@@Special Article Diffuse Panbronchiolitis Hiomi Homma

Diffuse Panbronchiolitis (DPB), as distinguished of the airway system. from so called GOPD (bronchial , chronic and chronic pulmonary emphysema), 2. Epidemiology brochiectasis or alveolitis, has been noted since The nationwide study revealed that cases with 1966 in Japan '. Through clinical, radiologic, DPBare distributed from the northernmost to the physiologic and pathologic analysis based on sourthernmost districts of Japan. accumulated data by Hommaand Yamanaka1^, 1) Age of onset: The age ofonsetisfromthe a nationwide survey with the cooperation of teens to the nineth decade in both sexes and the 30 universities, national and municipal institutions age of initial examination increases gradually after throughout the country was organized in 1980 middle age. to investigate the and the morbidity of 2) Sex ratio: Male to female ratioisabout 1.4 the disease under the aid of the Ministry of Health to 1, but considering the rate of those examined, and Welfare of Japan6*. The results obtained by there seems no essential difference due to sex. this project team during 1980 to 1982 disclosed 3) Smoking: No close relationship with the the features of clinical and pathological findings, habit of smoking is noted. the gist of which was already reported7'19. As 4) Complication: 84.8% of the cases have or stated later, DPB is associated with HLA-Bw54 once had chronic parasinusitis. It must be em- antigen which is found specifically in Japanese phasized that this is one of the characteristics of and Chinese and not in Caucasians, suggesting that DPB. Incidence of chronic parasinusitis in patients' DPBmay be an ethnically specific disease. families is 20.0%. 5) Diagnosis prior to admission: Chronic 1. The description of the disease bronchitis (30.4%), (26.2%), and DPB is a chronic situated mainly Bronchial asthma (24.2%) are most frequently in the respiratory , present diffusely suspected or diagnosed. in both lungs and causing severe respiratory dis- order. The lesions are composed of respiratory 2. Pathology and peribronchiolitis. The features of pathological findings are sum- The name, diffuse panbronchiolitis, was given marized as follows (Figure 1 and 2): to this disease by Yamanaka, head of the Depart- 1) The lesions diffusely distribute in bilateral ment of Pathology, St. Luke's International lungs and are exclusively located in the respiratory Hospital. The word "Diffuse" means, of course, bronchioles. diffuse scattering of extensive lesions in both 2) Peripheral alveoli distal to the lesion are lungs, the word "pan-" is used in the same sense intact. as pan- of panvasculitis, as the wall of the respira- 3) Thickening of the walls of respiratory tory bronchiole is thin and the lesion extends bronchioles with infiltration of and easily to the whole layer. This bronchiole means a plasma cells. The narrowings of the bronchioles respiratory bronchiole, and not a non-respiratory are caused by round cell infiltration or edematous *Professor, University of the Air, Chiba. **Presented at the 83rd Annual Scientific Session of the Japanese Society of Internal Medicine, held on April 5, 1986, in Tokyo.

@@JapJ Med Vol 25, No 3 (August 1986) @@329 @@Homma

@@Fig.1. Macroscopic appearance of cut surface.

@@Fig. 3. Chest X-ray findings.

@@ I66.O±54.6 (N=32)

104.4±16.4 (N=32) 71.7±16.1 (N=41) @@Fig.2. Microscopic appearance. 54.3±14.3 i (N=41)

granulation tissues. * 4) Cicatricial narrowing and constriction of

112.7±2I.9 118.7±24.1(N=23) (N=23) 64.3±9.2 the respiratory bronchioles with proliferation of (N=40) %VC FEV,.0% %TLC %RV %DLco %DLco Pao2 corrected granuiomatous tissues and accumulation of foamy /VA cells within the wall and neighboring area in later @@ Fig. 4. Characteristic of the pulmonary function stage. disorder. 5) Secondary ectasis of the proximal terminal semination difficult to be seen. Bronchogram and nonrespiratory (airway) bronchioles. frequently shows slight secondary dilatation of the 6. Clinical pictures terminal bronchioles which indicate the obstruc- 1) Initial symptoms and the mode of onset: tion of the respiratory bronchioles. Initial symptomsare , cough Schematic classification of X-ray findings is and small amountof tenaceous , frequently presented8^ in Figure 3. CT image is useful to accompanied by wheezing. Early occurrence of clarify the location of fine nodular lesions . Selec- is not unusual. Mode of onset is tive alveolobronchography shows how to occur usually insidious. Sooner or later bacterial pul- the secondary brochiolectasis following the monary infection comes up accompanying in- obstruction of the primary lesions1 . creased amount of yellowish sputum. 3) Pulmonary function: 2) X-ray and CT image and Bronchography: Mixed ventilatory impairment consisted of Miliary or fine nodular dissemination in both slight restrictive and marked obstructive disturb- lung fields is characteristic picture, often accom- ance, early hypoxemia later accompanied by panied by hyperinflation which makes the dis- hypercapnea and cor pulmonale. The Figure 4

@@330 @@JapJ Med Vol 25, No 3 (August 1986) @@Diffuse Panbronchiolitis

shows the characteristic of the pulmonary fuuc- @@Table 1. Antigen frequencies for the HLA-Bw54 in tion disorder11\ The alveoli are in the state of various ethnic groups. @ @ N o. B w 5 4 (+ ) % N o. B w 5 4(+ )% overdistention, but the alveolar walls are not B lac k E ng lis h 2 88 (1 A fric an 143 0 F ren c h 4 37 0 destroyed, kept normal, and pulmonary com- 184 0 G erm an .104 0 Cap e Co lo ur ed fi 0 H un g aria n 105 0 pliance and diffusion capacity remain within O th er B lac k 32 0 Ita lia n 5 22 0 J ew ish A sh ke na z; 127 0 .8 normal range. As the disease progresses, alveolar M o ng o loid J ewi sh No n-A sh ken az i 62 0 C hin e se 48 10. 4 S ca nd in av ia n 2 64 0 hypoventilation increases and ap- 950 14. t S co t 25 0 No. Americ an In dian 27 0 So . Af rica n 13 0 So. Ameri can In dian 42 0 S pa n ish 2 22 0 pears. In the course of manyyears, it enters the M e x ica n 84 0 S w is s 87 0 O the r 26 0 Y ug o sla v 76 0 states of , right heart O the r C a ue a 169 0 C a u ca s ian burden and cor pulmonale. Further, as to ventila- 8 67 0 A s ia n In d ian 40 0 tion, slight restrictive disturbance is noted, as the A us tra lian 159 0 A u s trian 56 0 fibrous tissue proliferates from the respiratory C a na d ia n 100 0 C z ec h 140 0 bronchioles to the proximal part. Namely, from D ut ch 96 0 the aspect of ventilation it is characterized by a H is toc om pa tib ility T e s ting , 198( combination of strong obstructive and slight 16.8) compared with controls consisted of 184 restrictive disturbances. Our cinebronchographical healthy persons (ll.4%). According to histocom- study disclosed the collapse of segmental bronchi patibility testing 198018), HLA-Bw54 was found during forced expiration . specifically in Japanese and Chinese and not in 4) Immunological aspect: Caucasians (Table 1). Therefore, the above men- Titers of cold hemagglutinin are generally tioned facts suggest that DPBmay be a ethnically markedly elevated in patients with DPB. The specific disease and that there is a gene controlling amount of IgA is also increased in most DPB cases13"15). susceptibility linked with a Japanese-specific HLA antigen. Analysis of T subsets by OKT series monoclonal disclosed a significant 8. Diagnosis elevation of the OKT4/OKT8ratio compared with From the above mentioned morphological healthy controls due to increase in OKT4+ and changes, X-ray image and pathophysiology, the decrease in OKT8+1 . These are considered as following diagnosis guide was made. The follow- characteristic features in immunological aspects ing principal clinical findings shall be filled in all of DPB. items. Histologic proof when obtained shall 5) Sputum bacteriology: establish the diagnosis. Chronic bronchitis, bron- Hemophilus influenzae (44%) and Pneumococci chial asthma and chronic emphysema should be (12%) are most often identified in the initial stage, differentiated carefully. later followed by Pseudomonas superinfection. 1) Clinical symptoms: cough, sputum, short- Pseudomonas infection, when occurs, is stub- ness of breath on exertion. born and incurable, fluctuates but progresses 2) Physical signs on the chest: moist (usually gradually and finally a fatal outcome ensues due crepitant) and dry relaes. 3) Chest X-ray findings: diffuse scattered to pulmonary insufficiency. granular shadows in bilateral pulmonary areas, 7. Etiology The etiology of DPB is unkonwn. However, pulmonary4) Pulmonaryhyperinflation.function tests and blood gas there have been increasing reports on DPB cases findings: Among4 items, diminution in FEVi>0% observed in same family16\ Chronic parasinusitis (below 70%), diminution of vital capacity (below is well knownabout its high incidence in members 8.0% of predicted value), increase in residual air of one family. Recent studies17* on HLAantigens above 150% of predicted value) and hypoxemia in DPB patients disclosed that HLA-Bw54 was (below 80 mmHg), 3 or more must be met. found most frequently in DPB cases (68.4%, 5) Complication: chronic parasinusitis. X2=36.2, corrected P=2.04xl0~9, relative risk 6) Immunological tests: elevated CHA, in-

@@JapJ Med Vol 25, No 3 (August 1986) @@331 @@Homma

@@ 1976 77 78 79 2 3 4 5 6 7 8 '82 9 10 II 12 1

6700 6300 2500 8200 9400 9700 8200 7300 7000 20 28 12 5 31 17 21 20 I

45 60 50 58 48 58 52 56 100

@@Fig. 5. A clinical course of one of typical cases. Case K.M. 55 y.o. male creased IgA, elevation of OKT4/OKT8ratio (when progressive pulmonaryinsufficiency accelerated by possible). Pseudomonas pulmonary infection. 7) HLA-Bw54antigen (when possible). A clinical course of one of typical cases is What must be noted here is, commonto any shown in Figure 5. Prognosis after the Pseudo- other study on diseases, that cases collected first monas aeruginosa superinfection is very poor, have all undisputable symptoms and findings, namely, 5 year-survival rate is only 8%. Even with as the disease becomes more widely recognized, laborious treatment, combining various anti- early or slight cases can be diagnosed with scanty bioticus, including inhalation, i.v. injection etc, symptoms or findings and better prognosis are detected and the amountof sputummay obtained, which are general principles. decrease or disappear temporarily, but will appear with aggravated symptoms with gradually increas- 9. Prognosis ing difficulty in the control of hypoxemia and Missing of early diagnosis and early treatment hypercapnia and finally a fatal outcome results with corticosteroids maybe followed by relentless with respiratory insufficiency. Table 2. Therapeutic plan 10. Treatment First stage (spastic contraction of airway + hypoxemia) Theauther considers the therapeutic measures 1. Steroid to be in 3 stages (Table 2)19). 2. O2 administration In this first stage, the sputum culture is nega- Second stage (spastic contraction of airway + pulmo- tive. Main symptoms are short breath on exertion nary infection + hypoxemia) and slight cough. If any, the sputum is scanty 1. Steroid (when needed) 2. and mucoserous. Crepitant rales over both lungs, 3. Bronchodilator + expectorant and often wheezing are heard. Blood gas analysis 4. O2 (whenneeded) shows hypoxemia. 5. As prophylaxis against infection by P. aeruginosa, The treatment for this stage is steroid ad- injections of OEP*, PT**, ET***, EXT**** ministration and oxygen inhalation. Steroid Third stage (spastic contraction of airway + pulmonary administration is aimed at radical cure of this infection by P. aeruginosa + hypoxemia + hypercapnia + disease, starting with 30 mg daily calculated as right heart failure) prednisolone. The dose is reduced by 10 mg 1. Steroid 2. Antibiotic after two weeks, and ends with 5 mg a weeks. Decrease in dosage depends on the disappearance 3. Bronchodilator + expectorant 4. O2 in low concentration of hypoxemia, i.e. normalization of PaC>2, and 5. Measures for right heart failure improvement in the shortness of breath on exer- 6. Treatment against infection by P. aeruginosa: tion. Usually great improvement is observed injections of OEP*, PT**, ET***, EXT**** *Original endotoxin protein **Protease toxoid within one week of treatment. The second treat- ***Elastase toxoid ****Exotoxin ment, oxygen administration, is a symptomatic

@@332 @@JapJ Med Vol 25, No 3 (August 1986) @@Diffuse Panbronchiolitis

one for hypoxemia and short wind, a flow of dilators and expectorants may be combined as 1-2 / per minute is usually adequate. Further, in the treatment in the second stage, but spastic if active parasinusitis is present, it should be contraction of the airway is severe and intractable treated. in this stage, and the use of steroids cannot be In the advanced second stage, pulmonary avoided. High concentration of Oxygen adminis- infection appears with Hemophilus influenzae tration for hypoxemia may increase carbonic and sometimes Pneumococcus, observed clinically acid gas in this stage, and the concentration should by the appearance of colored and increased be adjusted constantly, depending on the blood amount of sputum in addition to wheezing and gas analysis values. hypoxemia. The X-ray image helps us to observe The above is an outline of the treatment, but the therapeutic course. Wheezing is not parox- the prognosis becomes poor with the superifection ysmal as in bronchial asthma, and does not usually by P. aeruginosa. So the vaccine therapy is being appear at midnight or early morning, but charac- studied as one of the measures for it. One starts teristically lasts all through the morning, improv- with an injection of minute quantities of original ing in the afternoon. At this time the treatment is endotoxin protein, protease toxoide, elastase first aimed at the aforesaid bacterial infection of toxide and exotoxin, and increasing the dose the lung, giving antibiotic and expectorant. Com- gradually to produce antibodies in the body of bining an expectorant and a bronchodilator for the host. This method has two objectives. The inhalation is also effective. For spastic contraction first one is to use it in a patient of the aforesaid of the airway the same bronchodilator is used second stage, i.e. without pulmonary infection as for bronchial asthma. If pulmonary infection by P. aeruginosa in order to prevent P. aeruginosa is controlled well, wheezing disappears and, there- superinfection. The second is to use it in a patient fore, steroid is not always needed. Oxygen, of in the third stage, i.e. with complication of pul- course, is given, when needed as a symptomatic monary infection by P. aeruginosa, to colonize therapy. P. aeruginosa and to improve symptoms and In the third stage, stubborn and incurable findings. At present, the effect is expected to infection of the lung by P. aeruginosa appears improve the patient's prognosis2. predominant, respiratory insufficiency progresses gradually. The treatment at this time consists of ll. Conclusion the measures for P. aeruginosa infection, spastic Our present knowledge and treatment of contraction of the airway and respiratory insuffi- diffuse panbronchiolitis, which is considered an ciency. Morphological changes include destruc- incurable disease of unknown cause have been tion of the respiratory bronchiolar wall, obstruc- reported. The best and only method we have tion of the lumen due to cicatricial tissues with today to rescue the patients from this disease is deposition of carbon particles and subsequent "early diagnosis and early treatment". Infection dilatation of bronchioles proximal to this obstruc- by P. aeruginosa is one of the turning-points to tions. The sputum becomes strongly purulent, a poor prognosis, and conversely as a turning- increasing to as much as 100 - 200 ml, sometimes point to a radical cure. And I'd like to emphasize 300 ml a day. Hypoxemia becomes severe, and that interrogation as well as percussion and aus- carbon dioxide increases, too. Edema appears, cultation findings play the chief roles as ever. if right cardiac insufficiency develops. There has been an increasing number of papers To treat P. aeruginosa infection, there has been reporting cases with bronchobronchiolitis ob- literans (BBO). We classify them into two cate- an increasing numberof effective avail- able recently and the treatment has becomemuch gories, one of unknown etiology and the other easier than before, but even if sputum and P. accompanying rheumatoid arthritis. Both of them aeruginosa decrease or disappear temporarily, have obliteration in small bronchi and non-respira- aggravation often reappears, with long-term tory bronchioles of 1 - 3 mmin diameter and quite recurrence of progression and regression. Bronco- different pathology from DPB.

@@JapJ Med Vol 25,No 3 (August 1986) @@333 @@Homma

REFERENCES 10) Maeno H, et al: Selective Alveolo-bronchography in DPB. Bronchology 5: 53, 1983. 1) Yamanaka A, et al: The problems in chronic bron- ll) Araki T, et al: Pulmonary function disorders in DPB chitis and bronchial asthma from pathological view- and . Nippon Kyobu Rinsho points. Nippon Rinsho 24: 851, 1966. 42: 1043, 1983. 2) Yamanaka A, et al: The problems in chronic obstruc- 12) Tanimoto H: Cinebronchography in DPB. Resp. and tive pulmonary disease: special reference to diffuse Circ. 29: 487, 1981. panbronchioliotis. Intern Med 23: 442, 1969. 13) Hirata K, et al: An immunological study in DPB. Nippon Kyobu Rinsho 38: 90, 1979. 3) HommaDis 13: H:383,Diffuse1975. panbronchiolitis. Jap J Thorac 14) Sugiyama Y, et al: Levels of cold hemagglutinin 4) Homma H: Diffuse panbronchiolitis (diffuse re- in patients with DPB and various respiratory dis- spiratory bronchiolitis). Jap J Int Med 65: 644, 1976. eases. Respiration 3: 694, 1984. 15) Yoshimura K, et al: Immunological studies on DPB. 5) Tanimoto H: Clinical picture of diffuse panbron- JapJ Thorac Dis 22: 992, 1984. chiolitis. Nippon Kyobu Rinsho 29: 430, 1970. 16) Suzuki M, et al: Familial cases in DPB.JapJ Thorac 6) Izumi T: Annual report on the study of diffuse Dis 19: 645, 1981. disseminated lung disease (Director H. Hommaby 17) Suzaki H, et al: HLA antigen in Sinobronchial Grant-in-Aid from the Ministry of Health and syndrome. J Jap Bronchoesophagol Soc 34: 270 Welfare) P. 3, 1983. 1983. 7) HommaH, et al: Diffuse Panbronchiolitis. A Disease 18) Terasaki PI: Histocompatibility testing 1980. The of the Transitional Zone of the Lung. Chest 83: 63, 1983. ULCA Tissue Typing Lab P. 959, 1980. 19) HommaH: Diffuse panbronchiolitis. Asian Med J 8) Tanimoto H and Nakata K: Present status of the 25: 665, 1982. study on DPB. Igaku-no-Ayumi 121: 257, 1982. 9) Honda K and Nishimura K: CT image and X-ray 20) Yoshimura K, et al: Use of multicomponent vaccine in patients with intractable findings. Medicina 21: 2624, 1984. lower infection associated with DPB.Jap J Thorac Dis to be published.

@@334 @@JapJ Med Vol 25, No 3 (August 1986)