□ 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 ad- ditive 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- 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 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 bron- choalveolar lavage fluid (BALF) findings. BALF was re- markable for the presence of eosinophils. BALF was nega- tive 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 hy- drochloride (Homoclomin) 20 mg, besilate (Talion) 20 mg, hydrochloride (Zyrtec) 10 mg, tofisopam (Grandaxin) 150 mg, loxoprofen sodium (Loxo- nin) 120 mg, baclofen (Lioresal) 15 mg, ambroxol hydro- chloride (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) be- fore 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- Figure 2. Chest computed tomography on admission. (a) trate (Cerocral) (13), and minocycline hydrochloride (Mino- Chest CT at the level of the tracheal carina shows non-seg- mycin) (2). Even though every drug has the possibility of mental reticular opacity with infiltrative changes. (b) Chest causing drug-induced AEP, an antihistaminic drug, such as CT at the level of the lower lung field shows ground-glass homochlorcyclizine hydrochloride, has almost never been re- opacity. ported to cause AEP and is thought not to be a potential causative agent. Antihistaminic drugs generally work as self but calcium stearate, an additive of this tablet. This is competitive antagonists of binding to cellular re- the first report in which specific testing of each additive of ceptors and have additional properties, including suppression the offending drug causing AEP was performed, and re- of eosinophil function (14). Thus, it is assumed that this

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Table 3. Results of Lymphocyte Stimulation Test (1)

Table 4. Results of Lymphocyte Stimulation Test (2)

Figure 3. Clinical course. kind of drug is rarely a cause of an allergic reaction such as additive agent. At this time, based on the clinical course and eosinophilic pneumonia. DLST findings, we made a diagnosis of AEP in this patient We analyzed each additive of homochlorcyclizine hydro- caused by calcium stearate. Until recently, information of chloride (Homoclomin) administered to this patient, because each additive of medications was not easily obtained in Ja- the possibility of homochlorcyclizine hydrochloride itself pan, but since 2002, details of each additive are listed in the causing AEP seemed to be very low. In our second round of package insert. It is important to know that any additive of DLST results, only calcium stearate was positive, and none medications could cause AEP. Once an additive is specified of the DLST-negative drugs contained calcium stearate as an as a causative agent of AEP, drugs containing the additive

1014 DOI: 10.2169/internalmedicine.45.1674 should be avoided. gies (18). This suggests the possibility that calcium stearate We used DLST to identify the causative drug of AEP. The or its metabolite is antigenic in certain conditioned people. diagnosis of a drug allergy is based mainly upon a very de- Once a patient has shown an allergy to the chemical, it is tailed history and on clinical findings. Recently, an in vitro difficult to avoid exposure due to its use in a wide range of test, the DLST has been made available. The sensitivity and materials. This may be why this patient’s recovery was de- specificity of the DLST have been reported to be 78% and layed. 85%, respectively (15, 16). Another test to confirm a causa- It is possible that the von Recklinghausen’s disease expe- tive drug is the drug provocation test (DPT). The DPT is an rienced by this patient was a risk factor for drug-induced in vivo study and is thought to be able to determine the can- eoshinophilic pneumonia. Von Recklinghausen’s disease is didate drug responsible for allergy more definitively (17). an autosomal dominant disorder characterized by medium- However, the DLST is superior to the DPT in that it is eas- brown skin macules called café-au-lait spot and fibromatous ily and safely performed, and is applicable to many drugs. tumors of the skin. The responsible gene of this disease is In addition, it is thought that a positive result of the DLST NF1 on chromosome 17q11.2 (19), which encodes the might support the diagnosis of drug allergy, although a neurofibromin protein, a suppressor of the growth factor re- negative result does not exclude the possibility of drug- ceptor signaling pathway. Loss of heterozygosity of NF1 induced pneumonia (16). In the present case, we needed to and an activated disorder of the growth signaling pathway in test a large number of agents, therefore we employed the the somatic cells is thought to lead to tumor formation in DLST to identify the causative agent, with the results being this disease. In addition, an increase in serum nerve growth clearly positive only for calcium stearate. We consider the factor (NGF) expression in von Recklinghausen’s disease DLST to be an excellent tool for determining the causative has been reported (20, 21). Recently, NGF was reported to agent of drug-induced pneumonia, and that the results of the activate human peripheral blood eosinophils, suggesting a DLST are reliable. possible role for NGF in conditions associated with eosino- Because calcium stearate is widely used, exposure to it is philia, including allergic disease (22). Therefore, it is possi- difficult to avoid. Calcium stearate is a fatty acid salt and is ble that von Recklinghausen’s disease played a role in de- used as a stabilizer and plasticizer in tablet manufacturing. veloping drug-induced AEP or delayed recovery of this pa- Additionally, it is Generally Recognized as Safe (GRAS) by tient. the FDA, and widely used in food and cosmetics in the In conclusion, we describe a case of drug-induced eosino- United States. In Japan, it is listed in the Japanese Pharma- philic pneumonia caused by calcium stearate, a component copoeia and was approved as a food additive in 2004. Cal- of an antihistaminic agent. Because calcium stearate is cium stearate is generally regarded as a relatively nontoxic widely used as an additive in tablets, this patient needs to and less irritating chemical. In accordance with this recogni- avoid a broad range of tablet-form drugs. The present case tion, there has been no report of allergies caused by calcium indicates the importance of the further examination of each stearate, but it has been reported that stearic acid, the pri- additive of a causative agent for drug-induced eosinophilic mary metabolite of calcium stearate, causes cosmetic aller- pneumonia.

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