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prevalence of airway responsiveness. This of course is a theoretical possibility. There are no data and no discussion in the paper by Pattemore and coworkers (8) to assess the relevance to their population. In our unpublished but abstracted population of 500 university students in their 20s (9), despite a cumulative prevalence of asthma in excess of 10%, we did not encounter a single instance of current use of an agent that would either preempt or reverse airway hyperresponsiveness. The occasional situation where masking drugs were used (chiefly inhaled beta, agonists, or ingested H, blockers) were dealt with by withholding the agent for the appropriate length oftime prior to the histamine challenge. Based on our observations, it seems unlikely that drug-induced changes would have a large effect on the prevalence or magnitude of airway hyperresponsiveness in a random population such as was described in Pattemore's article. D. W. COCKCROFT, M.D.

Royal University Hospital Division oj Respiratory Medicine Saskatoon, Saskatchewan, Canada I. Reed CEo Basic mechanisms of asthma: role of inflammation. Chest 1988; 94:175-7. 2. Kraan J, KoeterGH, Mark Th W v d, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Immunol 1985; 76:628-36. 3. Kerribijn KF, van Essen-Zandvliet EEM, Neijens HJ. Effects of longterm treatment with inhaledcorticosteroidsand beta-agonists on the bronchialresponsiveness in childrenwithasthma. J Allergy Clin Immunol1987; 79:653-9. 4. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336:1391-6. 5. Lowhagen 0, Rak S. Modification of bronchial hyperreactivity after treatment with sodium cromoglycate during pollen season. J Allergy Clin Immunol 1985; 75:460-7. 6. Woolcock AJ, Yan K, SalomeCM. Effectof therapyon bronchialhyperresponsiveness in the long-termmanagementof asthma. Clin Allergy1988; 18:165-76. 7. Hargreave FE, Dolovich J, Newhouse MT, et al. The assessment and treatment of asthma: a conference report [Rostrum]. J Allergy Clin Immunol 1990; 85:1098-111. 8. PattemorePK, Asher MI, Harrison AC, MitchellEA, Rea HH, Stewart AW. The interrelationship among bronchial hyperresponsiveness, the diagnosisof asthma,and asthmasymptoms. Am Rev Respir Dis1990; 142: 549-54. 9. Cockcroft OW, Berscheid BA, Murdock KY, Gore BP. Sensitivity and specificity of histaminePC2 0 measurements in a random population. J Allergy Clin Immunol 1992; (In Press).

gest that there is further clarification required before such an interpretation can be arrived at. Clearance of radiolabeled material from the lung is a complex process that is dependent on vascular clearance from peripheral lung parenchyma along with movement up the TB tree of secretions contained in the bronchial lumen. Obviously, changes in the character of the mucus secretion and inflammatory exudate impose varying loads on the system. Our experience (2) is with this latter function, and we have reported a dramatic capacity of the intrabronchial clearance system to adapt to added load in a different disease (bronchiectasis) but one in which mucosal inflammation plays a significant role. Our observations that tracheal mucus velocity can be more than doubled when the cilia are not genetically abnormal, in the face of increased load, implies that measurement of this variable specifically, in addition to the studies reported in the paper by Messina and coworkers (1) would strengthen their position or suggest still other pathophysiologic explanations for the phenomenon of decreased total clearance during acute asthmatic attacks that they have reported. Disturbances during and after acute asthmatic exacerbations were also reported in nasal mucociIiary transport; however, in the nose clearance improved significantly during the attack and was markedly and progressively impaired during the follow-up period of 2 wk (3). There is much to be learned about mucociIiary clearance both concerning each segment of the system and the coordination and control of the total function both in normal persons and in those patients suffering from obvious clearance problems according to clinical assessment. The information reported by the previously mentioned authors is interesting and important and needs to be followed up with more specific studies of each limb of the system to the extent possible at the present time.

L. BAUM, M.D. Medical Director, Israel Lung Association, Te! Aviv GERALD

Tznx ZWAS, M.D. Department oj Nuclear Medicine Chaim Sheba Medical Center, Tel Hashomer 100

KATZ, M.D.

Pulmonary Division, Chaim Sheba Medical Center, Tel Hashomer YEHUDA

Ram, M.D.

Department oj Otorhinolaryngology, Chaim Sheba Medical Center, 'Fel Hashomer CHANGES IN MUCOCILIARY CLEARANCE DURING ACUTE EXACERBATIONS OF ASTHMA

To the Editor: The paper by Drs. Messina, O'Riordan, and Smaldone (1)on changes in mucociliary clearance during acute exacerbations of asthma that appeared in the REVIEW reported on changes in mucociIiary clearance (MC) in acute asthma using a technique that measures decay of radioactivity in the lung and interpreted the difference they noted in this decay between periods of attack and periods of improvement as indicating changes in mucociliary clearance. We believe that most persons dealing with various types of cases of acute asthma intuitively conclude that there is a serious problem in clearance of secretions, thus the current authors' conclusion seems supported by clinical logic. There is a problem, however, in our mind with the interpretation that the differences demonstrated by the technique reported suggest that mucociliary clearance (primarily implying a mucosal effect in which inflammation plays an important part) is the specific function impaired in asthmatic attacks resulting in retention of secretions and all ofthe complications that result from this pathologic event. The experience of our group would sug-

I. Messina MS, O'Riordan TO, Smaldone GC. Changes in mucociliary clearanceduring acute exacerbations of asthma. Am Rev RespirDis 1991; 143:993-7. 2. Baum GI, ZwasT, Katz I, Roth J. Mucociliaryclearancefrom central airways in patients withexcessive sputum production withand without primary ciliary dyskinesia. Chest 1990; 98:608-12. 3. KurashimaK, Ogawa H, Ohka T,Fujimura M, Matsuda T. Mucociliary transport disturbance after an asthmatic attack. Arerugi 1990; 39:631-5.

From the Authors: We thank Dr. Baum and colleagues for their comments. Our study was an attempt to document and quantify mucociliary function during exacerbations of asthma. Although our findings are consistent with autopsy data and clinical suspicion, we do not know the pathophysiologic basis for them, and we fully agree with Baum and coworkers that further studies are needed to explain our findings. We suggest in our paper that these mechanisms are likely to be multifactorial and interrelated. We agree that the production of excessive mucus should not directly lead to excessive retention of inhaled

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particles. Baum and colleagues have found increased tracheal mucous velocity, in patients with cystic fibrosis, in the presence of airway inflammation. This is not inconsistent with our finding that the convalescent mucociliary clearance rates of the patients in our study are similar to normal control subjects at this laboratory who had a similar distribution of aerosol (1). In other words, the convalescent asthmatics have intact mucociliary clearance, even though mild asthmatics are likely to have residual significant mucosal inflammation (2). What is the pathophysiologic basis for the difference between our acute and convalescent results? That we do not know the answer to this question is reflective of the fact that we do not know preciselythe causes of severeexacerbations of asthma. The relationship between inflammation and mucociliary clearance has not been determined. It is possible that low levelsof inflammation may stimulate clearance of secretions while more severe inflammation may disrupt mucociliary structures. However, this is merely speculation and further studies need to be done to see if there is any substance to it, or whether other factors may be more important. ThOMAS G. O'RIORDAN M.B., M.R.C.P.I. MATTHEW S. MESSINA, M.D. GERALD C. SMALDONE, M.D., PH.D.

Pulmonary Disease/Critical Care Division Department of Medicine, State University of New York at Stony Brook Stony Brook, NY 1. Ilowite JS, Smaldone GC, Perry RJ, et al. Relationship between tracheobronchial particle clearance rates and sites of initial deposition in man. Arch Environ Health 1989; 44:267-73. 2. Djukanovic R, Roche WR, Wilson J, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57.

CELLULAR AND MOLECULAR BASIS OF THE ASBESTOS-RELATED DISEASES

To the Editor: Rom and colleagues (1) are to be commended for an excellent reviewof the cellular mechanisms of asbestosis. Nonetheless, the section concerning asbestosis and the pathogenesis of lung cancer seems to us to be poorly supported. The authors state that "asbestos-related bronchogenic cancer occurs on a background of alveolitis" and that "it is probably not possible to separate the process of carcinogenesis of the lung from inflammation and fibrosis in the asbestos worker with> 20 yr of exposure." We disagree. The authors cite four human studies, discussed here, as evidence for their conclusions: (1) In the first report, Doll (2) investigated the causal relationship of asbestosis and lung cancer. Cases wereselected by the coroner when he questioned asbestosis as a contributory cause of death; i.e., the cases were selected because they had asbestosis and thus cannot answer the question of whether asbestos causes lung cancer without asbestosis. Doll also noted that previous studies had shown a higher incidence of lung cancer in subjects with asbestosis than in those with silicosis, an observation inconsistent with the conclusion that carcinogenesis is related primarily to alveolitis and fibrosis rather than to asbestos exposure alone; (2) The second study (3) is based on data presented only in abstract form and has not appeared in a peer-reviewed journal; (3) The purpose of the third study, based on an abstract (4) as well as a peer-reviewed article (5), was to relate radiographic infiltrates to histologic manifestations of asbestosis (interstitial fibrosis) in heavily exposed insulation workers who had died of lung cancer. It was not designed to answer the question of whether the risk of lung cancer is increased by heavy asbestos exposure without asbestosis. Asbestos bodies were lacking in eight to 12 of their cases (depending on the series), and thus it is not clear that all of the fibrosis represented asbestosis. No cases of lung cancer without asbestos exposure were examined for the presence of fibrosis to control for fibrosis related to the tumor; (4) The purpose of the fourth study (6) was to relate type and

location of lung cancer in patients with elevated asbestos fiber burden to type and location in those with little burden. We were surprised to find that this study was used to support the hypothesis that asbestosis must precede an asbestos-related lung cancer. In this study there was an absence of gross and histologic fibrosis in 10 of 60 cases of lung cancer with moderate to high concentrations of asbestos fibers, i.e.,concentrations that caused asbestosis in some persons. Further, no significant difference in degreeof fibrosis could be found in persons with or without these moderate to high burdens of asbestos fibers. The lack of good correlation of fiber burden and fibrosis provides some evidence for differences in individual susceptibility to the fibrogenic properties of asbestos dust. It is our hypothesis, based on this study, that the same lung burden of asbestos fibers associated with asbestosis can cause lung cancer, even in the absence of asbestosis, given a sufficient latency period. Wethink that the evidence linking the process of alveolar inflammation and fibrosis to carcinogenesis is inconclusive. We believe that asbestos causes fibrosis, that it increases the risk of lung cancer, and that both fibrosis and lung cancer occur together in some individuals. Because of differences in host responses to asbestos, some persons will have an asbestos-related cancer without asbestosis. We believe that such cases must be evaluated individually using exposure history supported by lung asbestos fiber burdens. ANTHONY COSENTINO, M.D., MARTHA L. WARNOCK, M.D.

University of California, San Francisco, CA 1. Rom WN, navis WD, Brody AR. Cellular and molecular basis of the asbestos-related diseases. Am Rev Respir Dis 1991; 143:408-22. 2. Doll R. Mortality from lung cancer in asbestos workers. Br J Industr Med 1955; 12:81-6. 3. Hughes JM, Weill H. Asbestos related cancer in relaxation to X-ray evidence of pulmonary fibrosis. Am Rev Respir Dis 1989; 139:A214. 4. Suzuki Y, Selikoff IJ. Pathology of lung cancer among asbestos insulation workers (abstract). Fed Proc 1986; 54:744A. 5. Kipen HM, Lills R, Suzuki Y, Valcuikas lA, Selikoff IJ. Pulmonary fibrosis in asbestos insulation workers with lung cancer: a radiological and histopathological evaluation. Br J Industr Med 1987; 44:%-100. 6. Warnock ML, Isenberg W. Asbestos burden and the pathology of lung cancer. Chest 1986; 89:20-6.

From the Authors: Drs. Cosentino and Warnock have challenged our judgment on one of the areas of asbestos-related disease that most observers would agree remains an issuethat is not completely resolved.Weare pleased to point out the difficulties in developing consensus on the concordance of fibrosis and lung cancer in asbestos-exposed workers and why we lean the way that we do (1). Doll reported several studies in his report (2) including necropsies of 18cases of lung cancer that had been referred to the coroner when, in the coroner's opinion, there was a question of asbestosis being a contributory cause of death. Fifteen had asbestosis and all were> 20 yr from onset of first exposure, except one who was 16 yr, and duration of exposure ranged from 13 to 32 yr with only three below 20 yr. Interestingly, three did not have asbestosis and none of these were exposed more than 10 yr and none were> 20 yr from onset (2, 12, 11 yr), Thus none met the "20 yr rule" of duration from onset characteristicof asbestos-related disease. All of those with asbestosis and lung cancer were heavily exposed (> 9 yr) prior to the 1931 asbestos hygiene regulations in Britain, and the three without asbestosis were first exposed after the mandated regulations drastically reduced exposure. The point is that a short-duration of exposure « 10yr) and a malignancy near the onset of exposure « 10yr) is unlikelyto meetthe standards oflatency causal in asbestosrelated disease. For example, a 47-yr-old asbestos-exposed individual with 2 yr of heavy exposure the previous 2 yr is likely to have many fibers in his lung tissue without fibrosis, and the etiology is certainly more likely to be his two pack per day cigarette smoking habit begun at age 11. Second, Doll performed an epidemiologic study on 113 men with> 20 yr asbestos exposure, and 11 lung cancer deaths

Changes in mucociliary clearance during acute exacerbations of asthma.

237 prevalence of airway responsiveness. This of course is a theoretical possibility. There are no data and no discussion in the paper by Pattemore a...
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