Mucociliary Clearance and Transport in Bronchiectasis: Global and Regional Assessment

Toyoharu Isawa, Takeo Teshima, Tomio Hirano, Yoshiki Anazawa, Makoto Miki, Kiyoshi Konno, and Masakichi Motomiya

Department ofMedicine, The Research Institutefor Chest Diseases and Cancer, Tohoku University, Seiryoumachi, Sendai, Japan

which enables the actual visualization of the dynamic Globalandregionalmucociliarydearanceandtransportin mucociliary transport in the lungs as it is (10,11,12). A the lungs was studied in 20 patients with bronchiectasis quantitative analysis of time-activity curves was made by radioaerosolinhalationlung cine-scintigraphyand the to obtain the lung retention ratio, airway deposition quantitative analysis following inhalation of ultrasonically ratio, airway retention ratio, airway clearance effi generated @Tc-taggedhuman serum albumin aerosol ciency, and alveolar deposition ratio (11,12), and the (mass mediandiameter;1.93 @mwith geometrics.d. of time-activity curves were qualitatively evaluated. 1.52).InbrOnchIeCtatiClungregions,depositionofinhaled aerosolwas diminishedor inhomogeneous.Transportof inhaled radioactivity from the bronchiectatic regions was MATERIALS AND METHODS deranged in 95% of the patients (19/20). The following Twenty hospitalized patients with bronchiectasis, 18 to 81 abnormalmucoustransportpatternswere regionallyob yr of age, were studied. Their mean age was 48 yr. Nine were served; stasis in 12 ofthe 20 patients(1 2/20), regurgitation maleand 11werefemale.Theirchiefcomplaintson admission or reversed transport in 14/20, straying in 8/20, spiral or were hemoptysis in 10, increased sputum production in 9, zigzagtransportin1/20,and/orvariouscombinationsof and chest pain in 1. Bronchopulmonary neoplasms, tubercu these four abnormal transport patterns. When coughs losis,aspergillosis,cardiovasculardiseases,pulmonary vascu occurred,regurgitationandstraybecamemoremarkedin lar diseases such as thromboembolism, hemosiderosis or the bronchiectatic regions. These regional abnormalities in blood-clottingdisorders were ruled out. The diagnosis of mucoaliarytransportseem to be responsiblefor the de bronchiectasis was established by bronchography either during velopmentof infectionsand hemoptysisin the bronchiec the current hospitalization or prior to admission. Three had tatic regions. bronchiectasis only in the right, eight only in the left, and nine J NuciMed 1990;31:543-548 in both the rightand the leftlungs.Nineteenofthe 20 patients showed involvement of the lower lobe bronchi. Seventeen showed bronchiectasis dominantly of cylindrical type, two, varicose,and one, saccular(13). Past historyindicatedpneu monia or bronchial asthma in infancy in 11, sinusitis in 2, t is known that in bronchiectatic regions, both yen and pulmonarytuberculosis,lung abscessor increasedcoughs tilation and perfusion are diminished (1,2,3). Restric of adult onset without known causes in 7. Sputum culture tive or obstructive disturbance or both is documented on admission indicated hemophilus influenzae in 12, pseudo as lung functional derangement in patients with bron monas aeruginosain 4, alpha streptococci in 3 and peptococ chiectasis (4,5,6). Much is not known yet, however, as cus in 1. Vital capacity (VC) averaged74% of the predicted, to how mucociliary clearance or mucous transport and in 10 ofthe 20 patients it was less than 70%(14). Forced mechanisms actually functions in the bronchiectatic expiratory volume in 1 sec divided by forced vital capacity (FEV1%) averaged 68%, and in 10 of the 20 patients it was regions of the lungs (7,8,9). No one has reported find <70%.Lungfunctiontest,chestx-rays,blood-gasanalysis, ings in mucous transport or mucociliary clearance in and perfusionlungimagingweredone in all patientswithin 3 the bronchiectatic regions from the standpoint of visual days of aerosol inhalation studies. All 20 patients were on observation of the function. We have studied mucoci mucolytic agents such as bromhexine and 10 on beta-stimu liary clearance function in 20 patients with bronchiec lators. Four were ex-smokers who had not smoked in over 5 tasis by radioaerosol inhalation lung cine-scintigraphy, yr, and there was only one current smoker of 60 pack-years. Whenthe patientswereafebrileand stablewithlesscoughs ReceivedAug. 24. 1989; revision accepted Nov. 10, 1989. and sputum production,they werestudiedwith radioaerosol For reprints contact: Toyoharu Isawa, MD,Departmentof Medicine, The ResearchInstitute for Chest Diseasesand Cancer, Tohoku Lk*VerSIty, inhalation lung imaging as follows; ultrasonically generated 4-1Sdiryoumachi,Aoba-ku,Sendai980,Japan. technetium-99m- (99mTc).@albuminaerosol (mass median di

Mucociliary Clearance and Transport in Bronchiectasis •Isawa et al 543 ameter 1.93 micron with geometric s.d. of 1.52 (15)) was airways were obtained by subtracting from the corrected ong inhaled with the patient in the sitting position with normal inal regional time-activity curves the corresponding regional tidal breathing through the mouth with the nose clipped and radioactivity, equivalent to the one that deposited in the distal immediately after completion ofaerosol inhalation the mouth nonciliated airways, including the alveolar space that we called wasrinsedand radioactivityof the thorax wasmeasuredfrom “alveolardepositionratio―(11,12,16).Calculationof quanti the anteriorby a gamma camerawith the patientin the supine tative parameters such as lung retention ratio, airway deposi position. Approximately 3 mCi (1 11 MBq) deposited in the tion ratio, airwayretention ratio, airwayclearance efficiency, thorax immediately following inhalation. Radioactivity was alveolar deposition ratio (11,12), and disappearance rate of continuously recorded to a computer in a frame mode of 10 radioactivity from the ciliated airways (1 7) were made for the sec each for over 90 to 120 mm. Following the measurement entire right and the entire left lungs separately or the right and of radioactivity in the supine position as described above, left lungs in combination. Data were compared with corre anterior,posteriorand right and left lateralviews of radioae sponding values obtained from 36 normal subjects(1 7). Corn rosol inhalation lung images were taken with the patient in parison of the corrected time-activity curves between bron the sitting position. chiectaticand nonbronchiectaticROIswasmade. Radioaerosol inhalation lung cine-scintigraphy was corn Unpaired and paired Student t-tests were used for statistical piled from the 540 or 720 10-sec frames and the distribution analysis. ofinhaled radioaerosoland the dynamic mucociliarytransport patterns were visually inspected in the bronchiectatic regions RESULTS as well as globally in the whole lungs including the trachea (10,11,12). Mucous transport patterns such as stasis or, in Cine-ScintigraphicObservation other words, temporarybut frequentstopping and startingof The deposition of inhaled aerosol in the bronchiec radioactivity in the airways in the course ofmucous transport, tatic lung regions were decreased or nearly absent in 18 regurgitation or reversal of mucous transport, straying or and inhomogeneous in 2 ofthe 20 patients. All but one migration of radioactivity from one region to another of the showed abnormal mucous transport patterns in the same lung or from one lung to the opposite lung, and spiral bronchiectatic regions such as stasis (12/20), regurgita or zigzag motions or winding paths of radioactive clusters tion (14/20), stray (8/20), and spiral or zigzag motion instead of the usual axial course were recordedin the bron (1/20), while in the normal lung regions no particular chiectatic regions (12). Regionsof interest (ROIs)includingthe entire right lung, abnormality in mucous transport was visually noted. the entire left lung, the bronchiectatic and the nonbronchiec Time-Activity Curves tatic lung regions were demarcated over the right and left Although time-activity curves from any normal lung lungs with a light pen and respective regional time-activity curveswereobtainedfromthoseROIs.Bronchiectaticregions regions smoothly declined with time as shown in Figure were demarcated manually with the aid of bronchography, 1, those from the bronchiectatic lung regions showed aerosol inhalation, and perfusion lung imaging. The latter irregularly rising or declining curves (Fig. 2A). Figure usually showed a decreased or absent perfusion in the bron 2B-C indicated actual sequential aerosol inhalation chiectatic regions. After physical half-life correction of the lung images ofa patient with right lower lobe bronchiec time-activity curves, net time-activity curves from the ciliated tasis, who showed time-activity curves as shown in

e@ i@ ID 81@1 T@O4J l.tlIV O@E P@ p@ @@l@1P'GTIlE (cu.HT ‘F@@f) a 21 64@ @:1S:Ø@ @1e @:1S:@@ 9489 @5:1S:@5 6@9 Ø:1S:@ 2? 54@ @:1Ø:@

FIGURE1 Curves A, B, and C indicate time-activ ity curvesfrom the entireright lung,the leftlung,andthelowerhalfof theright lung,respectively,ofa 26-yr-oldnormal nonsmoker(No.81858801).Abscissa: framenumber(each10 see),ordinate: counts per frame. Each superimposed straight line indicatesa corresponding exponential function fitted to each time activity curve. In normal lung, time-ac tivity curves from any lung regions I J@t show more or less similar steadily de 0 1@ 4@ !@ @ae dining tendency. (F@

544 The Journal of Nuclear Medicine •Vol. 31 •No. 5 •May 1990 @ 1@ @: .@•

ID 61@1 ‘r@oaiIJ'IIV Q.P.E P'C. ca@a@r@ @‘@L.lPGTIlE (co.NT ‘F@@) a — 16736 @:jØ: 21 — 57@ @:1O:@Ø

FIGURE2 (A)The upper(a) andlower(b)curves indicate time-activity curves from the ciliatedairwaysin the uppertwo-thirds @ C - I I I I I I I I I I and the lower one-third of the right 7@ A (F@tE) lung, respectively, of an 81-yr-old male patient (No. 6150001), a current smokerwith chronicobstructiveair @ @-.. .. ., ways diseaseand bronchiectasisof the rightlower-lobebronchi.He developed recurrentpneumoniasin the right lower lobeprobablydueto strayingofmucus therewith coughfrom the airwaysin the upper lung regions and in addition to generalized impaired mucociliary clearance. Both curves initially show nearlyhorizontallinesand werethen interruptedby a suddendecreaseand an increase in radioactivity, respec tively, indicatinga cough (arrow). Fol. lowing the cough, the upper curve (A) showsirregularbutgenerallydeclining tendency,whilethe lowercurve(b),a risingtendency.The former indicatesa slow mucous transport characterized bystasisandregurgitation,whilethe latter indicates straying of mucus into .!. ‘@ - thebronchiectaticrightbase.Thispa tienthappenedto bestudied10 times over a 4-yr periodand always showed a similarpattern. (B) Static aerosol in halation lung image (anterior) of the samepatientbeforecough between approximate frame numbers 300 and 330. Notethat only little radioactivityis presentinthenghtlowerlungfield(big arrow).Radioactivityintheleftbaseis alsodiminished(smallarrow).(C)Static aerosolinhalationlung image(anterior) after cough between approximate framenumbers450and480.Notethat radioactivityintherightbaseincreased after cough, indicatingthat mucus strayedfrom the upper airways to the lower brOnChieCtatiClung region (big arrow).A moreor less similarphenom enon was seen in the left base where mildbronchiectasiswas also present C (smallarrow).

Mucociliary Clearance and Transport in Bronchiectasis •Isawa et al 545 (%) difference in lung retention ratios as compared with 100 normals, but airway retention ratios and airway depo 90 sition ratios showed significantly higher values than the 80 95% confidence intervals ofthe normals (p < 0.05 each)

70 (Fig. 3A—B).Airway clearance efficiency was signifi cantly smaller than normals. The average disappearance 60 rate of radioactivity from the ciliated airways in the 50 bronchiectatic patients was below normal only in the 40 first 30 mm following inhalation of aerosol and there 30 was no significant difference thereafter as compared with the 95% confidence interval ofthe normals. 20 10 DISCUSSION 0 0 10 20 30 40 50 60 70 80 90 100 110 120 24 The term bronchiectasis describes bronchial or bron A MIN HR chiolar distortion and scarring leading to abnormal Cs) I 00 dilatation, peribronchial alveolar tissue damage, oblit

90 eration ofthe distal bronchi or bronchioles and obstruc tive endoartentis (18,19,20). These anatomical findings 80 may explain regionally abnormal ventilation (1) and 70 perfusion (2,3) in bronchiectasis. In addition to these 60 anatomical changes, a possible hypoventilation in the

50 bronchiectatic regions may contribute to the decrease in regional perfusion due to hypoxic vasoconstriction 40 (21,22). The deposition of inhaled radioaerosol was 30 actually greatly diminished in the regions of bronchiec 20 tasis (7,8,9), indicating regional hypoventilation (1). 10 Bronchiectasis can be either “wet―or “dry―according

0 to the presence or absence of concomitant infection 0 10 20 30 40 50 60 70 80 90 100 110 120 B 2: (18,23), and various ultrastructural anomalies of cilia have been found and thought to be of pathogenic FIGURE3 (A)Airwayretentionratiosintherightandleftlungscombined significance (23,24,25). A relatively inefficient cough in in the nine subjects who had bronchiectasisin both lungs. ridding bronchiectatic segments of their secretions has When multiplestudieswere done in the samesubject,the been observed by a combined cinefluorographic-man data obtainedat the firststudywas used.Airwayretention ometric study, because the central airway collapse oc ratiosinthe ninepatientswithbronchiectasisintherightand leftlungswere significantlyhigherthanthe 95% confidence curs while the bronchiectatic segments remain dilated intervalof airway retentionratios in the right and left lungsof (27). Disturbance in mucociliary clearance is naturally 28 normalsubjects (17). (B)Airway retentionratios in the left anticipated under these circumstances but little is de lungsintheeightpatientswhosebronchiectasiswas located scribed regarding what is actually taking place in the onlyinthe leftlung.Airwayretentionratiosinthe leftlungin the eight patientswere significantlyhigherthan the 95% bronchiectatic regions in terms of mucous transport. confidenceintervalof airwayretentionratiosin theleftlungs The most striking abnormality in the bronchiectatic of 28 normalsubjects(17). regions was the behavior of radioactivity or in other word mucous transport as observed by radioaerosol inhalation lung cine-scintigraphy. This display modality Figure 2A (#6150001). Time-activity curves did tell was developed to see the actual mucociliary transport whether mucous transport was normal or not, but they inside the thorax in vivo (10,11,12). By the cine-scin themselves did not specify what kind of abnormal mu tigraphic technique, we have found that there are basi cous transport patterns were responsible for their irreg cally four abnormal transport patterns on the large ular shapes. airways in obstructive airways disease; namely, stasis, QuantitativeParameters regurgitation, stray, and spiral or zigzag motion, The alveolar deposition ratio was significantly whereas in normal nonsmoking subjects mucous trans smaller in the patients with bronchiectasis (33.7% ± port was always cephalad or axial in direction and 2.3%;mean±s.e.c.)ascomparedwithnormals(39.2% nearly constant in velocity (11,12). These abnormalities ± 1.8%) by unpaired Student t-test (p < 0.05) (17). In were seen less frequently in interstitial lung diseases patients whose bronchiectasis was present only in the (28) or in pulmonary vascular diseases (29). These left lung and/or in patients who had bronchiectasis visual regional abnormalities on cine-scintigraphy were both in the right and left lungs, there was no significant more or less substantiated by the shapes of the time

546 The Journalof NuclearMedicine•Vol. 31 •No. 5 •May1990 activity curves from the ciliated airways in the corre REFERENCES sponding lung regions as shown in Figure 2B—C.In the present analysis, normal lung regions showed steadily 1. Bass H, Henderson JAM, Heckscher T, Oriol A, Anthonisen declining time activity curves (Fig. 1), but those from NR. Regional structure and function in bronchiectasis. A the bronchiectatic regions showed irregular or abruptly correlative study using bronchography and ‘33Xe.Am Rev rising or declining curves or nearly horizontal curves RespirDis 1968;97:598—609. 2. IsawaT. Studies on the distribution of the pulmonary blood interrupted by a declining tendency. These abnormal flow in the lungs by radioisotope scanning. V. Chest diseases time-activity curves were confirmed by cine-scinti otherthanpulmonarytuberculosis,bronchogeniccarcinoma graphic observation to correspond to regurgitation, and pulmonary sarcoidosis. Sd Rep Res Inst Tohoku Univ straying, stasis, or zigzag motion of the mucous trans C(Med)1966;13:168—185. port (12). By looking at only the shapes of time-activity 3. Windheim Ky. Perfusionsszintigraphischeuntersuchungen der lunge bei bronchiekiasen. Pneumonologie 1970; 143:193— curves, however, no differentiation was possible be 196. tween the four abnormal transport patterns recogniz 4. Cherniack NS, Vosti KL, Saxton GA, Lepper MH, Dowling able by aerosol inhalation lung cine-scintigraphy. HF. Pulmonary function tests in fifty patients with bronchiec It has been found that coughs are not only inefficient tasis. J Lab C/in Med 1959; 53:693—707. in getting rid of secretions as suggested by Fraser and 5. Cherniack NS, Carton RW. Factors associated with respira toryinsufficiencyin bronchiectasis.AmJMed 1966;41:562— associates (27), but that they are also liable to induce 571. regurgitation and/or straying of mucus into the bron 6. Pande JN, Jam BP, Gupta RG, Guleria JS. Pulmonary yen chiectatic regions as shown in Figure 2A—C.All the tilation and gas exchange in bronchiectasis. Thorax 1971; patients studied were on mucolytic agents and half of 26:727—733. the patients were given bronchodilators. Although a 7. Lourenco RV, Loddenkemper R, Carton RW. Patterns of distribution and clearance of aerosols in patients with bron mucolytic agent was found to facilitate mucociiary chiectasis.Am Rev Respir Dis 1972; 106:857—866. clearance (30), beta-stimulators do not seem to do so 8. Svartengren M, Mossberg B, Philipson K, Camner P. Muco (31,32,33). If pathogen containing mucus reaches the ciliary clearance in relation to clinical features in patients bronchiectatic regions as in cases of straying, regurgi with bronchiectasis.Eur J Respir Dis 1986;68:267—278. tation and stasis, or ifmucus produced in the bronchiec 9. Currie DC, Pavia D, Agnew JE, et al. Impaired tracheobron chial clearance in bronchiectasis. Thorax 1987;42:126—130. tatic regions cannot be transported as efficiently as from 10. Isawa T, Teshima T, Hirano T, Ebina A, Konno K. Radioae the normal regions, there would be an ample time for rosol inhalation lung cine-scintigraphy.A preliminary report. pathogens to multiply in the bronchiectatic lung regions TohokufExpMed 1981;134:245—255. to induce regional inflammatory changes there. Acutely 11. Isawa T, Teshima T, Hirano T, Ebina A, Konno K. Muco inflamed mucosa on the basis of well developed bron ciliary clearance mechanism in smoking and nonsmoking normal subjects.J NuciMed 1984;25:352—9. chial circulation (34) may tend to bleed. Presence of 12. Isawa T, Teshima T, Hirano T, Ebina A, Motomiya M, bronchial arterial hypervasculanty and bronchopul KonnoK. Lungclearancemechanismsin obstructiveairways monary anastomosis may even accelerate hemoptysis disease.J NuciMed 1984;25:447—454. (35). 13. Reid LM. Reduction in bronchial subdivision in bronchiec Whether such abnormal transport patterns have pri tasis. Thorax 1950;5:233—247. 14. Baldwin WD, Cournand A, Richard DW Jr. Pulmonary marily helped develop the bronchiectasis or whether insufficiency. I. Physiological classification, clinical methods they are the results of bronchiectasis itself remains an of analysis, standard values in normal subjects. Medicine unsolved question. The present study confirms the well 1948; 27:243—278. known fact that bronchiectatic patients are easily in 15. Anazawa Y, Isawa T, Teshima T, Hirano T, Miki M, Konno fected, and their bleeding (19) seems to be explained K. Measurement of size of aerosols produced by different aerosol generators and effect of physical factors on aerosol by abnormalities in mucociliary clearance and/or mu size. JJpn Thorac Soc 1988; 26:863—867. cous transport in the bronchiectatic regions. Bronchial 16. IsawaT, Teshima T, Hirano T, Ebina A, Konno K. Estima hygiene, a trial to keep the bronchiectatic regions “dry― tion ofalveolar deposition of inhaled radioaerosol. Tohoku J and an unhesitating use of antimicrobial agents at the ExpMed 1985;145:259—267. first sign of infection and on a long-term basis (36) 17. Isawa T, Teshima T, Hirano T, et al. Normal values for quantitative parameters for evaluation of mucociliary clear would be the best policy in taking care of patients with anceinlungs.TohokuJ Exp Med 1989;158:119—131. bronchiectasis. 18. Reid LM. The pathology of obstructive and inflammatory airway diseases. Eur J Respir Dis 1986; 69(suppl l47):26—37. 19. Luce JM. Bronchiectasis. In: Murray JF, Nadel JA, eds. Textbookofrespiratorymedicine,FirstEdition.Philadelphia: ACKNOWLEDGMENTS WB SaundersCo; 1988:1107—1125. 20. Spencer H. Diseases of bronchial tree. In: Spencer H, ed. Pathologyofthe lung,Third ed. Oxford:PergamonPressLtd; The authors thank Dr. Hiroshi Ogawa of the Daiichi Ra 1977:115—149. dioisotope Laboratories, Ltd. for his generous supply of “Al 21. IsawaT, ShiraishiK, YasudaT, et al. Effect of oxygen bumin kits―used in this study and Ms. Seiko Kondo for her concentration in inspired gas upon pulmonary arterial blood clerical assistance in preparing the manuscript. flow.Am RevRespirDis1967;96:1199—1208

MucociliaryClearanceandTransportinBronchiectasis•Isawaet al 547 22. lsawa T, Teshima T, Hirano T, Shiraishi K, Matsuda T, 30. IsawaT, Teshima T, Hirano T, Ebina A, Konno K. Evalua Konno K. Regulationof regionalperfusiondistributionin tion of mucociliary clearance in the lungs by radioaerosol the lungs.Effectof regionaloxygenconcentration.Am Rev inhalation lung cine-scintigraphy—effect of bromhexine. J RespirDis1978;118:55—63. Jpn ThoracSoc 1984;22:899—909. 23. Cole PJ. Inflammation: a two-edged sword—themodel of 31. Isawa T, Teshima T, Hirano T, Ebina A, Konno K. Effect of bronchiectasis.Eur J Respir Dis 1986;69(suppl l47):6—lS. oral salbutamol on mucociliaryclearance mechanisms in the 24. CorbeelL, CornillieF, LauwerynsJ, BoelM, Van Den Berghe lungs.TohokufExpMed 1986;150:51—61. G. Ultrastructuralabnormalitiesofbronchialciliain children 32. Isawa T, Teshima T, Hirano T, Ebina A, Anazawa Y, Konno withrecurrentairwayinfectionsandbronchiectasis.ArchDis K. Effectofbronchodilationon the depositionand clearance Child 1981; 56:929—933. of radioaerosolin bronchialasthmain remission.J NuclMed 25. Waite DA, WakefieldSI, Mackay JB, Ross IT. Mucociliary 1987;28:1901—1906. transportand ultrastructuralabnormalitiesin Polynesian 33. Isawa T, Teshima T, Hirano T, et al. Does a beta 2-stimulator bronchiectasis.Chest 1981; 80:896—898. really facilitate mucociliary transport in the human lungs in 26. Fox B, BullTB, Makey AR, Rawbone R. The significanceof vivo?A studywith procaterol.Am Rev RespirDis 1990:in ultrastructural abnormalities of human cilia. Chest 1981; press. 80(suppl):796—799. 34. Liebow AA, Hales MR. Lindskog GE. Enlargement of the 27. Fraser RG, Macklem PT, Brown WG. Airway dynamics in bronchial arteries and their anastomoses with the pulmonary bronchiectasis.Am JRoenzgenol1965;93:821—835. arteries in bronchiectasis.Am J Pathol 1949;25:211—220. 28. Isawa T, Teshima T, Hirano T, Ebina A, Konno K. Muco 35. Ishihara T, Inoue H, Kobayashi K, et al. Selective bronchial ciliary clearance mechanism in interstitial lung disease. To arteriographyand hemoptysisin nonmalignantlungdisease. hokufExpMed 1986;148:169—178. Chest1974;66:633—638. 29. Isawa T, Teshima T, Hirano T, Ebina A, Anazawa Y, Konno 36. Stockley RA, Hill SL, Burnett D. Nebulized amoxicilhinin K. Mucociliary clearance in pulmonary vascular disease. Ann chronicpurulentbronchiectasis.C/inTherapeut1985;7:593— NuciMed 1988;2:41—47. 599.

548 The Journal of Nuclear Medicine •Vol. 31 •No. 5 •May 1990