Oral 5-aminosalicylic acid agents (mesalazine and sulfasalazine) and azathioprine are the mainstays of treatment for inflammatory bowel disease. Reports of pulmonary toxicity induced by oral 5-aminosalicylic acid agents or azathioprine in patients with inflammatory bowel disease are very rare; to date, only 38 cases have been reported worldwide. We, herein, report a case involving a 26-year-old man who was diagnosed with eosinophilic pneumonia after using mesalazine and azathioprine for the treatment of Crohn's disease and recovered after treatment. We also found that the fraction of exhaled nitric oxide level was elevated in this patient. After treatment, the fraction of exhaled nitric oxide level decreased and the symptoms improved. The present case shows that fraction of exhaled nitric oxide is related to the disease activity and treatment effectiveness of druginduced eosinophilic pneumonia.
Oral 5-aminosalicylic acid (5-ASA) agents such as mesalazine and sulfasalazine are the mainstay of treatment for mild to moderate IBD. Although sulfasalazine is an effective treatment for IBD, up to 30% of patients experience adverse effects such as nausea, vomiting, abdominal discomfort, diarrhea, headache, pancreatitis, agranulocytosis, and pulmonary toxicity. The newer sulfa-free 5-ASA agent, mesalazine, delivers increased amounts of the active compound while limiting the adverse effects mostly caused by sulfapyridine.
Extraintestinal manifestations associated with IBD are seen in 21% to 41% of patients with IBD.
The fraction of exhaled nitric oxide (FENO) is a marker of airway diseases including asthma, eosinophilic inflammation, and bronchial wall inflammation. FENO levels increase in eosinophilic inflammation. Recently, FENO was utilized in some cases such as asthma, inflammatory disease, and drug-induced eosinophilic pneumonia. After treatment, FENO levels were reduced.
Reports of drug-induced pulmonary toxicity in patients with IBD are rare; only 38 cases have been described worldwide. Domestic reports of drug-induced pulmonary toxicity in patients with IBD include 1 case of eosinophilic pneumonia and 1 case of interstitial pneumonia. Only 2 cases of eosinophilic pneumonia due to mesalazine have been reported in patients with CD. Only 3 cases of AZA-induced eosinophilic pneumonia have been reported worldwide. We, herein, describe a patient with CD who developed the rare complication of eosinophilic pneumonia during mesalazine and AZA treatment. The patient's disease activity and treatment effectiveness were evaluated with FENO.
A 26-year-old man with a 3-week history of coughing presented to Gachon University Gil Medical Center. He had been diagnosed with iron deficiency anemia 2 years previously. Ten months previously, he underwent small bowel resection and anastomosis for treatment of a small bowel perforation and was diagnosed with CD based on the biopsy findings (inflammation and noncaseating granuloma formation on the bowel wall) (
The patient was a lifelong nonsmoker and nondrinker and had not recently traveled to any foreign countries. He had no significant family medical history. After the diagnosis of CD, he was treated with mesalazine at 3 g/day for 10 months. During the first week after the diagnosis, he had received prednisolone at 30 mg/day; this dose was tapered and discontinued. He developed tenesmus and hematochezia after 6 months of treatment with mesalazine, and prednisolone was restarted at 15 mg/day and the dose was tapered for 3 weeks. Four weeks before his visit to our hospital, the hematochezia reappeared along with abdominal pain and an elevated CRP level. Because of disease exacerbation, 50 mg of AZA was added until the day of hospital admission.
The patient's abdominal pain had subsided at the time of hospital admission, but he exhibited dry coughing with white sputum, dyspnea, and chest discomfort. He had no chills or fever. His blood pressure was 110/70 mmHg, pulse was 106/min, body temperature was 36.5℃, and peripheral capillary oxygen saturation was 97%. He had clear consciousness but exhibited a sickly appearance. Both the right and left lung fields were clear during chest auscultation. Peripheral blood test results revealed the following: white blood cell count, 7,020/mm3 (neutrophils, 60.7%; eosinophils, 7.4%); hematocrit, 10.8 g/dL; and platelet count, 784,000/mm3. The blood chemistry results were as follows: serum total protein, 7.7 g/dL; albumin, 4.1 g/dL; AST, 13 U/L; alanine transaminase, 12 U/L; BUN, 11.9 mg/dL; creatinine, 0.7 mg/dL; and CRP, 7.09 mg/dL. A chest radiograph acquired at the time of admission showed signs of subpleural consolidation and suspicious cystic lesions in both lungs (possible pneumonia) (
Because of signs of atypical pneumonia and elevated eosinophil count of 519.5/mm3, the possibility of eosinophilic pneumonia was considered, and mesalazine and AZA were discontinued. Findings of sputum AFB smear, fungal smear, bacterial culture, and cytological examination, and results of QuantiFERON Gold test, virology test, Chlamydia IgM test,
Mesalazine was continued for 10 months. A chest radiograph after 1 week of AZA treatment showed a reticulonodular density and peripheral blood tests showed increased eosinophils; BAL also showed increased eosinophils (14%). Based on these results, the patient was diagnosed with mesalazine- or AZA-associated eosinophilic pneumonia. After discontinuation of mesalazine and AZA and 2 weeks of treatment with prednisolone at 30 mg/day, all pulmonary symptoms of the patient resolved; follow-up chest CT after 5 days also showed improvement (
Our patient had a 1-year history of CD, and his pulmonary symptoms occurred 10 months after the initial administration of mesalazine and after 1 week of AZA treatment. Multifocal subpleural consolidations and ground-glass opacities in both the left and right basal lung fields were present on the initial chest radiograph and chest CT. BAL was performed for a definitive diagnosis. Eosinophilia was detected in the patient's peripheral blood (7.4%) and BAL fluid (14.0%). His clinical signs and radiologic findings improved after discontinuation of mesalazine and AZA and the 2-week steroid treatment. The FENO was 74 ppb on BAL at diagnosis, decreasing to 13 ppb after treatment.
The inflammatory status of acute eosinophilic pneumonia (AEP) may be reflected in the FENO level, which has been shown to be higher in patients with than in those without AEP. In addition, the FENO level has been shown to decrease with steroid treatment.
AEP is a distinct pneumonia syndrome. The etiology and pathophysiology of AEP are unclear; however, AEP is often associated with drug treatment.
Sulfasalazine (sulfapyridine bound to 5-ASA) and mesalazine (5-ASA alone) are treatment options for patients with variations of IBD such as CD and UC.
AZA is a purine analog inhibiting the synthesis of purine nucleotide. The pathogenesis of AZA is not well understood. There are 2 alternative pathways; one to 6-thiouric acid mediated by xanthine oxidase and the other to 6-methylmercaptopurine mediated by thiopurine methyltransferase.
The pulmonary adverse effects of mesalazine and AZA include fever, fatigue, dyspnea, chest pain, and coughing.
To date, 38 cases (39 patients) of mesalazine-related pulmonary involvement have been reported worldwide. Among them, eosinophilic pneumonia was the most common presentation.
The present study had 2 main limitations. First, we were unable to elucidate the mechanism of the mesalazine- or AZA-induced eosinophilic pneumonia. Second, re-challenge with mesalazine and AZA was not performed because the patient did not have symptoms of IBD. Mesalazine-induced eosinophilic pneumonia usually occurs after 2 to 6 months of treatment. In some case reports, this varied from a few days to years after treatment. AZA induced pulmonary toxicity occurs within 1 month after initiation of treatment for IBD. In IBD patients, AZA-induced eosinophilic pneumonia has rarely been reported. Our patient had a 1-year history of CD, and his pulmonary symptoms occurred 10 months after the initial administration of mesalazine and only after 1 week of AZA treatment. In this regard, the AZA was more likely related to the eosinophilic pneumonia than to mesalamine, considering the time interval between drugs. Ideally, AZA re-challenge would be a definitive diagnostic tool. However, this seemed unethical because the patient has no symptoms to date.
Despite these limitations, this is the first report of eosinophilic pneumonia in a patient treated with mesalazine and AZA for CD. We also found that the FENO level was elevated in this patient with drug-induced eosinophilic pneumonia. After treatment of the drug-induced eosinophilic pneumonia, the FENO level decreased and the symptoms improved. In this regard, the FENO level might be related to the disease activity and treatment effectiveness of drug-induced eosinophilic pneumonia.
In conclusion, we have described a 26-year-old man who was diagnosed with eosinophilic pneumonia after treatment with mesalazine and AZA for CD and who recovered after treatment. Additionally, the present study shows that the FENO is related to disease activity and treatment effectiveness of drug-induced eosinophilic pneumonia.