thepathologyof asthma, with special reference to … · ciliated respiratory epithelium and the...

J. clin. Path. (1960), 13, 27.

THE PATHOLOGY OF ASTHMA, WITH SPECIALREFERENCE TO CHANGES IN THE BRONCHIAL

MUCOSABY

M. S. DUNNILLFrom the Department of Pathology, the Radcliffe Infirmary, Oxford

(RECEIVED FOR PUBLICATION AUGUST 14, 1959)

The pathological features of 20 cases dying in status asthmaticus have been studied. In grosssections the lungs showed no emphysema, but mucus plugs in the air passages and focal areasof collapse were outstanding features. Five cases showed cystic bronchiectasis which was ofa similar distribution to the focal areas of collapse, occurring in the upper lobes as commonlyas in the lower lobes.

Histologically, shedding of the ciliated bronchial mucosal cells was prominent and this isattributed to a transudation of oedema fluid from the submucosa. Areas of regeneration of themucosa, with the presence of simple stratified epithelium, were seen frequently. The loss of theciliated respiratory epithelium and the transudation of oedema fluid into the bronchial lumen,with interference with the action of the remaining ciliated cells, are considered to be the essentialfactors in the failure of clearance of the bronchial secretions in asthma. It is postulated thatbronchospasm plays little or no part in the shedding of the bronchial mucosa or in thepathogenesis of the asthmatic attack.

As long ago as 1883 Curschmann noted thepresence of ciliated columnar respiratory cells inthe sputum of patients suffering from asthma.Ellis (1908) observed detachment of the bronchialmucosa, with consequent ulceration of a bloodvessel, in a necropsy on a patient dying in statusasthmaticus. Houston, De Nevasquez, and Trounce(1953), in a clinico-pathological study of nine fatalcases of asthma, mentioned partial or completedetachment of the bronchial mucosa as a constantfinding. The epithelium was intimately mixedwith mucus and eosinophils and assisted in pluggingthe bronchial lumen. They considered that thisdetachment of the epithelium was due to amechanical separation consequent upon contrac-tion of the bronchial muscle. The crenation ofthe bronchial wall was taken as evidence of musclespasm, but the illustrations purporting to showthis were not altogether convincing. It was to seeif some other more logical explanation of thenecropsy findings in asthma could be found thatthe following series of cases was studied.

MaterialLungs collected at necropsy from 20 patients dying

in status asthmaticus have been examined. The lungs

were fixed by perfusion with 10% formol salinethrough the main bronchus or, where this was notfeasible because the bronchus was completely blockedby mucus, through the pulmonary artery. Up to20 blocks of tissue were examined from each lung,and sections were stained with haematoxylin andeosin, Weigert's haematoxylin and Van Gieson, by

TABLE ICLINICAL DETAILS OF CASES

CaseNo.

l2345678

91011121314151617181920

Age(yr.)

10 mths.4101521242527

282934384143445054566467

Sex

FFFFFFFM

MMFFFF

F

FF

Duration of Family Special FeaturesDisease (yr.) History in Lungs

2 mths.1+6+13+19212225

2625932

Many years430182743

30

Nil

Nil+

Nil++

Nil+

Nil4,+,Nil

Bronchiectasis andscattered nodularfibrosis

Bronchiectasis

Bronchiectasis

Bronchiectasis

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M. S. DUNNILL

FIG. ;....;Cut surfce'olunfroCas6sowinmucsplgsimedc.,:'., x 1

FIG. I-Cut surface of lung from Case 6 showing mucus plugs in medium-sized bronchi, x 1.

the periodic-acid-Schiff method, by Robb-Smith'sreticulin method, with Masson's trichrome stain, andwith phosphotungstic acid haematoxylin. Someclinical details of the cases are given in the table.

Gross Findings in the LungsThe appearances of the lungs at necropsy when

death has resulted from status asthmaticus arecharacteristic. On opening the thoracic cage it isat once apparent that both lungs are acutely dis-tended. They fill the chest, completely coveringthe pericardium, nearly meeting in the midlineanteriorly, and failing to collapse once the negativeintrathoracic pressure has been released. Gough(1955) has likened them to the lungs in drowning.In the cases examined in this series, bullous,centrilobular, or focal emphysema was not foundin a single instance. A frequent but not invariablefinding was the presence of small focal areas ofcollapse, and these were seen in Cases 1, 2, 3, 5, 7,10, 11, and 18. They were not confined to onesurface or lobe of the lung but were seen just asfrequently along the anterior margins and at theapices as at the bases. They appeared as firm,

dark, airless, segmental areas depressed below thelevel of the distended lung.The cut surface of the lung showed a striking

picture with numerous grey, glistening mucousplugs scattered throughout the air passages (Fig. 1).These plugs were always seen in the small bronchi,but in some cases extended up to and occluded amain bronchus. In Case 8 both main bronchiwere tightly packed with viscid mucoid material,and, in spite of the fact that intratracheal perfusionwith formol saline under a pressure of 5 feet ofwater was attempted, little or none entered thelung. More often, however, a few segmentsbecame distended by fixative while the rest of thelung stayed distended with air.

In Cases 8, 11, 15, and 17 areas of cysticbronchiectasis were present. The asthmatic ispeculiarly prone to develop bronchiectasis,because if a bronchus is completely occludedabsorption collapse of the lung distal to it willresult. Bronchiectasis quickly follows this state,as Lee Lander and Davidson (1938) have shown.Evidence that this is the mechanism involved inthe, production of bronchiectasis in asthmatics is

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THE PATHOLOGY OF ASTHMA

FIG. 2.-Cut surface of lung in Case 15 showing cystic bronchiectatic spaces in upper lobe and apex of lower lobe, JA.

provided by the distribution of the lesions in thelungs studied. The upper and middle lobes orapex of the lower lobe were as often affected asthe basal segments of the lower lobes (Fig. 2);the lesions thus followed a distribution similarto the focal areas of collapse already mentioned.The changes seen in the bronchi described in thispaper do not, however, concern the mucosa ofthe bronchiectatic spaces. One further point ofinterest with reference to the cases showingbronchiectasis is that these were the only caseswith any degree of right ventricular hypertrophy.Liebow, Hales, and Lindskog (1949) have shownthat large precapillary bronchopulmonary arterialainastomoses occur in bronchiectasis, and it hasbeen suggested that this is an important factor inthe causation of pulmonary hypertension and rightventricular hypertrophy in this condition.

HistologyLumen of the Respiratory Passages.-The most

striking feature in any section from an asthmaticlung is the presence of a dense exudate in thebronchial lumen (Fig. 3). This can be seen as anoccluding plug in the segmental bronchi, but itmay extend distally as far as the respiratorybronehioles. The appearance of the exudate inhaematoxylin-and-eosin preparations is somewhatvariable. There is a mass of basophilic mucoidmaterial, in which spirals of cells are entwined,but often areas of the exudate have a moreeosinophilic appearance. Sections stained by theC.

periodic-acid-Schiff method show that only thebasophilic parts of the exudate are stronglypositive. The eosinophilic part of the exudate ispresumably proteinacious in character; it doesnot give the staining reactions of fibrin withphosphotungstic-acid-haematoxylin or Masson'strichrome.The cellular content of the exudate consists of

eosinophils which are scattered fairly evenlythroughout the mucoid portion and some epithelialcells. The possibility of the ep:thelial cells beinga post-mortem artefact was considered, as thesecells undoubtedly do become detached easily afterdeath, particularly if fixation is inadequate. Theidea was rejected, however, as in places the cellsare so intimately mixed with mucus. In additionthey sometimes appear in the centre of theexudate in a bronchus with a normal liningmucosa indicating that they have come fromanother part of the bronchial tree. These mucosalcells appear singly or in groups, and they may benormal ciliated columnar cells or goblet cells.Another point in connexion with the exudate

worthy of note is the paucity of neutrophilpolymorphonuclear leucocytes. Histologically innone of the cases, including those withbronchiectasis, was there evidence of acutepyogenic infection.Mucous Membrane of the Bronchi.-In some

areas the bronchial mucosa may appear normal,but in those bronchi plugged with exudate thereare obvious pathological changes. Commonly

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a-t i;VA

c:\\95.'i 4 ....... .. ~~~~~~~~~~~g.2

FIG. 3.-Low-power view showingbronchus plugged by exudate inCase 7. Note the absence ofemphysema in the surroundinglung. Haematoxylin and eosin,x 14.

there is a marked degree of mucosal oedema withseparation of the superficial columnar cells(Fig. 4). Eventually these cells become detached,and the remaining mucosa consists only of a fewreserve or basal cells (Fig. 5). More interestingstill are areas of regeneration which can be seenat focal points in the bronchial wall. Mitoticactivity among the deeper cells is increased, andthe epithelium is of the simple stratified type(Figs. 6 and 7). These areas were seen in all cases,but were much more marked in some than others.In Case 8 all the bronchi examined were lined bythis metaplastic or regenerating epithelium. Theappearances are very reminiscent of those seen byWilhelm (1953) and Otto and Wagner (1956) whenthe trachea and bronchi were undergoing repairfollowing experimental trauma. In the asthmaticlung these areas represent places where the mucosahas become detached and repair is taking place.All stages can be seen, from areas where onlya few basal cells are present, through areas ofmetaplasia with simple stratified epithelium, tothe normal pseudo stratified columnar, ciliated,respiratory epithelium. These metaplastic cells

have recently been detected in the sputum ofasthmatics by Cohen and Prentice (1959).

Eosinophils can be seen occasionally in theintact but oedematous bronchial mucosa, andpresumably diapedesis of these cells occursthrough the mucosa.One of the most pronounced changes in the

bronchial wall is the thickening of the basementmembrane. This was seen in all except the twoyoungest patients in the series, Cases 1 and 2. Itpresents as a thick eosinophilic band to which thecells of the bronchial mucosa are closely applied.The membrane stains red in van Gieson prepara-tions, green with Masson's trichrome, and pinkwith the P.A.S. technique. In sections stained forreticulin it is black, but sometimes, particularly inthose cases where it is greatly thickened, it has abrownish collagenous component. In chronicbronchitis the basement membrane becomesthickened, but thickening is more variable andnever so pronounced as in asthma.

Beneath the basement membrane, apart fromthe infiltration by eosinophils, the most strikingfeature is the dilatation of the capillary blood

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FIG. 4- Section of a medium-sized bronchus in Case 7, showing FIG. 5.-Section showing a medium-sized bronchus lined by reserve.mucosal and submucosal oedema. Haematoxylin and eosin, or basal cells only. Columnar and ciliated cells are present ittx 400. the exudate. Haematoxylin and eosin, x 112.

FIG. 6.-Section showing medium-sized bronchus lined by simple FIG. 7.-Commencing redifferentiation of bronchial epithelium withstratified epithelium. Haematoxylin and eosin, x 400. marked mitotic activity. Note the thickened basemaut -ean-

brane. Masson's trichrome, x 400.



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2M. S. DUNNILL

vessels. These vessels, often possessing ratherswollen endothelial cells, are closely applied to thebasement membrane. The connective tissue inwhich these vessels lie consists of strands of widelyseparated collagen giving the impression ofoedema (Fig. 4). Furthermore, the mucosa over-lying these areas often shows oedema withseparation of the cells. It is interesting to notethat Wilhelm (1953) found that prominentsubmucosal inflammation, following removal ofthe tracheal epithelium, prolonged mitotic activityin the regenerating epithelium and delayed itsdifferentiation.The Bronchial Wall.-The mucous glands

appear active but not hypertrophied as they are inchronic bronchitis (Reid, 1954).The smooth muscle in the walls of the bronchi,

especially those of 0.4-0.6 mm. diameter, showsconsiderable hypertrophy. Crenation of thebronchial mucosa of the type seen in animalsdying-of anaphylactic shock (Dixon and Warren,1950), and said to indicate bronchospasm, wasnot noted. Indeed, the smaller bronchi and thebronchioles appeared if anything rather dilated(Fig. 3) with the bronchial wall stretched over thedense exudate in the lumen. In some of the largeair passages it is true that irregularities can be seenin. the bronchial mucosa with the formation ofdiverticula. Frequently these represent the mouthsof the mucous gland ducts, and this can be demon-strated by serial sections. In other cases they maypossibly represent the contraction of the bronchialsmooth muscle, but even so it is difficult to creditthat they would affect the diameter of the airpassages in which they are present.

DiscussionIn a recent lecture Young (1959) cited three

main factors in the production of an asthmaticattack: (1) Spasm of the smooth muscle of thebronchi, (2) swelling of the mucou, membrane,and (3) production of excessive glairy mucus.Clinically the concept of bronchospasm dependsupon the auscultatory sign of a high-pitchedexpiratory rhonchus or wheeze. This is a soundproduced in an air passage due to partial occlusionof its lumen, and there is nothing in the sounditself to differentiate obstruction by oedema of thebronchial mucous membrane, or by mucus, fromspasm of the bronchial muscle. Anatomicalevidence that asthma is due to bronchospasm isbased, first on the presence of hypertrophiedsmooth muscle in the bronchial wall, and secondlyon the doubtful finding of the crenation of thebronchial mucosa.

There is ample evidence for the allergic originof bronchial asthma in its association with hayfever and urticaria, the frequency of eosinophiliain the peripheral blood, and positive skinsensitivity tests to foreign proteins. Segal andAttinger (1957) have stated that the allergicreaction is associated with (1) capillary dilatation,(2) increased capillary permeability, (3) increasein the protein content of intercellular fluid,(4) engorgement of lymphatic and bloodcapillaries, (5) accumulation of eosinophils, and(6) accumulation of mucus secretion in the wallsof the bronchioles. The anatomical counterpartsof these six points can be clearly seen in thesubmucosa of the bronchi where there is oedemaand capillary dilatation.

Pathologically the outstanding feature of theasthmatic lung lies in the failure of clearanceof the bronchial secretions. Two factors areimplicated in this, first the " glairy " quality of themucus itself, and secondly the loss of ciliaryaction in the bronchial mucous membrane.Florey (1958) has pointed out that the exudatefrom an inflamed mucous membrane consists notonly of mucus produced by glands in the wall andby goblet cells but also of a protein-ladentransudate which arises from the increasedpermeability of the dilated capillaries in thesubmucosa. A similar process seems likely tooccur in asthma. It has already been noted thatthe exudate in the bronchial lumen is nothomogeneous and only partly mucoid in nature.In fact this is in keeping with the allergic basisof the disease. The dilated capillaries lie inoedematous connective tissue just below thebasement membrane, and some of the oedemafluid must pass through the mucosa into thebronchial lumen. The presence of this serous fluidexudate closely applied to the bronchial mucosawill affect the ciliary action of the mucosal cells.Hilding (1932) has shown that serous fluid severelycurtails the action of cilia, which are much moreeffective when dealing with pure mucus.Movement of the exudate will also be retarded

by the shedding of the mucosal cells, which was anoticeable feature in this series and was alsoemphasized by Houston et al. (1953). Theexplanation offered by these authors for thedetachment of the mucosal cells was that it is dueto muscle spasm and consequent crenation of themucous membrane with mechanical separation ofthtr epithelium. A more likely factor in thisdisturbance of the mucosa would be thetransudation of oedema fluid across the mucousmembrane. There is no situation in human

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THE PATHOLOGY OF ASTHAIA

pathology where contraction of smooth musclecauses detachment of an epithelial surface, but inthe skin, e.g., in eczema and the bullous eruptions,disorganizatAon of epithelial architecture by oedemawith underlying capillary dilatation, increasedcapillary permeability, and transudation ofprotein-laden fluid is commonplace. Disturbancesof epithelial continuity are even more likely tooccur in the delicate respiratory mucosa followingallergic submucosal oedema.The submucosal oedema may also play some

part in the thickening of the bronchial basementmembrane. Robb-Smith (1952) has suggested thathyalinization of the basement membrane in thenasal mucosa, following numerous attacks ofinflammation, is related to the accumulation ofplasma protein and mucopolysaccharide in theinflammatory oedema fluid. Resolution of thisoedema results in a condensation of these proteincomplexes to form " hyaline." A similarmechanism might apply in asthma with continualformation and resolution of submucosal oedema.

It is sometimes claimed that bronchospasmmust play some part in the production of an

asthmatic attack because of the therapeutic actionof adrenaline which relaxes the bronchial smoothmuscle. Sheldon and Otis (1951) have shown thatan increase in the vital capacity in an asthmaticafter adrenaline has been given is not alwaysaccompanied by a decrease in air flow resistanceas would be expected if adrenaline relaxed thebronchial smooth muscle. They consider thatadrenaline acts as a vasoconstrictor on thepulmonary and bronchial arteries, therebydecreasing the quantity of blood in the thorax andallowing more room for air. In some cases air

flow resistance is decreased, and here adrenalinemay constrict the dilated vessels in the bronchialsubmucosa, thereby decreasing mucus secretionand submucosal oedema. An explanation forthe hypertrophied bronchial musculature may befound in the hypothesis that in cases where ciliaryaction is defective or absent this muscle plays somepart in clearing the bronchial secretions byperistaltic contractions, as suggested by Holdenand Ardran (1957) in a bronchographic studyusing cineradiology. In asthma where ciliaryaction is so deficient this muscle would undergo awork hypertrophy.

I am grateful to Dr. A. H. T. Robb-Smith forreading the manuscript and for much helpfuld:scussion during the preparation of this paper. Mrs.D. Jackson took the photographs and Miss M.Reading gave technical assistance.

REFERENCESCohen, R. C., and Prentice, A. I. D. (1959). Tubercle (Lond.), 40,44.Curschmann, H. (1883). Dtsch. Arch. klin. Med., 32, 1.Dixon, F. J., and Warren, S. (1950). Amer. J. med. Sci., 219, 414.Ellis, A. G. (1908). Ibid., 136, 407.Florey, H. W. (1958). In General Pathology, ed. H. W. Florey,

2nd ed., p. 120. Lloyd-Luke, London.Gough, J. (1955). Lancet, 1, 161.Hilding, A. (1932). Amer. J. Physiol., 100, 664.Holden, W. S., and Ardran, G. M. (1957). J. Fac. Radiol. (Lond.),

8, 267.Houston, J. C., De Nevasquez, S., and Trounce, J. R. (1953). Thorax,

8, 207.Lander, F. P. L.. and Davidson, M. (1938). Brit. J. Radiol., 11, 65.Liebow, A. A., Hales, M. R., and Lindskog, G. E. (1949). Amer. J.

Path., 25, 211.Otto, H., and Wagner, H. (1956). Beitr. path. Anat., 116, 436.Reid, Lynne McA. (1954). Lancet, 1, 275.Robb-Smith, A. H. T. (1952). Proc. roy. Soc. Med., 45, 811.Segal, M. S., and Attinger, E. 0. (1957). In Clinical Cardiopulmonary

Physiology [American College of Chest Physiciansl, ed. B. L.Gordon, p. 283 et seq. Grune and Stratton, New York.

Sheldon, M. B., and Otis, A. B. (1951). J. appl. Physiol., 3, 513.Wilhelm, D. L. (1953). J. Path. Bact., 65, 543.Young, F. H. (1959). Chest and Heart Bull., 8, 4t.

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