Clinical course of one asthma patient (64 years old, female), who had an increased proportion of neutrophils in bronchoalveolar lavage (BAL) fluid, was observed in relation to the proportion of BAL cells and ventilatory function. The patient had large asthma attacks two times during her clinical course for 15 months observed. 1. An
increased proportion of BAL neutrophils and suppression of ventilatory function were found after her first large asthma attacks. The increased proportion of BAL neutrophils
continued for more than 5 months. A reduction in the proportion of BAL neutrophils was found 3 months after her second large asthma attack, accompanied by improvement of clinical symptoms and ventilatory function. The numbers of total cells and neutrophils in BAL fluid were also reduced. Transient increase in number of BAL lymphocytes was found 13 months after the first large attack when the number of BAL neutrophils was markedly decreased. The number of BAL eosinophils did not change during her clinical course.経過中に気管支肺胞洗浄(BAL)液中に一過性の好中球増多が観察されたアトピー型喘息症例について,若干の臨床的観察を加えた｡症例は,64才の女性で,臨床症状,および血清IgE高値,ハウスダストに対するIgE抗体陽性などから,アトピー型喘息と診断された｡なお,経過観察し得た15ヵ月の間に2回の大発作が観察された｡1.第1回の大発作後,BAL液中好中球増多と換気機能の低下が観察された｡そして,このBAL液中好中球頻度は明らかな改善が見られた｡BAL液中の総細胞数および好中球の絶対数も徐々に減少傾向を示し,好中球頻度と同様,第2回目の大発作3ヵ月後には著明な減少が観察された｡同時にこの時期には,BAL液中リンパ球の増加も見られた｡しかし,BAL液中好酸球数は15ヵ月の経過観察中ほとんど変化は見られなかった

Hiramatsu, Junichi

Kajimoto, Kazuhiro

Kawaraya, Masashi

Kimura, Ikuro

Kitani, Hikaru

Mifune, Takashi

Mitsunobu, Fumihiro

Nakagiri, Yoshiyasu

Sugimoto, Keisuke

Tada, Shinya

Tanizaki, Yoshiro

Yokota, Satoshi

Okayama University Digital Information Repository

気管支肺胞洗浄液中に一過性の好中球増多をきたしたアトピー型喘息

Okayama University Scientific Achievement Repository

52 Bronchoalveolar neutrophilia in asthmaTransient bronchoalveolar neutrophilia ma patient with atopic asthmaYoshiro Tanizaki, Hikaru Kitani, Takashi MifuneFumihiro Mitsunobu, Kazuhiro Kajimoto, KeisukeSugimoto, Satoshi Yokota, Junichi Hiramatsu,Masashi Kawaraya, Yoshiyasu Nakagiri I), ShinyaTada2) and Ikuro Kimura2)Division of Medicine, 1) Gynecology, Misasa MedicalBranch, 2)Second Department of Medicine, OkayamaUniversity Medical schoolAbstract: Clinical course of one asthma patient (64 years old, female), who had anincreased proportion of neutrophi Is in bronchoalveolar lavage (BAL) fluid, was observedin relation to the proportion of BAL cells and ventilatory function. The patient hadlarge asthma attacks two times during her clinical course for 15 months observed. 1. Anincreased proportion of BAL neutrophi Is and suppression of venti latory function werefound after her first large asthma attacks. The increased proportion of BAL neutrophi Iscontinued for more than 5 months. A reduction in the proportion of BAL neutrophilswas found 3 months after her second large asthma attack, accompanied by improvementof clinical symptoms and ventilatory function. The numbers of total cells andneutrophils in BAL fluid were also reduced. Transient increase in number of BALlymphocytes was found 13 months after the first large attack when the number of BALneutrophils was markedly decreased. The number of BAL eosinophils did not changeduring her cl inical course.Key words: Bronchial asthma, transient BAL neutrophilia, ventilatory functionIntroductionRecently, airway inflammation m patientswith bronchial asthma has been noted as amajor mechanism causing asthma attacks. Inthe inflammatory process, lymphocytes,neutrophils, eoosinophils, and basophils,which migrate from the bloodstream, playtheir important roles in the mechanism ofonset of the disease (1-7). Of these cells,lymphocytes, eosinophils and basophils havebeen clarified to participate in pathophy-siological changes in the airways of asthma,since these cells are activated in allergicBronchoalveolar neutrophilia in asthma 53Table 1. Allergo-immunological examinationsreaction sites and release lymphokines orchemical mediators (8 -13). However, it ISstill uncear whether neutrophils in the air-ways participate in the mechanism of onsetof asthma. Our previous studies have shownthat an increased proportion of neutrophils inbronchoalveolar lavage (BAL) fluid wassometimes found in patients with asthma,particularly in those with steroid-dependentintractable aasthma (SDIA) (14,15). Ourstudies have also demonstrated that an In-creased proportion of BAL neutrophils inasthma patients is closely related to long-term glucocorticoid therapy (15).In the present study, clinical characteristicsof a patient who showed transient increase inthe proportin of BAL neutrophils were exam-ined in relation to clinical symptoms, theproportion of BAL cells, and ventilatoryfunction.ImmunoglobulinsIgE 504 IU!m4IgG 1388mg/dtIgA 381mg/dtIgM 67mg/dtRAST scoreHouse dust 1 2+Mitel 3+Candida 0+Skin testHouse dust +Japanese Cedar +Silk +CandidaLympocyte subsetsCD4 52%CD8 20%CD4/8ratio 2.6Blood cellsRBC 398XW/cmmHb 12.2g/dtWBC 10600/cmmSt 29%Sg 53%Lym 13%Mo 5%Eo 0%Ba 0%Case reportThe patient was 64 years old, female, withatopic asthma. She had had asthma attacks,but not large, for 2 years before she wasadmitted to Katsuyama hospital (which waslocated at north side of Okayama prefecture)on April 7, 1988, because of her first largeattack. On her admission to the hospital,she had various examinations for her asthma.The results of allergo-immunological exami-nations were shown in Table 1 : she wasevaluated as atopic asthma, because the levelof serum IgE was high and IgE antibodies tohouse dust mite was found in her serum.However, peripheral eosinophilia was notfound on her admission.When she was admitted to the hospital, shehad large asthma attack in which breathsound were markedly decreased and moistrales (bubbling) were heard over both lowerlung fields on auscultation. She complainedof marked dyspnea and recurrent cough allday long, particularly at night. Clinical andlaboratory findings on her admission, fever,yellowish sputum, increased number of pe-ripheral neutropphils and a high value ofCRP (13.5 rug / d£), showed that she hadrespiratory infection. Thus, she was treatedwith antibiotics, expectorants, broncho-dilators and glucocorticoids. Her symptomsand laboratory findings were markedly im-proved 2 months after her admission and shewas discharged on July 15, 1988. After thenshe had slight respiratory infection, whichinduced her second large asthma attack. Thenshe was admitted to our hospital, as shownin Fig. 1.54 Bronchoalveolar neutrophilia in asthmahad never asthma attacks after her secondlarge asthma attack. The fourth BAL exami-nation was carried out 4 months after hersecond large asthma attack (one month afterthe third BAL examination). The proportionof each BAL cell in this examination was58.0% macrophages, 36.2% lymphocytes, 5.6% neutrophils and 0.2% eosinophils Theseresults show that reduction in the proportionof BAL neutrophils, which was accompaniedby increase in the proportion of BAL lympho-cytes, was found during her clinical course(Fig. 2).i • iMOO5 8 1I!II!JI!II!J_ 1110IIIIIIl!ll!lVentlllltoryfunctionSAL exam.WBC/omm 1_.4"". I!GOCRP("""") 13.1 1.0 0 •~gAIoy·I'''' ..~) i ,Fever +--CoughA.tttm. etwdc: .a. i • iii..... i4 5 8 7 10 11 12 1 2 31988 1989Fig. 1. Clinical course of the patient withatopic asthma (64 years old, fe-male). The patient had large asthmaattacks two times during her clinicalcourse for 15 months observed. BALTotal cell number in BAL fluid was alsoreduced as the proportion of BAL neutrophilsdecreased, as shown in Table 2. The numberof BAL lymphocytes was increased at thethird BAL examination. The number of BALneutrophils was reduced at the second BAL6 7 8 9 10 11 12 1 2 3 4 5 61988 1989Fig. 2. Changes in the proportion of eachBAL cell of the patient (64 years old,female) during her clinical course for15 months observed. An increasedproportion of BAL neutrophils wasobserved at the first and second BALexamination. After then the propor-tion of BAL neutrophils decreasedand the proportion of BAL lympho-cytes tended to increase. (c==J)macrophages, (~) lymphocytes,(.) neutrophils, (IDBID eosinophils.examinations and ventilatory func-tion tests were performed four times,as shown by the number in parenthe-SIS.SAL examinationBronchoalveolar lavage (BAL) was per-formed four times during all her clinicalcourse after her first large asthma attack, bya previously reported method (14 -16). Theproportion of BAL cells 2 months after herfirst large asthma attack was as follows :33.0% macophages, 10.4% lymphocytes, 56.2% neutrophils, 0.2% eosinophils, and 0.2%basophils. The results showed marked increasein the proportion of BAL neutrophils. Thesecond BAL examination was performed 7months after her first large asthma attack.Although she was free of attacks at thattime, the second BAL examination resultsstill showed marked increase in the propor-tion of BAL neutrophils. In the third BALexamination, which was performed 3 monthsafter her second large asthma attack, theproportion of BAL neutrophils was markedlydecreased : 45.2% macrophages, 48.6% lym-phocytes, 5.6% neutrophils, and 0.6% eosin-ophils. Her clinical course was good and she100908070.J!J 60"8 50ci 40Cll<ft. 302010o~VI--Bronchoalveolar neutrophilia III asthma 55examination, and markedly reduced at thethird and fourth BAL examination. Thenumber of BAL eosinophils did not changeduring all her clinical course (Table 2).Table 2. Total cell number and number ofeach cell in bronchoalveolar lavage(BAL) fluidTotal cell number BAL celIe (xl0 4/ml)BAr;exa.lnation (x106 , (xl04 /ml) Mac Lp Neut E08/ sec in V25 in the third ventilatory functiontests which were performed 3 months afterher second large asthma attack. The valuesof each ventilatory parameter were clearlyimproved 4 months after her second largeasthma attack: 2.42 £ (+5.2%, compared tothe value in the first ventilatory functiontests) in FVC, 1.73 £ (+35.2%) in FEV1.0,4.65 £ / sec (+36.4 %) in PEFR, 1.56 £ / sec(+92.6%) in Vso and 0.83 £ /sec (+219.2%)in V2S, as shown in Fig. 3.1. 'June 20,1988 18.8 31.3 10.3 3.3 17.6 0.12. Nove_ber 2.5 • 5.014, 1988 18.6 25.8 12.8 2.0 10.9 0.1---..........3. AprilS, 2.0 4.0 ;ll1989 12.3 12.4 5.6 6.0 0.7 0.14. June 6, ~===-~ :II1989 9.9 7,4 4.2 2.7 0.4 O. I ~1.5 3.0 fO..::IMac, _crophages; Lynt, lYMphocytes; "eut r neutrophile: ~ 1.0 2.0 ~.IVBos, eoeinophl1s. 0 /it 0.5 D 1.0 t0-.,..--w e.-n IfVentilatory functionVentilatory function tests, using a Box8piror 81-8 (Chest Co.), were carried out 4times when she was free of attacks. In thefirst ventilatory function tests, which wereperformed 2 months after her first largeasthma attack, the values of each ventilatoryparameter were 2.30 £ in FVC, 1.28 £ inFEV1.0, 3.41£ / sec in PEFR, 0.81£ / sec inV50 and 0.26 £ /sec in V25' respectively, dem-onstrating marked decrease in the values of. .FEV1.0, V50 and V25. The results in the secondventilatory function tests (performed 7months after her first large asthma attack)were similar to those in the first ventilatoryfunction tests. These obstructive ventilatorydysfunction gradually improved as the pro-portion of BAL neutrophils decreased. Thevalues of each ventilatory paramenter were2.33£ in FVC, 1.58 £ / sec in FEV1.0, 3.92.e/ sec in PEFR, 1.07 £ / sec in V50 and 0.35 £8 7 8 8 10 11 12 1 2 3 4 5 81888 1989Fig. 3. Improvement of ventilatory functionof the patient (64 years old, female)during her clinical course for 15months observed. Percent improve-ment of each ventilatory parametercompared to the initial value afterher first large asthma attack was+5.2% in FVC (.-e), +35.2% inFEV 1.0 (0-0), + 36.4% in PEFR(/:,-/:,) , +92.6% in V50 (0-0) and+219.2% in V25 (x-x)DiscussionRecently, airway inflammation has beenconsidered to be important in the mechanismof asthma (1-7). It is necessary for inflam-matory cells, which are observed in localallergic reaction sites, to be activated to playtheir roles. Of these inflammatory cells such56 Bronchoalveolar neutrophilia in asthmaas lymphocytes, eosinophils and basophils, allcells except neutrophils have been shown tobe activated at local allergic reaction sitesand release lymphokines or chemical media-tors (8 -13). However, there are no evidencesabout activation of neutrophils in the air-ways (11,17). Furthermore, although thereare a few reports about BAL neutrophilia inbronchial asthma (18), clinical significance ofBAL neutrophils is unclear. Thus, it IS un-clear whether neutrophils participate in themechanism of onset of asthma.Table 3 shows 7 patients with bronchialasthma who had an increased proportion ofBAL neutrophils (more than 50%). Case 1 inTable 3 is the patient whose clinical coursewas discussed in this study. The othersix patients with bronchial asthma hadglucocorticoid therapy for a long time. Theywere evaluated as having steroid-dependentTable 3. Asthma patients with BAL neutro-phils of more than 50%IgE GlucocorticoidsPatientsAge Sex (Iu/lt) RAST Dose Duration(HD) (mgjday) (years)1oK·S. 64 F 5042+2.S·B. 56 F 105 7.5 43.T·H. 45 M 233 12.5+K 154.M·T. 71 M 108 ..... 7.5 6S.H·O. 56 M 1820 2+ 10.0 56.K·T. 52 M 65 20.0 127.T·F. 37 M 201 - 10.0+K 7K: deposit type of glucocorticoids(Kenacort A®)intractable asthma (SDlA), and their symp-toms have not been improved. They alwaysrequire glucocorticoids for their asthmaattacks. In none of them, the proportion ofBAL neutrophils has not shown a tendency todecrease despite long-term treatment includ-ing glucocorticoids. In contrast, in case 1, theproportion of BAL neutrophils was reducedduring her clinical course. Her symptoms andventilatory function were clearly improvedand she did not require glucocorticoids afterher second large asthma attack. Of the 7patients with an increased proportion of BALneutrophils, as shown in Table 3, case 1 hadnot SDlA and showed transient BALneutrophilia.Our previous studies have demonstratedthat bronchial asthma is classified into threeclinical types : Ia. simple bronchoconstrictiontype, lb. bronchoconstriction + hypersecretiontype, and n. bronchiolar obstruction type (19,20). Of these clinical asthma types, type lbasthma is characterized by increased propor-tion of BAL eosinophils, and type n asthmais characterized by increased proportion ofBAL neutrophils (14, 21-23). These findingssuggest that an increased number of BALneutrophils is closely related to clinical fea-ture of type n asthma. Our previous studieshave also shown that an incrrease in theproportion of BAL neutrophils is related tolong-term oral glucocorticoid therapy (15). Inthese steroid-dependent intractable asthma,persistent BAL neutrophilia may be inducedby long-time glucocorticoid regimen.It was unclear in this study whether thereare some differences between mechanismscausing transient and persistent BALneutrophilia. Further studies are necessary toclarify mechanisms inducing BAL neutro-philia.Bronchoalveolar neutrophilia in asthma 57References1. deMonchy, SGR, Kauffman, HF, VengeP, Koefer K, Sluiter HJ, Jansen HM,deVries K: Bronchoalveolar eosinophiliaduring allergen-induced late asthmaticreaction. Am Rev Respir Dis 131 : 373-376, 1985.2. Kirby JG, Hargreave FE, Gleich GJ,O'Byrne PM : Bronchoalveolar cell profilesof asthmatic and nonasthmatic subjects.Am Rev Respir Dis 136 : 379-383, 1987.3. Gonzalez MC, Diaz P, Galleguillos FR,Ancic P, Cromwell 0, Kay AB : Allergen-induced recruitment of bronchoalveolarhelper (OKT4) and suppressor (OKT8) Tcells in asthma. Am Rev Respir Dis 136 :600-604, 1985.4. Wardlaw AJ, Dunnette, S., Gleich GJ,Collins JV, Kay AB : Eosinophils and mastcells in bronchoalveolar lavage in subjectswith mild asthma. Am Rev Respir Dis 177:6269, 1988.5. Pauwels R : The relationship betweenairway inflammation and bronchialhyperresponsiveness. Clin Exp Allergy 19:395-398, 1989.6. Kelly CA, Stenton SC, Ward G, HendrickDJ, Walters EH : Lymphocyte subsets inbronchoalveolar lavage fluid obtained fromstable asthmatics, and their correlationswith bronchial responsiveness. Clin ExpAllergy 19: 169-175,1989.7. Wardlaw AJ, Kay AB : The role ofeosisnophil in the pathogenesis of asthma.Allergy 42 : 321-335, 1987.8. Tanizaki Y, Sudo M, Kitani H, Araki H,Oki K, Tsuji M, Takahashi K, Kimura 1, :Eosinophilic leucocytes and arylsulfataseactivity in bronchoalveolar lavage fluid ofpatients with bronchial asthma. Acta MedOkayama 42: 227-230, 1986.9. Chan-Yeung M, Chan H, Tes KS, SalariH, Lam S : Histamine and leukotrienesrelease in bronchoalveolar fluid duringplicatic acid-induced bronchoconstriction. JAllergy Clin Immunol 84 : 762-768, 1989.10. Wardlaw AJ, Hay H, Cromwell 0, CollinsJV, Kay AB : Leukotrienes, LTC. and LTB.,III bronchoalveolar lavage III bronchialasthma and other respiratory diseases. JAllergy Clin Immunol 84 : 19-26, 1989.11. Bousquet J, Chanez P, Lacoste JY,Enander I, Venge P, Peterson C, AhlstedtS, Michel F-B, Godard P : Indirect evidenceof bronchial inflammation assessed bytitration of inflammatory mediators inBAL fluid of patients with asthma. JAllergy Clin Immunol 88 : 649-660, 1991.12. Wenzel SE, Wescott JY, Larsen GL:Bronchoalveolar lavage fluid mediatorlevels 5 minutes after allergen challenge inatopic subjects with asthma: Relationshipto the development of late asthmatic re-sponses. J Allergy Clin lmmunol 87 : 540-548, 1991.13. Walker C, Kaegi MK, Braun P, Blaser K: Activated T cells and eosinophilia inbronchoalveolar lavages from subjects withasthma correated with disease severity. JAllergy Clin Immunol 88 : 935-942, 1992.14. Tanizaki Y, kitani H, Okazaki M, MifuneT, Ochi K, Harada H : Cellular compositionof fluid in the airways of patients withhouse dust sensitive asthma, classified byclinical symptoms. Internal Medicine 31 :333-338, 1992.15. Tanizaki Y, Kitani H, Okazaki M,Mifune T, Mitsunobu F, Kimura I : Effectsof long-term glucocorticoid therapy onbronchoalveolar cells in adult patients withbronchial asthma. J Asthma 30 : 309 - 318,1993.58 Bronchoalveolar neutrophilia in asthma16. Tanizaki Y, Kitani Y, Okazaki M,Mifune T, Mitsunobu F, Honke N, KimuraI : Pathophysiological changes in the air-ways of asthma patients with aging. Jpn JAllergol 41 : 1380-1387, 1992.17. Griffin E, Hakansson L, Formgrem H,Jorgensen K, Peterson C, Venge P : Bloodeosinophil number and activity in relationto lung function in patients with asthmaand with eosinophilia. J Allergy ClinImmunol. 87: 548-557, 1991.18. Fabbri LM, Baschetto P, Zocca E, MilaniG, Piviotto F, Piebani M, Burlina A,Licata B, Mapp C: Bronchoalveolarneutrophilia during late asthmatic rea-ctions induced by toluene di-isocyanate. AmRev respir Dis 136 : 36-42, 1987.19. Tanizaki Y, Komagoe H, Sudo M,Morinaga H, Shiota Y, Tada S, TakahashiK, Kimura I : Classification of asthmabased on clinical symptoms : asthma typein relation to patient age and age at onsetof disease. Acta Med Okayama 38 : 471 -476, 1984.20. Tanizaki Y, Kitani H, Okazaki M,Mifune T, Mitsunobu F, Tanimitsu M,Honke N, Kusaura Y, Ochi K, Harada H,Soda R, Takahashi K, Kimura I : Asthmaclassification by a score calculated fromclinical findings and examinations in sub-jects sensitive to inhalant allergens. ActaMed. Okayama 46: 295-301, 1992.21. Tanizaki Y, Kitani H, Okazaki M,Mifune T, Mitsunobu F, Kotoh N, Tada S,Takahashi K, Kimura I : Asthma Classifica-tion by score calculated from clinical find-ings and examinations. Jpn J Allergol 41 :489-196, 1992.22. Tanizaki Y, Kitani H, Okazaki M,Mifune T, Mitsunobu F, Honke N, KusauraY, Kimura I : Asthma classification bypathophysiology and IgE-mediated allergicreaction: New concepts for classificationof asthma. Acta Med Okayama 46 : 381-387, 1992.23. Tanizaki Y, Kitani H, Okazaki M,Mifune T, Mitsunobu F, Okano T, HonkeN, Kimura I : A new modified classificationof bronchial asthma by clinical symptoms.Clinical features of each asthma type.Internal Medicine in press.Bronchoalveolarneutrophiliainasthma気管支肺胞洗浄液中に一過性の好中球増多をきたしたアトピー聖職息谷崎勝朗,貴谷 光,御船尚志,光延文裕,梶本和宏,杉本啓介,横田 聡,平松順一,瓦屋正志,中桐善康1),多田慎也2),木村郁郎2)岡山大学医学部附属病院三朝分院内科,l)同産婦人料 , 2)医学部第2内科経過中に気管支肺胞洗浄 (BAL)液中に一過性の好中球増多が観察されたアトピー型喋息症例について,若干の臨床的観察を加えた｡症例は,64才の女性で,臨床症状,および血清IgE高値,ハウスダストに対するIgE抗体陽性などから,ア59トピー型鴨息と診断された｡なお,経過観察し得た15カ月の間に2回の大発作が観察された｡1.第1回の大発作後,BAL液中好中球増多と換気機能の低下が観察された｡そして,このBAL液中好中球頻度は明らかな改善が見られた｡BAL液中の総細胞数および好中球の絶対数も徐々に減少傾向を示し,好中球頻度と同様,第2回目の大発作3カ月後には著明な減少が観察された｡同時にこの時期には,BAL液中リンパ球の増加も見られた｡しかし,BAL液中好酸球数は15カ月の経過観察中ほとんど変化は見られなかった｡キーワード:気管支喋息,一過性BAL液中好中球増多,換気機能

気管支肺胞洗浄液中に一過性の好中球増多をきたしたアトピー型喘息

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