to improve the survival of patients with DPB, and most patients with DPB in Japan have ..... Kim, Y. W., S. K. Han, Y. S. Shim, K. Y. Kim, Y. C. Han, J. W. Seo, and.
Improvement of Survival in Patients with Diffuse Panbronchiolitis Treated with Low-dose Erythromycin SHOJI KUDOH, ARATA AZUMA, MASAHIKO YAMAMOTO, TAKATERU IZUMI, and MASAYUKI ANDO Fourth Department of Internal Medicine, Nippon Medical School, Tokyo; Medical School, Nagoya City University, Nagoya; Chest Disease Research Institute, Kyoto University, Kyoto; First Department of Internal Medicine, Kumamoto University, Kamamoto; and Research Group of Diffuse Pulmonary Disease Committee Organized by Ministry of Health and Welfare of Japan, Tokyo, Japan
Diffuse panbronchiolitis (DPB) is a chronic inflammatory disease of the airways with a high rate of mortality despite treatment with a combination of antibiotics and the use of supportive therapy such as oxygen administration. Low-dose erythromycin therapy (EM) (400 to 600 mg/d) has been found to improve the survival of patients with DPB, and most patients with DPB in Japan have been treated with this erythromycin regime since 1984. The purpose of this study was to evaluate the effects of treatment with erythromycin on the survival rate of patients with DPB in Japan. We compared the survival rates of 498 patients with DPB after dividing them into three groups according to the date of their first medical examination (Group a: 1970–1979, Group b: 1980–1984, Group c: 1985–1990). DPB had been diagnosed in these patients using the criteria of the Ministry of the Health and Welfare Diffuse Lung Disease Committee (MHW-DLDC), which includes chronic productive cough, shortness of breath, presence of roentgenologically smoldering symmetrical granular shadows in the middle and lower lung fields, limitation of airflow without decrease in DLCO, elevated serum cold hemagglutinin titers, and/or narrowing bronchiolus with infiltration of lymphocytes and foamy alveolar macrophages. These patients were registered in the DPB research group of the Ministry of Health and Welfare (MHW). Survival rates were statistically compared using the generalized-Wilcoxon test. The survival rate of Group c was significantly higher than that of Groups a (p , 0.0001) and b (p , 0.0001). In Group c, eight of 87 patients died; five died in the EM nontreated subgroup (n 5 24), and three died in the EM-treated subgroup (n 5 63). There was a significant difference in the survival rates between the two subgroups in Group c (p , 0.001). Treatment with EM was associated with a significant improvement in the rate of survival of patients with DPB. The efficacy of EM treatment increased the survival rate of patients with DPB, which was more significant in the older than in the younger patients. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. AM J RESPIR CRIT CARE MED 1998;157:1829–1832.
Diffuse panbronchiolitis (DPB) was first reported in 1969 by Homma and coworkers (1–3) as a new clinicopathologic entity characterized by chronic recurrent bronchiolitis and peribronchiolitis with infiltration of lymphocytes and plasma cells, often causing obstruction of the small airways through the formation of lymph follicles, granulomas, and scars. Clinical features of DPB are productive cough, shortness of breath, and coarse crackles on lung auscultation in more than 80% of the patients. Chest radiography shows bilateral diffuse granular shadows in more than 70% of the patients at first presentation, and in more than 90% of patients at a later stage of the disease. Analysis of arterial blood gases show hypoxemia less than 80 mm Hg. Decreased FEV1 less than 70% is commonly observed in such pa(Received in original form October 22, 1997 and in revised form February 4, 1998) Supported by grants from Ministry of Health and Welfare of Japan. Correspondence and requests for reprints should be addressed to Arata Azuma, M.D., Ph.D., Fourth Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan. Am J Respir Crit Care Med Vol 157. pp 1829–1832, 1998 Internet address: www.atsjournals.org
tients, but alteration of diffusion capacity is rare. In addition, titer scores of cold hemagglutinin are usually elevated to more than 64 times the normal value in these patients. Furthermore, human leukocyte antigen (HLA) B54 is a frequent haplotype in patients with DPB (63.2%), whereas it is present only in 11.4% of the normal healthy Japanese population (4). DPB had a poor prognosis before 1985 when treatment with several antibiotics and life-saving supportive therapy was used, prior to our report on the efficacy of erythromycin (EM) in patients with DPB (5). We further reported that low doses of EM improved the clinical symptoms after the disappearance of small nodular shadows, air-trapping of chest films, and normalization of respiratory functions and titer score of cold hemagglutinins (6). The mechanism by which EM may have a remarkable effect on DPB include the mimicking effect of vasointestinal hormone: motilide (7), anti-inflammatory effects (8), and the inhibition of secretory actions (9, 10). Anti-inflammatory mechanisms of EM include the downregulation of inflammatory cytokines: TNFa, IL-8, IL-4, and IL-1 (11), and chemotaxis of polymorphonuclear cells (PMN) (12), lymphocytes, and histi-
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ocytes (13, 14). These reports suggest that the action of EM would not be only antimicrobial but also anti-inflammatory. In the present study, we retrospectively investigated the effects of EM treatment on the survival rate of the patients with DBP (n 5 498) registered between 1970 and 1990.
METHODS Diagnosis The diagnosis of DPB was based on the clinical diagnostic criteria established by Homma and Yamanaka in 1969 collaborating with the Ministry of Health and Welfare of Japan (15). The diagnostic criteria for DPB are as follows. 1. Symptoms: chronic cough, sputum, and dyspnea on exertion. 2. Physical signs: coarse crackles, rhonchi, or wheezes on auscultation of the chest. 3. Chest radiographic findings: bilateral fine nodular shadows, mainly in the lower lung fields often with hyperinflation of the lungs. 4. Pulmonary function tests and blood gas analysis: FEV1 , 70% and PaO2 , 80 mm Hg. 5. Elevated titers of cold hemagglutinin: 3 64 and more. 6. Past history or coexistence of chronic parasinusitis. 7. Transbronchial biopsies, if taken, show thickness of the wall of the respiratory bronchiole with infiltration of lymphocytes, plasma cells, and foamy histiocytes expanded into the peribronchiolar area. DPB also includes patients with bronchiectasis considered to be in different stages of DPB.
Patients Patients who met the above seven criteria were registered as the DPB research group of the Ministry of Health and Welfare of Japan. Of the 595 registered patients 498 (290 male, 208 female) were divided into three groups for the purpose of analysis: 190 patients from 1970 to 1979 (Group a), 221 patients from 1980 to 1984 (Group b), and 87 patients from 1985 to 1990 (Group c). The characteristics of these patients are as described in Table 1. Because the diagnosis of DPB was done within 2 to 3 mo after the first examination, there were no significant differences in the commencement of DPB therapy between these three groups. Patients in Group b had an opportunity to receive new anti-Pseudomonas antimicrobial agents; new quinolone compounds, compared with patients in Group a who were given conventional antibiotics. Patients started to receive EM therapy (600 mg/d) after 1985, based on our first report that low doses of EM were extremely effective in DPB (5, 6).
Figure 1. Comparison of survival curves of the patients among three groups (a, 1970–1979; b, 1980–1984; c, 1985–1990). Survival ratio of Group c was significantly higher than that in the other groups. Significant differences were analyzed by the generalized-Wilcoxon test.
Statistical Analysis We used the Cox proportional-hazards regression to identify patientand disease-related variables associated with the survival of patients with DPB in each group. These variables include sex, age, and drugs for treatment. Survival rate was statistically compared using the generalized-Wilcoxon test.
RESULTS Survival Rate of Patients with DPB
Patients with DPB who met the diagnostic criteria ranged from 20 to 70 yr of age. There was no significant difference in the number of male and female patients (Table 1). The survival rate in Group c was significantly higher compared with Groups a (p , 0.0001) and b (p , 0.0001) (Figure 1). Contribution of Erythromycin for Survival Rate
In order to estimate the contribution of erythromycin (EM) in improving the survival rate of patients with DPB in Group c,
TABLE 1 BASELINE CHARACTERISTICS OF PATIENTS WITH DIFFUSE PANBRONCHIOLITIS* Group
Patients, n Male/female Age, yr , 30 30–39 40–49 50–59 60–69 . 70 Treatment E 1 EN N1O
a
b
c
190 78/112
221 88/133
87 40/47
19 23 45 59 35 9
21 30 60 55 45 10
6 6 17 24 22 7
ND ND
ND ND
63 24
Definition of abbreviations: ND 5 not determined; E 5 erythromycin; N 5 new quinoron group; O 5 others. * The patients from 1970 to 1979 and from 1980 to 1984 were classified in Groups a and b, respectively, and the patients from 1985 to 1990 were classified in Group c.
Figure 2. Contribution of treatment with EM on survival of patients with DPB. In patients in Group c treated with EM (n 5 63) the survival ratio was significantly higher than in simultaneous patients without EM treatment (n 5 24) (p 5 0.0056). On the contrary, survival curves of patients in Group a (n 5 192) who were not treated with EM before 1985 were not significantly different from those of non-EM-treated patients in Group c (p 5 0.2475).
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TABLE 3
COX PROPORTIONAL-HAZARDS REGRESSION ANALYSIS OF SURVIVAL FACTORS*
FACTORS DIRECTLY RESPONSIBLE FOR DEATH IN GROUP c*
Factors Overall, n 5 498 Sex Male Female Age, 1 yr aging First examination 1970 to 1979 1980 to 1984 1985 to 1990 Patients in Group c, n 5 78 Sex Male Female Age, 1 yr aging Therapy EM(2) EM(1)
Hazard Rate
1 0.953 1.042
Ranges (95%)
0.732–1.240 1.031–1.054
Age (yr) p Value
0.7178 0.0001
1 0.548 0.104
0.418–0.718 0.051–0.214
0.0001 0.0001
1 1.436 0.962
0.337–6.113 0.909–1.019
0.6245 0.1910
1 0.152
0.035–0.658
0.0118
EM-treated group, 3/63 42 44 71 Group without EM treatment, 5/24 36 38 49 57 60
Sex
Direct Factor
Female
Collagen vascular disease (intestinal perforation) DPB Gastric carcinoma (DPB completely cured)
Female Female
Male Female Male Male Male
DPB Acute pancreatitis DPB Brain tumor Gastric carcinoma
Definition of abbreviations: EM 5 erythromycin therapy; DPB 5 diffuse panbronchiolitis. * The 44-yr-old woman died of advanced respiratory failure (DPB) even with EM therapy. However, two male patients died of progressing respiratory failure (DPB) without EM treatment.
* Difference of first examination time and 1 yr aging are critical survival factors in all patients. EM therapy contributed to survival of patients with diffuse panbronchiolitis in Group c.
Death Factors
we compared the survival rate of patients who received EM with those of patients who received other antibiotics. The survival rate of patients treated with EM was significantly higher than that of patients treated with other antibiotics (Figure 2). Furthermore, to compare survival rates of patients in Groups a and c who had not been treated with EM, we calculated the 5-yr survival rate for these two groups and found that they were not significantly different (Figure 2). These findings strongly suggest that EM treatment improved the survival of patients with DPB and did not further change the overall disease management. Results of the Cox proportional hazards regression analysis also revealed that EM treatment improved survival rate of patients with DPB and that the effect was accentuated with aging (Table 2). Survival rate of aging patients with DPB was poor in Group a, in contrast to better survival rates even in the elderly patients in Group c (Figure 3). These findings make us speculate that EM therapy may largely contribute to the improvement of survival rates in elderly patients with DPB.
In Group c, eight of the 87 patients died; three patients in the EM-administered group (n 5 63) and five patients in the EMnon-administered group (n 5 24) died. Among all these eight deceased patients, three who were older than 50 yr of age died because of malignant tumors: gastric cancer (n 5 2), brain tumor (n 5 1). Three patients dying from DPB in Group c (a 44yr-old woman and two men, 36 and 49 yr of age) were all suffering from advanced DPB with diffuse bronchiectasis (DBE) and severe respiratory failure (Table 3).
DISCUSSION We have reviewed retrospectively the efficacy of treatment with 400 to 600 mg of EM on the survival of patients suffering from DPB. DPB is a common clinicopathologic entity in Japan that was first described by Homma and Yamanaka (1). We reported that EM treatment improved clinical symptoms and clinical chemistry factors in patients with DPB, which included chronic cough, sputum and dyspnea, elevated titer scores of cold hemagglutinin, increase of CD4/CD8 ratio, pul-
Figure 3. Comparison of survival curves of each decade in Group a (left panel) and in Group c (right panel). Survival rate became poor according to aging in Group a as opposed to the similar rate of survival in Group c. These results imply that low-dose EM therapy produced improved survival in elder patients with DPB. Each number indicates each decade.
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monary function tests, and shadows in chest radiographs (3). Recently, for radiographic evaluation searching centrilobular granular shadows, chest CT scanning was used (16). Improvement in DPB symptoms has also been reported by other investigators (17–19). Our results showed that patients in Group c who received EM therapy (n 5 63) showed a higher survival rate than did patients with DPB in Group a and b. Some patients in Groups a and b also received EM therapy after 1984. This might be the reason why the slope of the survival curves in Groups a and b decreased gradually (Figure 1). Improved survival is remarkable, especially in older patients (Figure 3). In order to further estimate the contribution of EM, we carried out two additional comparative analysis. One was the simultaneous comparison between EM-treated patients (n 5 63) and non-EM-treated patients (n 5 24) in Group c. EMtreated patients showed significantly higher survival rates than did non-EM-treated groups (p 5 0.0056) (Figure 2). In contrast, the comparison of two non-EM-treated groups (Group c, n 5 24, and Group a, n 5 192, before 1985) was not significantly different (p 5 0.2475) (Figure 2). These results suggest a possible contribution of EM therapy in the improvement of patients with DPB regardless of using changes in medical practices over the years in Japan. This is supported by the Cox-proportional hazards regression analysis of survival factors, which showed 0.152 hazard rate for survival of EMtreated patients compared with non-EM-treated patients (Table 2). But, the precise mechanism of EM in improvement of survival in patients with DPB remains unknown. Recently, new actions of 14-membered ring macrolides, including EM, clarithromycin (CAM), and roxithromycin (RXM) have been reported, indicating anti-inflammatory actions (20) and inhibition of bronchial secretion (9, 10). Anti-inflammatory mechanisms of EM indicate the downregulation of proinflammatory cytokines: TNFa, IL-8, IL-4, and IL-1 (11), chemotaxis of polymorphonuclear cells (PMN) (8, 12), and lymphocytes and histiocytes (13, 14). These reports suggested that the action of EM would not be antimicrobial but rather anti-inflammatory. In patients with DPB low-dose EM therapy revealed a decrease in the incidence of respiratory failure in patients whose sputum showed the existence of Hemophilus influenzae or Pseudomonas aeruginosa (3, 5, 6). These data support the proposal that the efficacy of EM in patients with DPB may also be anti-inflammatory, but not bacteriocidal. On the other hand, our results should be interpreted carefully. Although EM usage was associated with a better survival rate in patients with DPB, those not receiving EM died mostly because of other reasons (only two caused by DPB in Group c). In Group c, deaths caused by DPB were 1/63 in EM-treated and 2/24 in non-EM-treated patients, which were not significantly different. These results may suggest that EM treatment contributed to the improved rates of survival of patients with DPB and a decrease in not only the risk of death but also that of other diseases (Table 3). Three patients with advanced stages of DPB such as DBE had a poor prognosis despite the low dose EM therapy they received. These find-
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