 5-ASA. The initial delayed onset of symptoms followed by their immediate reoccurrence after re-exposure is consistent with hypersensitivity. Findings in the lymphocyte stimulation test further suggest that this is a type IV hypersensitivity reaction to 5-ASA with an anamnestic response to re-exposure. We postulate that the 7-week delay in initial symptoms occurred in our patient because the high steroid dose that he was receiving at the time was inadvertently treating his hypersensitivity. A lupus erythematosus-like illness characterized by fevers, arthralgia, arthritis, chest pain, and pericarditis has been reported in patients with ulcerative colitis and Crohn's disease who were undergoing treatment with sulfasalazine (8-11). Typically, with this form of adverse reaction, the onset of the symptoms is gradual. Patients have elevated erythrocyte sedimentation rates, with high titers of autoantibodies and presence of peripheral lupus erythematosus cells in one series (11). The time of onset of symptoms in relation to the medication is variable, ranging from 1 month(11) to 6 years (10). The sulfapyridine moiety of the sulfasalazine molecule is thought to be responsible for this lupuslike phenomenon, and most of the reported patients are phenotypically slow in acetylation. They have high serum concentrations of sulfapyridine even with normal doses of sulfasalazine, which facilitates development of the lupus erythematosus-like syndrome(8). The recommended treatment is steroids and discontinuation of sulfasalazine. Pericarditis, as an extraintestinal manifestation of inflammatory bowel disease, may develop independent of the gastrointestinal symptoms and may affect children and adults. Mukhopadhyay et al. (12) reported a 12-year-old boy who had pericarditis 2 years before symptoms of ulcerative colitis developed. Sarrouj et al. (13) reported a 37-year-old woman in whom pericarditis was the initial manifestation. After admission to the hospital, she experienced symptoms of colitis, and the diagnosis of ulcerative colitis was made after flexible sigmoidoscopy. Most cases of pericarditis have been associated with colonic disease of either ulcerative colitis or Crohn's disease. However, Rheingold(14) reported a 28-year-old woman with ulcerative colitis who had pericarditis with pericardial tamponade 2 weeks after colectomy for refractory colitis and shock. Steroids have been used successfully in the treatment of pericarditis. In some patients, indomethacin and aspirin have been used. Recurrences responsive to treatment have also been noted (12,15). The exact pathogenesis remains unknown, but its occurrence is an additional indicator that inflammatory bowel disease is a systemic disorder. CONCLUSION Pericarditis in inflammatory bowel disease is a rare occurrence with a multifactorial origin. It may develop as an acute hypersensitivity reaction within a few weeks of the institution of mesalamine therapy. Alternatively, it may develop more gradually, resembling lupus erythematosus in patients who are administered sulfasalazine. In most cases, it occurs as an extraintestinal manifestation of inflammatory bowel disease with colonic involvement. Most affected patients who have an adverse reaction respond well to steroid therapy, with discontinuation of the inciting medication. Pleurocarditis should be highly considered in any patient with inflammatory bowel disease who develops chest pain or breathing difficulty. We recommend that if the symptoms coincide with the recent institution of mesalamine, the medication be discontinued and steroid therapy initiated. With the increasing use of mesalamine, more cases may be recognized. Patients who are hypersensitive to mesalamine should not be expected to tolerate sulfasalazine.