ORIGINAL ARTICLE. Abstract. Introduction. Mitsuhiro Sumitani 1,2, Yoshihiro Tochino 2, Takao Kamimori 2, Hiroshi Fujiwara 2 and Terumichi Fujikawa 2

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1 ORIGINAL ARTICLE Additive Inoculation of Influenza Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine to Prevent Lower Respiratory Tract Infections in Chronic Respiratory Disease Patients Mitsuhiro Sumitani 1,2, Yoshihiro Tochino 2, Takao Kamimori 2, Hiroshi Fujiwara 2 and Terumichi Fujikawa 2 Abstract Background An increased incidence of pneumococcal infection triggered by influenza infection has been reported. Objective To examine the effectiveness of the additive inoculation of influenza vaccine (I-V) and 23-valent pneumococcal vaccine (P-V) to prevent lower respiratory tract infections. Methods 105 Japanese patients with chronic respiratory disease underwent the additive inoculation of I-V and P-V between October 2002 and January 2003, and their medical records were used to retrospectively examine the number of bacterial respiratory infections, number of hospitalizations, and length of hospital stay in the 2 years prior to and after P-V inoculation. Among them [chronic obstructive pulmonary disease (COPD): 45; bronchial asthma: 24; bronchiectasis: 20 (including diffuse panbronchiolitis); and other diseases: 16], 98 patients were evaluated, except for seven patients who died of diseases other than respiratory infections within the 2 years after P-V inoculation. Subjects were 51 to 91 years of age (median: 74 yrs), the male-female ratio was 63:42, and 32 patients were on home oxygen therapy. Results After P-V inoculation, decreases in the number of respiratory infections (3.16 vs infections; p=0.0004) and in the number of hospitalizations (0.79 vs hospitalizations; p=0.001) were observed. Furthermore, an analysis including other factors, i.e., number of patients on home oxygen therapy and influenza season, also revealed a decreased number of hospitalizations. Conclusions The additive inoculation of I-V and P-V in Japanese patients with chronic respiratory disease prevented the development of bacterial respiratory infections and warrants further study in patients with respiratory disease. Key words: COPD, community-acquired pneumonia, influenza vaccine, pneumococcal vaccine, Streptococcus pneumoniae () () Introduction The Global Initiative for Chronic Obstructive Lung Diseases (GOLD) 2006 Guideline has recommend the influenza vaccine (I-V) inoculation as evidence A and the 23-valent pneumococcal polysaccharide vaccine (P-V) inoculation as evidence B, an assessment close to evidence A (1). However, neither the GOLD 2006 Guideline nor previous GOLD guidelines have recommended the additive inoculation of I- V and P-V (2). The incidence of pneumococcal infection has been reported to increase when contracting influenza infection because the expression rate of the platelet-activating factor Department of Respiratory Medicine, Osaka City General Hospital, Osaka and Department of Respiratory Medicine, Yodogawa Christian Hospital, Osaka Received for publication December 4, 2007; Accepted for publication March 25, 2008 Correspondence to Dr. Mitsuhiro Sumitani, sumytany@nifty.com 1189

2 (PAF) receptor in the airways is elevated and Streptococcus pneumoniae binds to the receptor and then penetrates cells (3). In addition, the number of IL-10 that acts to suppress the defensive ability increases and facilitates the penetration of pathogenic bacteria into the human body (4). Christenson et al have reported that the additive inoculation of I-V and P-V lowers the rate of hospitalizations due to diseases, e.g., pneumococcal pneumonia and other types of pneumonia (5). We frequently treat elderly patients who are at risk of contracting pneumonia and, therefore, actively recommend and conduct the inoculation of P-V to chronic respiratory disease patients who are on routine medical care. By using the number of bacterial respiratory infections as a variable, we evaluated the usefulness of the additive inoculation of I- V and P-V in Japanese patients with chronic respiratory disease. Figure1. Studydesign.Numberofbacterialrespiratoryinfections,numberofhospitalizations,andlengthofhospital stayfor2yearsafterthe23-valentpneumococcalpolysaccharidevaccinetopatientswithchronicrespiratorydiseasewho wereinoculatedwiththeinfluenzavaccineeveryyearafter October2000. Subjects and Methods Subjects were 105 Japanese patients who were inoculated with I-V every year after October 2000 and with P-V between October 2002 and January 2003 among Japanese patients with chronic respiratory disease who were on regular ambulatory treatment in the Department of Respiratory Medicine at Yodogawa Christian Hospital, Osaka, Japan. Other than seven patients who died of diseases other than respiratory infections within 2 years after P-V inoculation, the medical records of 98 subjects were used to retrospectively examine and compare the number of bacterial infections, number of hospitalizations, and length of hospital stay in 2 years before and after P-V inoculation (Figs. 1, 2). The evaluation of the effectiveness of the additive inoculation of I-V and P-V to prevent lower respiratory tract infections in Japanese patients was initiated at week 4 after P-V inoculation when antipneumococcal antibodies stabilized. Patients, who actually received antibiotics for suspected bacterial infection, were counted. Furthermore, the number of days during which antibiotics were used, antibiotic consumption, influenza season, and number of patients on home oxygenation therapy were also examined. Antibiotics were administered to patients who showed purulent sputum, fever, cough, dyspnea, and other symptoms and for whom the respirologist strongly suspected bacterial respiratory infection even when the causative bacterium was Figure2. Dispositionofpatients.Subjectswere105Japanesepatientswhowereinoculatedwith I-VeveryyearafterOctober2000andwithP-VbetweenOctober2002andJanuary2003among Japanesepatientswithchronicrespiratorydiseasewhowereonregularambulatorytreatmentin thedepartmentofrespiratorymedicineatyodogawachristianhospital,osaka,japan.except forsevenpatientswhodiedofdiseasesotherthanrespiratoryinfectionswithin2yearsafterp-vinoculation,themedicalrecordsof98subjectswereusedtoretrospectivelyexamineandcomparethe numberofbacterialinfections,numberofhospitalizations,andlengthofhospitalstayin2yearsbeforeandafterp-vinoculation.lrti:lowerrespiratorytractinfection. 1190

3 Table1. PatientCharacteristicsn=105 Characteristicsof105patientswithchronicrespiratorydiseasewhowereinoculatedwiththe23-valentpneumococcalpolysaccharidevaccine. COPD:chronicobstructivepulmonarydisease,DPB:difusepanbronchiolitis,NIPPV:noninvasivepositivepresureventilation not identified through sputum culture. In all patients who were suspected of influenza infection, a diagnosis was made with the influenza test kit (Directigen TM Flu A + B, Becton, Dickenson Japan). The diagnosis of pneumonia was made when finding three or more of fever, cough, sputum, dyspnea, leukocytosis, and increased C-reactive protein (CRP), in addition to the detection of a new pulmonary filtrate on chest radiographs. This analysis included communityacquired pneumonia that developed in aspiration-prone patients but excluded aspiration-induced pneumonia that developed after vomiting. Furthermore, the severity of pneumonia was evaluated in accordance with the Japanese Respiratory Society (JRS) 2005 Guideline revised version (6) and with the Infectious Diseases Society of America (IDSA) 2007 Guideline (7). Sputum culture and blood culture were actively conducted in patents who required hospitalization for treatment to identify the causative bacterium. In this study, the pneumococcal antigen in the urine was not explored. Based on Infection Outbreak Reports announced by Osaka prefecture (8-11), the influenza season was defined as follows: start moment when the number of reported patients per week is 100 or greater; and end moment when the number is less than 100. Wilcoxon signed rank test was conducted for statistical analyses. A value of p<0.05 was considered statistically significant. Patient Background Factors This study included 105 Japanese patients with chronic respiratory disease, whose background factors were as follows: for gender, 63 males and 42 females; for age, 51 to 91 years of age; for smoking history, 36 current smokers, 33 ex-smokers, and 36 nonsmokers; and for underlying disease, 45 patients with COPD, 24 patients with bronchial asthma, and 20 patients with bronchiectasis [including diffuse panbronchiolitis (DPB)], and 16 patients with other underlying disorders (eight patients with pulmonary fibrosis, five patients with pulmonary old tuberculosis, two patients with chronic pulmonary embolism, and one patient with nontuberculous mycobacteria). There were 32 patients on home oxygen therapy, and four patients on noninvasive positive pressure ventilation (NIPPV). There were 15 patients on steroid therapy. The pulmonary function test was conducted in 28 of 45 patients with COPD. According to the GOLD 2006 guideline staging, eight patients were at stage II, seven patients at stage III, and 18 patients at stage IV. We categorized four patients on home oxygen therapy and one patient on NIPPV with home oxygen therapy who could not undergo a pulmonary function test to stage IV patients (Table 1). Patients who had complications were as follows: seven patients complicated by type B or C chronic hepatitis or cirrhosis; 13 patients complicated by diabetes mellitus; seven patients complicated by chronic heart failure mainly consisting of core pulmonale, and two patients complicated by rheumatoid arthritis. Results Except for seven patients who could not be observed for 2 years because they died of diseases other than respiratory infections within 2 years after P-V inoculation, 98 patients were evaluated in this study. The number of bacterial respiratory infections per patient decreased significantly (p= 1191

4 Table2. BacterialRespiratoryInfections Numberofbacterialrespiratoryinfectionsbeforeandaftertheinoculation ofthe23-valentpneumococcalpolysaccharidevaccine. MRSA:Methicilin-resistantStaphylococcusaureus ) from 3.16 infections before inoculation to 1.95 infections after inoculation. Bronchitis was predominantly treated on an ambulatory basis in patients with bacterial respiratory infections against which antibiotics were administered. Among the diseases that were treated at the hospital, pneumonia presented an increased percentage as compared with the percentage on an ambulatory basis. One patient died of methicillin-resistant Staphyrococcus aureus (MRSA)- induced pneumonia on day 47 after P-V inoculation (Table 2). Patients died of diseases other than respiratory infections as follows: three patients with lung cancer that was discovered after P-V inoculation; one patient with acute respiratory failure; one patient with heart failure; one patient with cardiopulmonary arrest; and one patient with sepsis that was provoked by lower extremity gangrene. The number of hospitalizations per patient decreased significantly (p=0.001) from 0.79 admission before inoculation to 0.43 admission after inoculation. No statistically significant difference was found in the length of hospital stay that slightly decreased after P-V inoculation. Sputum culture at the time of hospitalization revealed Haemophilus influenzae, Streptococcus pneumoniae, andpseudomonas aeruginosa in a small number of patients. The blood culture, that was analyzed in some of the patients, did not show positive specimens (Table 3). Influenza infection was observed in one patient before P-V inoculation and in three patients after P-V inoculation. Only one patient required hospitalization for treatment. All of these patients contracted type A influenza infection. The number of days during which antibiotics was used before and after P-V inoculation was examined on hospitalization and on ambulatory basis. Consequently, no statistically significant difference was found in hospitalized patients and ambulatory patients before and after the inoculation with respect to the number; however, the number tended to decrease after P-V inoculation. Many hospitalized patients underwent the combination therapy of two antibiotics from the day of hospitalization (Table 4). Regarding the severity of pneumonia at the time of hospitalization, class IV according to the IDSA criteria and moderate according to the JRS criteria were predominant (Table 5). Most patients evaluated were treated at Yodogawa Christian Hospital. None of patients evaluated were hospitalized at another hospital for treatment, and they were treated for five respiratory infections on an ambulatory basis (three infections before P-V inoculation and two infections after P-V inoculation). Analysis of the influenza season and influenza nonepidemic period revealed decreases in the number of bacterial infections and number of hospitalizations after P-V inoculation, regardless of the periods. After P-V inoculation, furthermore, the number of hospitalizations decreased in patients who were on home oxygen therapy. Half of the patients who required hospitalization for pneumonia treatment were patients who were on home oxygen therapy (Tables 5, 6). Discussion Among the pathogenic microorganisms of communityacquired pneumonia and pneumonia that develops at nursing homes today, Streptococcus pneumoniae accounts for 25 to 40% of them in Japan and the most predominant pathogen of pneumonia (6). This trend is observed worldwide (12, 13). Furthermore, Streptococcus pneumoniae has presented markedly high acquisition rates of drug resistance in Asian countries compared to Europe and the United States. Namely, the penicillin-resistant strains including penicillin intermediately-resistant Streptococcus pneumoniae (PISP) and penicillin-resistant Streptococcus pneumoniae (PRSP), 1192

5 Table3. HospitalizationofPatients Numberofhospitalizationsandlengthofhospitalstaybeforeandaftertheinoculationofthe23- valentpneumococcalpolysaccharidevaccine. P.aeruginosa:Pseudomonasaeruginosa,H.influenzae:Haemophilusinfluenza,Branhamela: Moraxelacatarhalis,S.pneumoniae,Streptococcuspneumoniae,MRSA:Methicilin-resistant Staphylococcusaureus,E.coli,Escherichiacoli,andK.pneumoniae,Klebsielapneumoniae, ns:notsignificant Table4. AntibioticUse Numberofdaysthatantibioticswereusedonanambulatoryandhospitalizationbasisbeforeandaftertheinoculationofthe23-valentpneumococcal polysaccharidevaccine. ns:notsignificant as well as the erythromycin-resistant strains have been reported to account for 64.3% and 77.9%, respectively (14). The increased number of bacterial strains against which treatment with antibiotics is ineffective has emerged as an important issue related to pneumococcal infections. Therefore, the prevention of pneumococcal infections is essential in the clinical setting. The GOLD 2006 Guideline has recommended the inoculation of I-V as evidence A and has evaluated the inoculation of P-V as evidence B (1). In patients with complications by diabetes mellitus, coronary artery disease, congenital heart failure, chronic pulmonary disease, and other dis- 1193

6 Table5. SeverityCategoriesofPneumonia Severitycategoriesofpneumoniaonambulatoryandhospitalizationbasisbeforeandaftertheinoculationofthe23-valentpneumococcalpolysaccharidevaccine. IDSA:InfectiousDiseasesSocietyofAmerica;JRS:JapaneseRespiratorySociety eases, the inoculation of P-V alone has been reported to have a pneumococcal infection-preventive effect (15-18) a preventive effect on the deterioration of pneumonia severity (19, 20) and a lowering effect on mortality from pneumonia in the elderly (21). Furthermore, the WHO (22) has indicated that the inoculation of P-V is effective not only for pneumococcal pneumonia but also for other types of pneumonia. However, the effect of P-V has been reported to be limited to only invasive pneumococcal pneumonia (23), and negative data on its effect have also been reported (24-26). Although the additive inoculation of I-V and P-V has never been recommended by the GOLD guidelines, we consider that the inoculation is of primordial importance in obtaining a better secondary bacterial infection-preventive effect. Since Streptococcus pneumoniae binds to the PAF receptor on cell surfaces and penetrates cells, the incidence of pneumococcal infection when contracting influenza infection increases. Therefore, the additive inoculation of I-V and P-V has been reported to lower the incidence of hospitalizations due to diseases, e.g., pneumococcal pneumonia and other types of pneumonia (5), the mortality from pneumonia (27), febrile duration, and length of hospital stay (28). Hence, we examined the lower respiratory infection-preventive effect of the additive inoculation of I-V and P-V in Japanese patients with chronic respiratory disease who underwent regular medical treatment on an ambulatory basis. This study also revealed decreases in the total number of bacterial infections and in the number of hospitalizations after P-V inoculation, indicating an additive effect of I-V and P-V. Regarding the influenza season, there were a greater number of patients with influenza infection after P-V inoculation. However, no secondary infection after contracting influenza infection was observed in patients before and after Table6. InfluenzaSeasons Thenumberofbacterialrespiratoryinfections,numberofhospitalizations duetobacterialrespiratoryinfections,andlengthofhospitalstayduringinfluenzaseasonsandinpatientsonhomeoxygentherapybeforeandafterp-vinoculationareshown.ns:notsignificant 1194

7 Figure3. Influenzaseasons.TabulatednumbersofpatientsperweekinInfectionOutbreakRe portsannouncedbyosakaprefecture(influenzaseasonsasdeterminedbythenumberofreported patientsperweek,aswelasthereportednumbersofpatientswithinfluenzainfectionareshown inthebox). P-V inoculation. Nor was there found an increase in the number of bacterial infections during the influenza season. As shown in Fig. 3, the number of patients with influenza in Osaka prefecture where Yodogawa Christian Hospital is located tended to increase after P-V inoculation. Therefore, the fact that the number of bacterial infections including secondary infections after influenza has not increased is worthy of appreciation. It is frequent that many patients with chronic respiratory failure who are on home oxygen therapy require hospitalization that is triggered by an infection. Therefore, it is admissible to consider that patients visit the hospital more frequently than required to undergo treatment with antibiotics at an earlier stage. The apparent increase in the incidence of bacterial respiratory infections is attributed to the counting of antibiotic use as bacterial infections. However, no significant difference was found in the number of bacterial infections before and after P-V inoculation, and the number of hospitalizations decreased. These facts lead us to consider that P-V inoculation reduces the severity of lower respiratory infections. The incidence of pneumococcal pneumonia leading to bacteremia is lower in Japan than in Europe and the United States, and the mortality from pneumococcal pneumonia is lower in Japan (29). In this study, none of patients had a positive blood culture. The only patient who died of pneumonia was a patient with COPD complicated by bronchial asthma who was affected with MRSA-induced pneumonia. Twenty-three pneumococcal capsular polysaccharides that are contained in P-V have been reported to cover!85% of the clinically isolated strains of Streptococcus pneumoniae (30). In particular, serotypes 6B, 19F, and 23F have frequently been isolated from 12.3 to 29.1% of patients from whom drug-resistant strains were isolated clinically (29), and the inoculation of P-V is considered to serve for the prevention of infections by penicillin-resistant Streptococcus pneumoniae (PRSP) as well. Increases in antibody titers after P-V inoculation have been reported in elderly patients with chronic respiratory disease, patients with respiratory failure, and patients on steroids (31, 32). However, it is difficult to determine antipneumococcal antibody titers, making the introduction of P-V into the routine clinical settings difficult. However, many patients who were inoculated with P- V in this study showed increases in antipneumococcal antibody titers, thus demonstrating the lower respiratory tract infection-preventive effect of the vaccine. The number of pneumococcus infections decreased from 5 before the inoculation of P-V to 2 thereafter. In the present study, we mainly conducted the sputum culture to indentify pathogens of lower respiratory tract infections. Therefore, we could identify pneumococcus infections only in seven patients. The diagnosis rate of pneumococcus infections is higher when conducting Gram stain of sputum or using the kit for the detection of pneumococcal antigen in urine than when performing sputum culture (33-35). Therefore, it is probable that the preventive effect of the vaccine on pneumococcus infections could have been more clearly demonstrated by conducting the staining procedure or using 1195

8 the kit. The effects of P-V have been reported to last for 5 to 7 years (36, 37). The number of hospitalizations per patient was 0.70 admission/2 years before inoculation and was 1.05 admission/5 years after inoculation in 37 patients who could be examined for the number of hospitalizations due to bacterial respiratory infections for 5 years after the inoculation of P-V among 98 in this study, although the former was not included in this study. Namely, the number of hospitalizations per single year decreased after the inoculation of P-V. In 2005 or later, however, the number of patients going back to their family doctor increased rapidly and patients with decreased ADL were transferred to the nursing home or other types of medical facilities. Therefore, cohorts of patients with a deteriorated performance status and patients who are prone to be affected by repeated bacterial infections of the respiratory tract were possibly excluded. We hence consider that these values should be used only for reference purposes. Nevertheless, 31% of patients with chronic respiratory disease were poorly immunoresponsive to P-V. Furthermore, the anti-6b and -19F antibody titers have been reported to return to the baseline values within 1 year after P-V inoculation (38). We found 2 patients who developed pneumococcal pneumonia after the inoculation of P-V. In this study, we did not determine the serotypes of the clinical isolates of Streptococcus pneumoniae. However, the two patients developed the infection within 1 year after the inoculation of P-V. Therefore, we presumed that they are possibly patients with poorly increased antibody titers or patients who developed pneumococcal pneumonia due to a bacterial strain that is not included in P-V. Therefore, we consider that a greater lower respiratory tract infection-preventive effect could be expected if a pneumococcal vaccine is highly effective so as to induce an increase in antibody titers also in poorly immunoresponsive subjects is manufactured. With the limited sample size in this study, the additive inoculation of I-V and P-V showed a lower respiratory tract infection-preventive effect that generated a statistically significant difference presumably because this study included as variables prevalence (39), clinical stage as assessed by forced expiratory volume in one second (40-42), and length of hospital stay (43) about which the presence of individual differences was demonstrated between patients with chronic respiratory disease and healthy subjects. 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