{'fraction_non_alphanumeric': 0.03175173121313157, 'fraction_numerical': 0.014619133111054117, 'mean_word_length': 5.354628422425033, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Gastroenterology case report of mesalazine-induced cardiopulmonary hypersensitivity.

Mesalazine is a 5-aminosalicylic acid derivative that has been widely used to treat patients with inflammatory bowel disease. Accumulating evidence indicates that mesalazine has a very low rate of adverse drug reactions and is well tolerated by patients. However, a few cases of pulmonary and cardiac disease related to mesalazine have been reported in the past, though infrequently, preventing clinicians from diagnosing the conditions early. We describe the case of a 32-year-old man with ulcerative colitis who was admitted with a two-month history of persistent fever following mesalazine treatment initiated 14 mo earlier. At the time of admission, mesalazine dose was increased from 1.5 to 3.0 g/d, and antibiotic therapy was started with no improvement. Three weeks after admission, the patient developed dyspnea, non-productive cough, and chest pain. Severe eosinophilia was detected in laboratory tests, and a computed tomography scan revealed interstitial infiltrates in both lungs, as well as a large pericardial effusion. The bronchoalveolar lavage reported a CD4/CD8 ratio of 0.5, and an increased eosinophil count. Transbronchial biopsy examination showed a severe eosinophilic infiltrate of the lung tissue. Mesalazine-induced cardiopulmonary hypersensitivity was suspected after excluding other possible etiologies. Consequently, mesalazine treatment was suspended, and corticosteroid therapy was initiated, resulting in resolution of symptoms and radiologic abnormalities. We conclude that mesalazine-induced pulmonary and cardiac hypersensitivity should always be considered in the differential diagnosis of unexplained cardiopulmonary symptoms and radiographic abnormalities in patients with inflammatory bowel disease.


Abstract
Mesalazine is a 5-aminosalicylic acid derivative that has been widely used to treat patients with inflammatory bowel disease. Accumulating evidence indicates that mesalazine has a very low rate of adverse drug reactions and is well tolerated by patients. However, a few cases of pulmonary and cardiac disease related to mesalazine have been reported in the past, though infrequently, preventing clinicians from diagnosing the conditions early. We describe the case of a 32-yearold man with ulcerative colitis who was admitted with a two-month history of persistent fever following mesalazine treatment initiated 14 mo earlier. At the time of admission, mesalazine dose was increased from 1.5 to 3.0 g/d, and antibiotic therapy was started with no improvement. Three weeks after admission, the patient developed dyspnea, non-productive cough, and chest pain. Severe eosinophilia was detected in laboratory tests, and a computed tomography scan revealed interstitial infiltrates in both lungs, as well as a large pericardial effusion. The bronchoalveolar lavage reported a CD4/CD8 ratio of 0.5, and an increased eosinophil count. Transbronchial biopsy examination showed a severe eosinophilic infiltrate of the lung tissue. Mesalazine-induced cardiopulmonary hypersensitivity was suspected after excluding other possible etiologies. Consequently, mesalazine treatment was suspended, and corticosteroid therapy was initiated, resulting in resolution of symptoms and radiologic abnormalities. We conclude that mesalazine-induced pulmonary and cardiac hypersensitivity should always be considered in the differential diagnosis of unexplained cardiopulmonary symptoms and radiographic abnormalities in patients with inflammatory bowel disease.

INTRODUCTION
Mesalazine, a 5-aminosalicylic acid derivative, is a medication widely used in the management of inflammatory bowel disease (IBD). The precise mechanism of mesalazine action remains poorly understood. However, it has been proposed that the drug acts locally on the colonic mucosa reducing inflammation through a variety of anti-inflammatory processes. These processes include the inhibition of proinflammatory cytokines (interleukin-1, -2, and -8 and tumor necrosis factor-α), the induction of the proliferator activated receptor-γ gene expression, or mesalazine acting as a potent antioxidant and free-radical scavenger [1] . The use of sulfasalazine in the treatment of IBD has been limited by the side effects, most of them secondary to the sulfapyridine component [2] . On the other hand, the use of mesalazine is usually well tolerated by patients, due to its favorable safety profile. Due to a limited number of cases of mesalazine-induced pulmonary disease and pericardial effusion, it has been difficult for clinicians to diagnose these diseases early. We describe the case of a patient with ulcerative colitis (UC) who, due to mesalazine treatment, simultaneously developed lung disease, pericardial effusion, and severe eosinophilia.

CASE REPORT
A 32-year-old non-smoking man with a 16-mo history of extensive UC treated with mesalazine (1.5 g/d) since the initial UC diagnosis and azathioprine (150 mg/d) for the last 13 mo was admitted to the hospital with a 2-mo history of asthenia, fever and night sweats. Prior to the appearance of the symptoms, UC was in clinical remission. Laboratory tests showed microcytic hypochromic anemia, a normal WBC count, and an increase in the erythrocyte sedimentation rate (91.0 mm/h) and the C-reactive protein level (10.3 mg/dL). Both chest radiograph and electrocardiogram were normal. At the admission, mesalazine dose was increased to 3 g/d. Blood, urine and stool samples were collected for culture prior to a 10-d course of intravenous antibiotic treatment with ciprofloxacin and metronidazole. Nevertheless, the patient continued to be febrile resulting in termination of the antibiotic therapy. Cultures drawn at admission, as well as serologic testing for human immunodeficiency virus, were all negative. A rectosigmoidoscopy showed no evidence of disease activity. A computed tomography (CT) scan of the chest revealed the presence of centrilobular pulmonary nodules in the left lower lobe and lingula, as well as mediastinal and axillary lymphadenopathy.
After a few days of hospitalization, a progressive increase in the WBC and eosinophil counts were detected in peripheral blood. Three weeks after admission, a blood test showed a WBC count of 12.6 × 10 9 /L and a severe eosinophilia of 7.8 × 10 9 /L (62.3%). Immunoglobulins (IgA, IgG and IgM) and complement levels were normal. Rheumatoid factor, anti-citrullinated peptide antibodies, and anti-nuclear antibodies were all negative, while the anti-neutrophil cytoplasmic antibody exhibited a positive cytoplasmic staining pattern (titer, 1:160). During this time, our patient developed clinical symptoms of dyspnea, a nonproductive cough, and thoracic pain. A second CT scan was performed, revealing the presence of a patchy ground glass opacification, centrilobular pulmonary nodules extending to both inferior lobes, and a 33.6-mm pericardial effusion not previously present ( Figure 1A and B). An echocardiogram showed a large pericardial effusion with no signs of hemodynamic instability. Additionally, pulmonary function testing revealed a marked decrease of 66.8% in the diffusion capacity for carbon monoxide (DLCO). The tuberculin skin test revealed no induration, and the QuantiFERON TB-Gold test was also negative. Bronchoscopy findings reported an inflammatory stenosis of the left principal bronchia. The bronchoalveolar lavage (BAL) showed an eosinophilia of 72.0%, with CD4 and CD8 counts of 29.0 and 56.0%, respectively (CD4/CD8 ratio: 0.52). Transbronchial biopsy examination demonstrated the presence of a dense eosinophilic infiltrate throughout the interstitium, alveolar spaces, and capillaries, consistent with eosinophilic pneumonia, but no indication of necrosis or granulomas ( Figure 2). One month after admission, mesalazine-induced eosinophilic pneumonia, pericardial effusion and severe eosinophilia were suspected. Consequently, mesalazine was withdrawn, and therapy with prednisone was initiated. A few days after discontinuation of mesalazine, our patient had a quick and significant clinical improvement as indicated by normalization of the hemoglobin level and eosinophil count. In addition, a chest radiograph and a CT scan of the thorax revealed a complete resolution of the mediastinal and axillary lymphadenopathy, pericardial effusion, pulmonary nodules and infiltrates ( Figure 1C and D). Despite continuous reduction in the DLCO (73.5%) 6 mo after discontinuation of mesalazine, our patient remained completely asymptomatic and capable of conducting a fully active life.

DISCUSSION
Clinicians treating patients with IBD exhibiting pulmonary symptoms face multiple causes for the onset of these symptoms. A respiratory involvement as an extraintestinal manifestation of UC (serositis, sarcoidosis, interstitial lung disease, or pulmonary embolism) should be taken into consideration. Furthermore, lung infections, triggered or worsened by the immunosuppressive medication, as well as pulmonary adverse reactions induced by the drugs used to treat the underlying disease, should also be considered as the underlying cause of the pulmonary symptoms in IBD patients [3] . The use of sulfasalazine has been related to multiple adverse drug reactions (ADRs), hence, mesalazine has become the first-line treatment for the induction and maintenance of remission of mildly to moderately active UC [2] . Although mesalazine is usually well tolerated by patients, some serious ADRs like 4071 April 7, 2015|Volume 21|Issue 13| WJG|www.wjgnet.com

A B
Ferrusquía J et al . Mesalazine-induced cardiopulmonary hypersensitivity common symptoms were non-productive cough, fever and dyspnea, which were present in 74.0%, 72.0% and 64.0% of the patients, respectively. Eosinophilia in peripheral blood was reported in 18 patients (46.0%), and pulmonary infiltrates with an interstitial pattern were the most frequent radiologic finding, appearing in 73.0% of patients. Similarly, eosinophilic pneumonia was the most common histologic finding, appearing in 41.0% of the biopsies. Mesalazine was suspended in 38 patients (97.4%), and 23 of them (60.5%) received systemic glucocorticoids as part of the treatment. Rechallenge was tried in seven patients, but recurrence was only seen in four of them (57.1%). Cardiac disease as an extraintestinal manifestation of IBD is very rare. When it does occur, acute pericarditis is the most frequent form of presentation [13] , but myocarditis, pericardial effusion, and cardiac tamponade have also been described [14,15] . Conversely, most cases of cardiac disease in patients with IBD are drug induced and, even when its pathogenesis is unclear, the consideration is that an idiosyncratic hypersensitivity reaction and a drug-induced lupus-like syndrome mechanism are related [16] . Although most cases of mesalazine-induced cardiac hypersensitivity in IBD patients are not severe, life-threatening complications have been reported [17] . The treatment for the condition consists of mesalazine suspension and administration of non-steroidal anti-inflammatory drugs or corticosteroids, taking into consideration that the former may exacerbate the underlying IBD in some patients [18] . Table 2 summarizes the principal characteristics of previously published cases of mesalazine-induced cardiac hypersensitivity in patients with IBD.
The Naranjo algorithm scale [19] was used to assess the probability of ADRs. The Naranjo algorithm scale is a questionnaire designed to determine the likelihood of whether ADRs are secondary to a drug rather than the result of other factors. ADRs of ≥ 9 points were considered to be definite, probable at 5-8 points, possible at 1-4 points, and doubtful at 0 points. Our patient scored 8 points, suggesting probable ADRs. However, due to the presence of eosinophilia in the peripheral blood, BAL and lung biopsy, the patient's deteriorating condition following mesalazine treatment followed by a significant improvement after discontinuation of mesalazine therapy, all strongly support our diagnosis, especially since other causes of cardiopulmonary disease were excluded. Azathioprine-induced pulmonary disease has also been described [20] , nevertheless, it is by far less frequent and in this case it did not seem to contribute to the patient's symptoms as he was receiving this medication at same dose for 13 mo prior to admission, throughout his entire hospitalization, and after being discharged. As clinical improvement was documented at the time mesalazine was stopped, we conclude this to be the cause.
Cardiopulmonary toxicity related to mesalazine is extremely infrequent making it difficult for clinicians to hepatitis, blood dyscrasias, pancreatitis, and interstitial nephritis have been reported [4] . Mesalazine-induced pulmonary side effects are rare, and its pathogenesis is not well understood. Nevertheless, it is thought that two mechanisms may be responsible for these side effects: (1) a toxicity mechanism that could be dosedependent; and (2) an immunologic mechanism that might be dose-independent [5,6] . Typical mesalazine-related side effects, which include fatigue, non-productive cough, fever, dyspnea and chest pain [7] , usually appear after 1-6 mo of treatment. In very rare cases, patients treated with mesalazine exhibited side effects as early as a few days or several years after the treatment [6] . Laboratory tests may reveal peripheral eosinophilia while pulmonary nodules and an interstitial infiltrate with a ground glass pattern are usually seen in the chest radiograph or CT scan. If performed, the BAL frequently shows an elevated count of eosinophils or lymphocytes, and a reduction of the CD4/CD8 ratio. In addition, pulmonary function tests usually demonstrate a reduced DLCO. Histopathologic findings include interstitial lymphocytic infiltrates, alveolar eosinophilic infiltrates, alveolar fibrosis, and non-necrotizing granulomas [5] . Differentiating mesalazine-induced lung disease from IBD-related pulmonary manifestation, as well as establishing a diagnosis, is challenging. It is known that mesalazine-induced lung disease usually affects the lung parenchyma [8] , whereas the IBD-related pulmonary manifestations typically involve the upper respiratory tract [9] . If the diagnosis remains unclear, a lung biopsy should be considered in order to exclude other conditions. Preferably, the presence of eosinophilia in peripheral blood, BAL, or lung tissue should be used as indicators for diagnosing mesalazine-induced lung disease. Otherwise, diagnosis should be based on clinical presentation, exclusion of other causes of lung disease, and a trial of drug discontinuation. One case reported a complete resolution of the symptoms after the reduction of the mesalazine dose [6] . In patients with severe respiratory symptoms or with a lack of improvement after mesalazine withdrawal, glucocorticoid therapy with prednisone (1 mg/kg per day) should be considered. Reintroduction of mesalazine is not usually recommended. Nonetheless, cases have been reported where rechallenge did not produce recurrence of pulmonary symptoms [10][11][12] . Thirty-eight cases of mesalazine-induced pulmonary disease were found in the literature. The principal characteristics of those cases are summarized in Table  1. There were 18 men (46.2%) and 21 women (53.8%) with a mean age of 42 years (range: 10-72 years) at the onset of symptoms. Thirty-three of them were diagnosed with UC (84.6%) and six had Crohn's disease (15.4%). Mesalazine dose at the onset of symptoms varied from 750 mg to 4.8 g/d. The time between initiation of mesalazine treatment and the onset of pulmonary symptoms ranged from two days to 4-5 years. The most Rechallenge was intended with olsalazine 1.5 g/d, with no recurrence; 7 Patient had no response to glucocorticoid therapy but showed improvement after mesalazine withdrawal; 8 After mesalazine removal a second rechallenge with sulfasalazine was intended with no recurrence of symptoms; 9 Patient required endotracheal intubation for severe respiratory insufficiency; 10 [16] 17/M UC 1.5 g 2 wk T, CP AP, PE Prednisolone Yes/Yes Doganay et al [52] 21/M UC 2 g 10 d T, D AM Budesonide No García-Morán et al [17] 39  [15] 32/M UC ND 10 yr T, CP, D Chronic pericarditis, PT

Prednisone No
Bernal-Sprekelsen et al [54] 54/M UC 1.5 g 3 wk T, CP AP, PE ASA Yes/Yes 1 Freeman et al [55] 26/M UC 1.6 g 3 wk T, CP AM Hydrocortisone Yes/No 2 Sierra Ausín et al [56] 47/M UC 3 g P. recognize and diagnose it in the regular practice. The drug-induced pulmonary and cardiac hypersensitivity should be considered in any IBD patient who develops unexplained lung or cardiac disease while on mesalazine. Early recognition of these ADRs may lead to prompt cessation of the drug, most likely resulting in a complete resolution of the symptoms and radiologic abnormalities.

ACKNOWLEDGMENTS
The authors would like to thank Stacie Griffis, MD and Eleanor Boyce for her help with the translation of the manuscript.

Case characteristics
A 32-year-old man with ulcerative colitis presented with fever, dyspnea, nonproductive cough, and chest pain 14 mo from the initiation of mesalazine treatment.

Differential diagnosis
Cardiorespiratory involvement as an extra-intestinal manifestation of ulcerative colitis (serositis, sarcoidosis, interstitial lung disease or pulmonary embolism); lung infections; and drug-induced adverse reactions.

Imaging diagnosis
Computed tomography scan showed the presence of a patchy ground glass opacification, centrilobular pulmonary nodules that extended to both inferior lobes, and a large pericardial effusion of 33.6 mm. An echocardiogram confirmed the presence of a large pericardial effusion without evidence of hemodynamic instability.

Pathological diagnosis
A transbronchial biopsy examination showed the presence of a dense eosinophilic infiltrate throughout the interstitium, alveolar spaces, and capillaries, consistent with eosinophilic pneumonia.

Treatment
Mesalazine was suspended, and therapy with prednisone was initiated. Azathioprine therapy was continued at the same dose, before, during and after hospitalization.

Related reports
Mesalazine-induced pulmonary and cardiac hypersensitivity are extremely infrequent entities, making it difficult for clinicians to recognize them. This diagnosis was supported by the presence of eosinophilia in the peripheral blood, bronchoalveolar lavage, and lung biopsy, the deterioration of our patient after an increment of the mesalazine dose, as well as the improvement of the patient after discontinuation of mesalazine therapy. Nevertheless, elimination of other causes is required prior to establishing mesalazine-induced pulmonary and cardiac hypersensitivity diagnosis.

Experiences and lessons
An early recognition and an extensive diagnostic workup are essential in recognizing mesalazine-induced lung and cardiac hypersensitivity in inflammatory bowel disease patients as drug withdrawal may result in a favorable outcome for the patient.

Peer-review
The authors described an interesting case of a patient with ulcerative colitis who developed lung and cardiac hypersensitivity related to mesalazine therapy. This article highlights the importance of considering drug-induced pulmonary and cardiac hypersensitivity in all inflammatory bowel disease patients who develop unexplained lung or cardiac disease while receiving mesalazine treatment.