Acute Eosinophilic Pneumonia Caused by Calciumstearate, An

□ CASE REPORT □ Acute Eosinophilic Pneumonia Caused by Calcium Stearate, an Additive Agent for an Oral Antihistaminic Medication Jun Kurai, Hiroki Chikumi, Masahiro Kodani, Takanori Sako, Masanari Watanabe, Masanori Miyata, Haruhiko Makino, Hirokazu Touge, Yutaka Hitsuda and Eiji Shimizu Abstract A 70-year-old man was admitted to our hospital because of dyspnea after taking an antihistaminic agent (homochlorcyclizine hydrochloride) for itching. Chest roentgenogram showed infiltration in the left lung field, and laboratory data revealed eosinophilia. Examination of the bronchoalveolar lavage fluid revealed an increased eosinophil count. A drug lymphocyte stimulation test was positive only for calcium stearate, an additive contained in the homochlorcyclizine hydrochloride tablet. The pulmonary infiltration and clinical symptoms subsided after withdrawal of all drugs and initiation of glucocorticoid therapy. Therefore, we con- cluded that this patient’s pulmonary disease was caused by calcium stearate, an additive for an antihistaminic drug. An allergic reaction to a drug’s additive material should be considered as a rare cause of drug-induced acute eosinophilic pneumonia. Key words: drug-induced eosinophilic pneumonia, drug lymphocyte stimulation test (DLST), antihistaminic agent, von Recklinghausen’s disease (DOI: 10.2169/internalmedicine.45.1674) stearate, was the cause of this patient’s AEP. Introduction Case Presentation Acute eosinophilic pneumonia (AEP), which was origi- nally described by Allen et al (1), is an acute febrile illness A 70-year-old man was admitted to our hospital because characterized by severe hypoxemia, diffuse pulmonary infil- of fever and progressive shortness of breath on August 20, trates, and an increased number of eosinophils in the bron- 2002. He had asteatotic dermatitis for 2 years. He visited a choalveolar lavage fluid (BALF). It lacks the signs and regional clinic 20 days before admission because of severe symptoms of infection or previous atopic illness and re- pruritus and was started on an antihistaminic agent, homo- sponds promptly to corticosteroid therapy. Many drugs, in- chlorcyclizine hydrochloride (Homoclomin), at the clinic. cluding antibacterial agents (2-5), antipyretic agents (6), an- He took this agent orally for 10 days. On August 10, he ex- tihypertensive agents (7), or anticancer agents (8), have been perienced symptoms including loss of appetite and general reported as the cause of AEP. However, antihistaminic fatigue. Two days later, he visited another hospital because agents have never been reported to cause AEP. We describe of a fever of 37.5 C and felt shortness of breath during a patient with AEP whose drug lymphocyte stimulation test physical activity. Chest roentgenogram at that time revealed (DLST) was positive for an antihistaminic agent homochlor- diffuse subpleural infiltrates mainly in the left upper and cyclizine hydrochloride (Homoclomin). Furthermore, the middle lung fields (Fig. 1), and he was hypoxic. He was DLST revealed that an additive agent in this tablet, calcium thus transferred to our hospital. Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori Uni- versity, Yonago Received for publication November 30, 2005; Accepted for publication June 5, 2006 Correspondence to Dr. Hiroki Chikumi, Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503 1011 DOI: 10.2169/internalmedicine.45.1674 of the volume was recovered. Table 2 summarizes the bronchoalveolar lavage fluid (BALF) findings. BALF was re- markable for the presence of eosinophils. BALF was negative for bacterial infection, and contained no atypical cells. The peripheral blood eosinophilia and the increase of eosinophils in the BALF suggested that he had developed an eosinophilic lung disease. The patient’s daily medications at the time of admission consisted of homochlorcyclizine hydrochloride (Homoclomin) 20 mg, bepotastine besilate (Talion) 20 mg, cetirizine hydrochloride (Zyrtec) 10 mg, tofisopam (Grandaxin) 150 mg, loxoprofen sodium (Loxo- nin) 120 mg, baclofen (Lioresal) 15 mg, ambroxol hydrochloride (Mucosal-L) 45 mg, teprenone (Selbex) 100 mg, salicylamide compounding agent (PL granule, a combination cold remedy) 3 g daily, and diclofenac sodium (Voltaren) used as needed. Among them, only Homoclomin had been started 10 days prior to the onset of symptoms, while all of other drugs had been prescribed for the previous 2 years. Figure 1. Chest radiograph on admission, showing diffuse We performed the drug-induced lymphocyte stimulation infiltrative shadows in left lung fields. test (DLST) for all of the above-described drugs. The DLST was judged to be strongly positive only for Homoclomin, but negative for the control agent Table 3. We successively He had smoked 40 cigarettes a day, but had quit smoking carried out DLST for each component of the Homoclomin 10 years previously (70-pack-year history). He had not been tablet, because Homoclomin consists of homochlorcyclizine exposed to toxic dusts, fumes, or asbestos. He had not been hydrochloride, calcium stearate, corn starch, lactose, and hy- exposed to any birds and had not recently taken a hot spring droxypropylcellulose. As shown in Table 4, DLST was posi- bath or traveled outside of Japan. He had suffered from pul- tive only for calcium stearate. Hydroxypropylcellulose itself monary tuberculosis at 20 years of age and was diagnosed was not tested for DLST because of limited volume of the as having von Recklinghausen’s disease at that time. sampling blood. However, since drugs containing hy- On admission, his height was 162 cm, his body weight droxypropylcellulose were negative in DLST, it is unlikely was 57 kg, his body temperature was 37.5℃, his heart rate that hydroxypropylcellulose induced AEP. After the careful was 88 beats/min, his respiratory rate was 22 breaths/min, examinations of patient’s clinical history, chest radiograph/ and his blood pressure was 132/60 mm Hg. He had multiple CT, and laboratory tests including detailed DLST, we finally nodules all over his body and café-au-lait spots as large as 5 reached a diagnosis, calcium stearate-inducing acute eosino- cm secondary to von Recklinghausen’s disease. Superficial philic pneumonia. lymph nodes were not enlarged. Coarse crackles were heard Soon after his hospitalization, all prescribed drugs were over the left lung field. stopped. The next day, intravenous prednisolone therapy (60 Laboratory data on admission are shown in Table 1. The mg daily) was started. He became felt well within 1 week. white blood cell count was slightly increased with peripheral The peripheral blood eosinophilia normalized immediately. eosinophilia. The C-reactive protein concentration was mod- On the seventh hospital day, an arterial blood gases under erately increased. Gas analysis of the arterial blood speci- the room air were significantly improved: pH 7.465, PaO2 men revealed hypoxia. The serum IgE concentration was 72.6 mm Hg, PCO2 39.2 mm Hg, HCO3 27.6 mmol/L. Four- within the normal range. Spirometry demonstrated a mild teen days later, prednisolone administration was carefully ta- obstructive pattern and diffuse capacity was moderately im- pered. His clinical course is summarized in Fig. 3. The pul- paired. Chest computed tomography (CT) on admission monary infiltrates shown earlier on chest CT had almost dis- showed non-segmental reticular opacities with infiltrative appeared by the time he was discharged from the hospital changes at the level of the tracheal carina. It was possibly on September 23, 2002. He was placed under outpatient the influence of emphysematous change which was pre- care without respiratory symptoms. dominant in the upper lung lobes (Fig. 2a). CT at the level of lower lobes shows extensive ground-glass opacity bilater- Discussion ally (Fig. 2b). Neither pleural effusions nor lymphadenopa- thy were present. We present a case of acute eosinophilic pneumonia due to On the second hospital day, bronchoalveolar lavage the antihistaminic agent homochlorcyclizine hydrochloride (BAL) was performed from the left lower lobe bronchus (Homoclomin). Further investigation by DLST for each ad- (left B8). Isotonic saline solution (150 mL) was instilled into ditive of this medication revealed that the actual component the anterior bronchus of the right left upper lobe, and 29% causing AEP was not homochlorcyclizine hydrochloride it- 1012 DOI: 10.2169/internalmedicine.45.1674 Table 1. Laboratory Findings on Admission Table 2. Bronchoalveolar Lavage Fluid Findings vealed that calcium stearate was the causative agent of AEP. Acute eosinophilic pneumonia was first described by Al- len et al (1) in 1989. Recently, the diagnostic criteria for this disease were suggested by Pope-Harman et al (9) and includes: 1) acute onset of any symptom (within 7 days) before presentation, 2) a fever ≧37.2℃, 3) bilateral infiltrates in the chest film, 4) severe hypoxemia, 5) lung eosinophilia (BAL differential with ≧25% eosinophils or a predomi- nance of eosinophils on open lung biopsy). The clinical course and laboratory tests of this patient met these criteria. Recently, many drugs have been reported to cause AEP, including salicylamide compounding agent (PL granule, a combination cold remedy) (10), serrapeptase (Dasen) (11), aspirin compounding agent (Bufferin) (12), ifenprodil tar-

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