Influence of Inhaled Corticosteroids on Community-acquired Pneumonia in Patients with Bronchial Asthma

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1 ORIGINAL ARTICLE Influence of Inhaled Corticosteroids on Community-acquired Pneumonia in Patients with Bronchial Asthma Masako TO, Yasuo TO, Hirokazu YAMADA, Chuhei OGAWA, Mamoru OTOMO, Naohito SUZUKI and Yasuyuki SANO Abstract Objective The aim of the resent study was to evaluate the influence of inhaled corticosteroids (ICS) on community-acquired neumonia (CAP) in atients with Patients and Methods All asthmatic atients who required hositalization for CAP from the beginning of 1989 through December 2001 were enrolled in this retrosective study. Patients who used oral corticosteroids daily were excluded. Patients were divided into two grous based on whether or not they used ICS, and we analyzed clinical characteristics of the neumonia. Sixtytwo atients (28 males, 34 females; mean age, 54.5 years) were enrolled in this study. Thirty-seven of 62 atients used ICS, with the mean dosage being g/day. Results We found no significant differences between the two grous with regard to mean age, serum albumin level, duration of asthma, ulmonary function and frequency of intravenous infusion of corticosteroids in the outatient deartment. There were no significant differences in body temerature, white blood cell count, and CRP value uon admission between the two grous. Differences were not significant in the eriod of resolution of the neumonia or in the frequency of athogens identified between the two grous. Conclusion ICS theray aears to have no influence on CAP in atients with We recommend that ICS should be continued to control asthma with adequate antibiotic theray when asthmatic atients have CAP. (Internal Medicine 43: , 2004) Key words: bronchial asthma, community-acquired neumonia, inhaled corticosteroid, microorganism, resolution eriod of neumonia Introduction Inhaled corticosteroids (ICS) are the most effective theray for asthma currently available and have been used in such atients with few systemic side effects. However, their influence on community-acquired neumonia (CAP) has not been well established. A few authors have reorted the influence of ICS on resiratory tract infections (1 5). These reorts contain not only atients with CAP but also many atients with acute bronchitis. The influence of ICS on CAP is not recisely clarified. We investigated the clinical characteristics of neumonia in asthmatic atients who did and did not use ICS. The aim of the resent study was to evaluate the influence of ICS on CAP neumonia in atients with Methods Patients All asthmatic atients who required hositalization for community-acquired neumonia from the beginning of 1989 through December 2001 were enrolled in this retrosective study. Patients who used oral corticosteroids daily were excluded, as were those with chronic bronchitis, chronic obstructive ulmonary disease (COPD) or bronchiectasis, those who were immunocomromised or who had a malignant disease. Patients were divided into two grous based on the use of ICS, and we analyzed the clinical characteristics of their neumonia. Patients had used ICS at least for 3 From the Deartment of Allergy and Resiratory Medicine, Doai Memorial Hosital, Tokyo Received for ublication May 6, 2003; Acceted for ublication March 2, 2004 Rerint requests should be addressed to Dr. Naohito Suzuki, the Deartment of Allergy and Resiratory Medicine, Doai Memorial Hosital, Yokoami Sumida-ku, Tokyo

2 Influence of ICS on Pneumonia Table 1. Characteristics of Patients at Admission ICS (equivalent doses of BDP) ( g/d) 777.9± ±0.0 Sex Age (y) Serum albumin (mg/dl) Male 18, Female ± ±0.35 Male 10, Female ± ±0.49 ICS: inhaled corticosteroid, BDP: beclomethasone diroionate. Table 2. Characteristics of Asthma Duration of asthma (y) FEV1 (l) FEV1% (%) Frequency of CS intravenous infusion in outatient deartment (revious year) 11.6± ± ± ± ± ± ± ±1.4 ICS: inhaled corticosteroid, CS: corticosteroids, FEV1:forced exiratory volume in 1 second. months before admission. Patients had never used ICS before admission. Asthma was diagnosed according to the Guideline of Global Initiative for Asthma (6). COPD was diagnosed referring to the Global Initiative for Chronic Obstructive Lung Disease (7). The definition of CAP was based on the definition used in the article by Ishida et al (8). Patients who met three of following criteria, including the 1), were diagnosed as having neumonia: 1) infiltrates on chest X-ray, 2) body temerature over 37 C within 24 hours of admission, 3) roduction of urulent sutum, 4) C-reactive rotein (CRP) value greater than 0.4 mg/dl, and 5) white blood cell count higher than 9,000/ l. In this article, 4) is add to the definition used in the article by Ishida et al (8) because some old atients with CAP show normal value of white blood cell count and high CRP value. Patients were excluded from this study when the above-mentioned abnormalities were attributed to another cause such as chronic inflammatory lung disease, collagen vascular disease and so on. Those with tuberculosis and atyical mycobacteriosis were excluded. Patients with atyical neumonia were excluded because of technical limitations of the examination. The resolution eriod was defined as the eriod from admission to the time when the body temerature, white blood cell counts and CRP value decreased to normal range. Identification of athogens When secific organisms were isolated from sutum, blood or leural effusion and comatible with the clinical course, they were considered as athogens. Organisms isolated before manifestation of neumonia were considered to have been colonized. Statistical analysis Results were exressed as mean±sd. Differences between the two grous were comared using Mann-Whitney s U test, the Chi square test or one-way ANOVA. <0.05 was considered to be significant. All data were analyzed using StatView J-4.5 (Abacus Concets, Inc., Berkeley, CA). Results Sixty-two atients were enrolled in this study. The mean age of the total study oulation was 54.5 years (range 16 83), and 28 were male and 34 female. Thirty-seven of the 62 atients used ICS and 25 did not. Mean dose of ICS was g/day with a range of 200 1,600 g/day in the atients who used ICS. All atients had mild to moderate As shown in Table 1, the mean age and serum albumin level did not differ significantly between the two grous. Table 2 shows characteristics of their Pulmonary function tests had been erformed within 1 year before admission. No significant differences were observed in the duration of asthma, ulmonary function and frequency of intravenous infusion of corticosteroids in the outatient deartment. With regard to the clinical characteristics of neumonia, 675

3 TO et al Table 3. Clinical Characteristics of Pneumonia in Study Subjects Body temerature ( C) WBC (/ l) ESR (mm/h) CRP (mg/dl) Resolution eriod (d) 37.8±1.0 11,530±4, ± ± ± ±1.1 10,156±4, ± ± ±4.0 ICS: inhaled corticosteroid, WBC: white blood cells, ESR: erythrocytes sedimentation rate, CRP: C-reactive rotein. Table 4. Frequency of Pathogens Detected in Sutum, Blood or Pleural Effusions Organism Percent of eisodes (%) Stretococcus neumoniae Haemohilus influenzae Stahylococcus aureus Klebsiella neumoniae unknown ICS: inhaled corticosteroid. Chi-square test: (>0.05). Table 5. Clinical Characteristics of Pneumonia in ICS Subjects <800 g/day (n=8) 800 g/day (n=18) >800 g/day (n=11) Body temerature ( C) WBC (/ l) ESR (mm/h) CRP (mg/dl) Resolution eriod (d) 37.9±0.8 11,390±3, ± ± ± ±1.3 12,088±4, ± ± ± ±0.6 11,066±4, ± ± ±5.0 ICS: inhaled corticosteroid, WBC: white blood cells, ESR: erythrocytes sedimentation rate, CRP: C-reactive rotein. Patients were divided into three grous based on the dosage of ICS. no significant differences were observed in body temerature, white blood cell counts, and CRP values on admission between the two grous (Table 3). No significant difference was detected in the number of days required for resolution of the neumonia (resolution eriod). Stretococcus neumoniae was the most frequently found athogen in both grous (Table 4). No statistically significant difference was observed in the frequency of athogens between the two grous. Patients were divided into three grous based on the daily dose of ICS and we analyzed the clinical characteristics of their neumonia. No significant differences were observed in body temerature, white blood cell counts, CRP values on admission, and the number of days required for resolution of the neumonia in the three grous (Table 5). Discussion Influence of ICS on CAP has not been well established. Only Kobayashi and Iikura have reorted a clinical study on the influence of ICS on CAP (9). They found no significant difference in the severity of neumonia, as well as white blood cell counts and CRP values on admission, between atients with and. But there are some limitations. It is clearly described that asthmatic atients with COPD or old tuberculosis are included in their study. But the number of those atients in each grou is not described. They do not clearly describe the characteristics of both grous (with or 676

4 Influence of ICS on Pneumonia ). Patients with COPD or old tuberculosis more easily acquire lower resiratory infection, which is difficult to cure. Gram negative rods were detected more frequently in atients with than without chronic airway inflammation. Frequent intravenous infusion of corticosteroid may induce immunosuression. To et al (10) reorted that the frequency of common athogens (Stretococcus neumoniae+haemohilus influenzae) was lower in atients with severe asthma than in atients with mild to moderate If asthmatic atients with chronic bronchitis and associated conditions had been included, or the number of atients with severe asthma was larger in the grou of atients with ICS, it is ossible that factors other than ICS (severity of asthma, comlicating diseases, etc.) influenced the infection. In the resent study, we strictly excluded atients in whom the above-mentioned factors might influence the clinical roerties of neumonia. Among our atients, the frequency of intravenous infusion of corticosteroid was similar between those using and not using ICS. Mean age, mean serum albumin and characteristics of asthma were also similar between those using and not using ICS. Asthmatic atients with neumonia only were enrolled to imrove recision. In addition, no significant differences were observed in the clinical roerties of neumonia between atients with or. The histological effects of ICS on the airway have been shown. Although thinning of the skin is well known as an adverse effect of toical steroid theray, there is no evidence of a similar rocess in the airways (11). Furthermore, Laitinen et al reorted that the airway eithelia of asthmatic atients recovered morhological function after a 3-month eriod of ICS theray (12). Lundgren et al found no evidence of eithelial structural abnormalities in atients treated with ICS for more than 10 years (13). Thus, ICS does not seem to disturb airway eithelial function or affect the roerties of airway infection. From our results and those of the histological studies, ICS theray aears to have no influence on community-acquired neumonia in atients with We recommend that ICS should be continued to control asthma with adequate antibiotic theray when asthmatic atients exerience resiratory tract infection. A limitation of the resent study was its retrosective design. Various doses of ICS were used in this study (200 g/ day 1,600 g/day). A high dose of ICS may influence the characteristics of neumonia in atients with Our data shows that doses of ICS (less than 1,600 g/day) does not influence body temerature, white blood cell count, CRP value on admission and the number of days required for resolution of the neumonia. Various antibiotics were used in the atients enrolled in this study. In this study, the majority of atients received enicillin, first or second-generation cehalosorin or macrolides. Some atients received carbaenem or new quinolones mainly because of enicillin allergy. Choice of antibiotics may influence the resolution eriod of neumonia. To check this oint, the atients were divided into grous based on the antibiotics used for neumonia and we analyzed the number of days required for resolution of the neumonia. No statistically significant difference was observed in the grous (data not shown). Also, our method of athogen detection has a limitation. Marston et al (14) reorted results of a rosective study of the incidence of community-acquired neumonia and they categorized atients as having definite, robable, or ossible infection with a secific organism according to definitions described in the reort. A few of our atients satisfied the criteria of definite. All other atients satisfied the criteria of ossible or robable according to their definition. Even if they were not definite, they were worth considering. A rosective study on the influence of ICS on community-acquired neumonia may rovide more recise information. However, a rosective design is difficult to imlement because almost all asthmatic atients in our hosital use now ICS. Although some mild asthmatic atients (some of atients taken care by their family doctor) do not use ICS, almost all moderate or severe asthmatic atients use ICS now. Around 1989, ICS theray was not very oular in Jaan, so some atients with moderate asthma were not given ICS. For this reason, the background (atient characteristics and clinical roerties of asthma) of our two grous was the same. Furthermore, the date on admission of atients in each grou is variable. Thus the rogress of antibiotics and diagnosis of neumonia in 10 years do not affect the result in both grous. Also, we strictly excluded factors that could influence the clinical roerties of neumonia. Thus, we feel that this study does rovide objective information on the influence of ICS on community-acquired neumonia in atients with In conclusion, ICS theray seems to have no influence on community-acquired neumonia in atients with We recommend that ICS should be continued to control asthma with adequate antibiotic theray when asthmatic atients have resiratory tract infection. References 1) Watanabe Y, Tanaka H, Ogawa T. Influence of beclomethason diroionate inhalation theray on resiratory bacterial infection in atients with an asthmatic attack. Arerugi (Jn J Allergol) 46: , 1997 (in Jaanese, Abstract in English). 2) Toogood JH. Comlications of toical steroid theray for Am Rev Resir Dis 141: S89 S96, ) Second reort of the Bromton Hosital/Medical Research Council Collaborative Trial. Double-blind trial comaring two dosage schedules of beclomethasone diroionate aerosol with a lacebo in chronic bronchial Br J Dis Chest 73: , ) Tarlo S, Broder I, Sence LA. Prosective study of resiratory infection in adult asthmatics and their normal souses. Clin Allergy 9: , ) Okimoto N, Sunagawa N, Asaoka N, et al. Influence of steroid inhala- 677

5 TO et al tion theray on microorganism of resiratory infections in atients with bronchial Kansenshogaku Zasshi 73: , 1999 (in Jaanese, Abstract in English). 6) Global Initiative for Global strategy for asthma management and revention NHLBI/WHO worksho reort. NIH Publication, 2 9, ) Global Initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management and revention of chronic obstructive ulmonary disease. NHLBI/WHO worksho reort. NIH Publication, 6 9, ) Ishida T, Hashimoto T, Arita M, Ito M, Osawa M. Etiology of community-acquired neumonia in hositalized atients: a 3-year rosective study in Jaan. Chest 114: , ) Kobayashi N, Iikura M. Bacterial neumonia in asthmatic atients. Arerugika 13: , 2002 (in Jaanese). 10) To M, To Y, Yamada H, Ogawa C, et al. Clinical roerties of community-acquire neumonia in atients with Nihon Kokyuki Gakkai Zasshi (JJRS) 41: 89 94, 2003 (in Jaanese, Abstract in English). 11) Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in Am Rev Resir Dis 148: S1 S26, ) Laitinen LA, Laitinen A, Haahtela T. A comarative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, arallel-grou controlled trial. J Allergy Clin Immunol 90: 32 42, ) Lundgren R, Soderberg M, Horstedt, Stenling R. Morhological studies on bronchial mucosal biosies from asthmatics before and after ten years treatment with inhaled steroids. Eur Resir J 1: , ) Marston BJ, Plouffe JF, File TM Jr, et al. Incidence of communityacquired neumonia requiring hositalization. Results of a oulationbased active surveillance Study in Ohio. Arch Intern Med 157: ,