Bronchiolitis fibrosa obliterans - Thorax · Bronchiolitis fibrosa obliterans enlarged, 410 g. in weight, with particularly marked hypertrophy of the right ventricle, which had a

Thorax (1966), 21, 209.

Bronchiolitis fibrosa obliteransH. S. BAAR1 AND J. GALINDO

From the Pathology Department, Pineland Hospital, Pownal, Maine

Bronchiolitis fibrosa obliterans, described first byLange in 1901, is an obliterative process of thebronchioles in which there is extensive damage tothe bronchial wall involving all the constituentelements (the epithelium, elastic tissue, andmuscle fibres), and the lumen is partially or totallyoccluded by bronchial exudate organized byfibroblasts and capillaries.The disease is extremely rare in man. LaDue

(1941), for example, made a specific search of thisentity in necropsy material and encountered butone case in 42,038 consecutive necropsies. On theother hand, in experimental dogs which had beenexposed to war gases, such as phosgene, chloro-picrin, and chlorine, Winternitz (1920) found thedisease consistently. Even in humans, the majorityof described examples are due to the inhalation ofpoisonous gases. Statements that the disease is notuncommon are based on the confusion of thediffuse widespread disease with an occasionalhistological finding of a bronchiolus withorganized exudate (Ehrich and McIntosh, 1932).The aetiology (McAdams, Jr., 1955; Blumgartand MacMahon, 1929; Amoroso and McNally,1949; Loblich, 1952) of this pathological entityis clear when it is associated with the inhalationof toxic gases capable of chemically damaging theelements of bronchiolar walls. Among those mostcommonly reported are oxides of nitrogen (NO2and N204, both of these being readily soluble inwater, thus forming nitric acid), war gases suchas have been mentioned above, and occasionallyother types of gases such as chlorine.A few examples have been directly related to

pulmonary infection, such as infection byPfeiffer's bacillus (Hiibschmann, 1916) or whoop-ing cough (Blumgart and MacMahon, 1929), andoccasionally to aspiration of a foreign body(Wegelin, 1908), while a few others have been ofunknown or uncertain aetiology in which thepatient was neither exposed to toxic gases nor hadclinical evidence of pulmonary infection. Thelatter group has been called 'primary bronchio-'Present address: 33 Sandon Road, Birmingham, 17, England

litis obliterans' by Loblich (1952). The case pre-sented in this paper would fit into the last categoryand is remarkable by the absence of any respira-tory symptoms except for a few days before death.

Clinically, there is considerable variation in thesymptomatology and also in the time lapsebetween the different symptoms and the under-lying aetiology, even if the latter is so definite asinhalation of toxic gases. The initial symptomsare those of chest pain and slight cough. Theseverity of the cough is related to the amount ofbronchial damage, and the respiratory symptomsare dependent on both the bronchial and thepulmonary parenchymal involvement. During thefirst clinical stage pulmonary oedema may occur,and the expectoration which accompanies coughmay be minimal or abundant and may or may notshow evidence of blood streaking. After the firstepisode there ensues a clinical plateau which maylast from a few days to as long as one month,during which the symptoms appear to abate orbecome stationary. However, following this periodof status quo, dyspnoea appears and becomesprogressively worse. Coughing becomes morefrequent, expectoration increases, and bloodstreaking of the sputum is more common. It isduring this stage of the affliction that fever,generally of low grade, may first appear. Thepatient is in obvious respiratory difficulty andcyanosis is usually present. The course of thedisease is as a rule a rather chronic one, butafter inhalation of poisonous gases death mayoccur rapidly. In a case described by Darke andWarrak (1958) the patient (case 1) died 14 daysafter exposure to nitrous fumes, and necropsyrevealed the presence of organizing bronchiolarexudate.The chest radiograph at this time shows

scattered miliary densities within both lungs, thispicture being reminiscent of miliary tuberculosis.Actually the clinical diagnosis was miliary tuber-culosis in several cases (Blumgart and MacMahon,1929; Assmann, 1934). However, the purifiedprotein derivative (P.P.D.) may be negative and

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H. S. Baar and J. Galindo

culture and animal inoculation are negative fortubercle bacilli.

In spite of a varying period of a clinicallystationary condition, the disease follows a clini-cally relentless course with ever-increasing re-spiratory difficulties and deepening cyanosis,usually terminating in death in a matter of weeksor months.At necropsy the picture is that of multiple

greyish or whitish nodules, highly suggestive ofmiliary tuberculosis. However, on close inspectionand palpation of the lungs in these areas itbecomes evident that the nodules are more whiteand their consistency much firmer than that ofmiliary tubercles. Caseation is absent, and withthe help of a lens one may discern in some of thenodules an eccentric, tiny lumen. Such lumina,which correspond to those of the bronchioles, areoften crescent-shaped. A few or many of thenodules may show no lumina at all. The edge ofthe nodule is not rounded but rather serrated, thisbeing due to the accompanying peribronchial in-filtration and/or fibrosis. In the majority of casesthere is no evidence of tuberculosis elsewhere inthe body, and the tracheo-bronchial and media-stinal lymph nodes are usually only unspecificallyinvolved. The lungs are congested, voluminous,and quite frequently they are oedematous, oozinglarge amounts of fluid on section. One may seehaemorrhages, usually in bronchial location,which are small in dimensions, generally only afew millimetres. Examination of the bronchiolesmay show extensive fibrous replacement of allelements of the bronchiolar wall and peribronchialfibrosis or a vascular peribronchial granulationtissue. The bronchiolar lumen may be occluded bya network of closely interwoven fibroblasts whichmay leave only the previously described eccentriccrescentic lumen, or one may s?e a mushroom-like projection of fibrous tissue attached to thebronchial wall by only a thin, fibrous pedicle.Vascular proliferation within the fibrous tissue isquite prominent in some places and mild in others.The remainder of the pulmonary parenchyma mayshow fibrosis and compensatory emphysema. Acase of typical bronchiolitis fibrosa obliterans willbe described which, apart from the rarity of thecondition, is remarkable by the absence of anyrespiratory symptoms in the presence of definiteradiological findings.

CASE REPORT

M.R., a white male, was born on 1 September 1908.There was no information concerning his birth orearly development. He was admitted to the Pineland

Hospital and Training Centre on 22 January 1954.The family history was negative. He was found tohave a spastic hemiplegia on the left side withatrophy of the left upper and lower extremities.There was a club foot on the left side. He had aspastic gait and nystagmus. There was a positiveBabinski sign on the left side and he had a severedefect of speech, being able to say only a few words.There was a partial stiffening of the left ankle-joint.A tuberculin patch test, done in January 1954, waspositive. Chest radiographs, taken repeatedly between1954 and 1962, were reported as within normal limits.However, a radiograph in March 1963 showed

'fine mottling of both lung fields'. Though examinationof the gastric lavage was negative for tubercle bacilliin culture and in animal inoculation, the radiologicalpicture was suggestive of tuberculosis, and so thepatient was put on para-aminosalicylic acid andisoniazid medication. Further chest radiographsshowed the same miliary densities apparently un-affected by the antituberculosis therapy, and thedifferential diagnosis between miliary tuberculosis,'collagen disease', or sarcoidosis had to be made. Anexamination for lupus erythematosus cells wasnegative, and a radiographic examination of thebones of the hand showed none of the changessuggestive of sarcoidosis. During this time the patientwas asymptomatic, and there was no shortness ofbreath and no cyanosis. The laboratory examinationshowed a total protein of 7-0 g./100 ml., albumin 4-9g./100 ml., and globulin 2-1 g./100 ml.; albumin/globulin ratio 2-3; calcium 9.7 mg./100 ml.; alkalinephosphatase 4-4 Bodansky units. Examination of theurine was within normal limits; the white blood cellcount was 7,000, with 2-1% eosinophils. In April 1963he sustained a chipped fracture of the twelfththoracic vertebra and a fracture of the left os ilei.The fractures healed well. In January 1964 the P.P.D.test was positive. He remained symptomless until 12June 1964, when he became cyanosed and orthopnoeicand died on 16 June.

Since admission in 1954 the patient had been in alarge ward with 30 other patients under the super-vision of a nurse and two attendants. Carefulinquiries after the necropsy ruled out the possibilityof accidental inhalation of poisonous gases.At necropsy the body was that of a strongly built,

well nourished white male with 180 cm. body length.All other measurements were corresponding andsymmetrical. The pleurae were thin, lustrous, anddelicate, and there was no fluid in the pleural cavitiesnor were pleural adhesions present. The right lungwas 810 g. and the left 630 g. in weight. On all cutsurfaces of each lung there were numerous pinheadmillet- (occasionally lentil-) sized, greyish-white, ratherfirm, irregularly outlined nodules (Fig. 1). The cutsurfaces were overflooded with frothy fluid. Thetracheo-bronchial and paratracheal lymph nodes wereenlarged; the largest, at the bifurcation, was the sizeof a hazel-nut. All were soft and, on the cut surfaces,red with greyish spots, but none showed areas ofcaseation, calcification, or tubercles. The heart was

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Bronchiolitis fibrosa obliterans

FIG. 1. Lung sections after formaldehyde fixation showing whitish, circular, indurated areas suggestiveof healing miliary tuberculosis.

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FIG. 2. A bronchiole appears completely obliterated by fibrous tissue whichoccurs in concentric rings. Verhoeff-Van Gieson. x400.

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FIG. 3. Two obliterated bronchioles with lamellarfibrous tissue and vascularization. Verhoeff-Van Gieson. x 400.

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enlarged, 410 g. in weight, with particularly markedhypertrophy of the right ventricle, which had amaximal thickness of 9 mm. There was a severecongestion of the liver, a 'strawberry' gall-bladder,and an atrophy of the left testicle which was 6 g.in weight and situated in the inguinal canal. Thebrain was 1,100 g. in weight and there was ahemiatrophy present, the right hemisphere of thecerebrum and cerebellum being smaller than the left.The right temporal lobe was shrivelled and con-tracted, and its pole showed a thin-walled, trans-lucent cyst, 4 cm. in diameter, which extended for2 to 3 cm. into the depth of the brain. Anothersimilar cyst, 5 cm. in diameter, was present on thevertex just behind the post-central gyrus and closeto the median fissure. A coronal section showedatrophy of the central grey matter and a dilatation ofthe lateral ventricle. There were extensive areas ofdemyelinization in the centrum semiovale. The otherorgans were not remarkable.

HISTOLOGY Both lungs were severely hyperaemic andshowed extensive areas of atelectasis. In manyexamined sections not a single normal small bronchusor bronchiolus was seen. A few were dilated, filledwith polymorphonuclear exudate, showed deepulceration of the wall, and were surrounded by a veryvascular granulation tissue. Many were seen as circles,

completely filled with granulation tissue, which waseither vascular or avascular and contained, occasion-ally, a foreign body giant cell. Occasionally, in theperiphery of the ring-structure, columnar epitheliumwas seen. In the absence of epithelial cells, suchstructures could be mistaken for arteries with anorganized and eventually recanalized thrombus orembolus. The differentiation was, however, clear inVerhoeff-van Gieson stains by the arrangement ofmuscle fibres and absence of a characteristic elasticmembrane (Figs 2 and 3). In some, elastic fibreswere absent, in others they were fragmented.Occasionally a polypoid granulation tissue was seengrowing into a bronchiolus. The pulmonary arteriesshowed myoelastic hypertrophy, some with subendo-thelial cushion-like proliferation of fibrous tissue(Fig. 4) and, occasionally, a complete obliteration of-the lumen by a vascular granulation tissue. Suchobliterated arteries were easily differentiated fromobliterated bronchioli by the presence of a wavyelastic membrane. Obliterated arteries were muchrarer than obliterated bronchioli and, in manyplaces, obliterated bronchioli were seen, surroundedby granulation tissue without a spacial relationshipto obliterated arteries.

We can therefore not agree with the thesis ofAmoroso and McNally (1949) that bronchiolitis

FIG. 4. Endarteritis obliterans. Verhoeff- Van Gieson. x 400.

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SUMMARY

FIG. 5. Cerebral arterioles showing mucoid degenerationof their wall. H. and E. x 150

obliterans is secondary to a granulomatous vascu-

litis. Rather the reverse relationship appears tobe indicated. Throughout all the interstitial tissueand within the alveoli were many haemosiderin-laden macrophages. However, there was no diffuseinterstitial fibrosis such as is seen in cardiogenicbrown induration nor the fragmentation of elasticfibres in the interalveolar septa, characteristic ofthis and of idiopathic pulmonary haemosiderosis.The brain showed fibrotic changes in the arach-noid, large areas of demyelinization and spongy

degeneration, and hyalinization of the walls ofarterioles and venules within the atrophic hemi-sphere (Fig. 5).

The clinical and pathological findings in a case ofbronchiolitis fibrosa obliterans are described.Concentric fibrous obliteration of the lumina ofbronchioles resulted in pulmonary hypertensivearteriopathy with proliferation of endothelialcushions and diminution of arteriolar lumina.Respiratory symptoms were absent in this patient.The spastic paralysis from which he suffered

was related to the cerebral lesions of hemiatrophy,ventricular dilatation, and cystic degeneration.

The authors wish to thank Mrs. E. Beverage fortechnical assistance and Mr. McKenzie for thephotography.

REFERENCES

Amoroso, W. L., and McNally, J. T. (1949). Granulomatous pul-monary vasculitis in association with bronchiolitis fibrosaobliterans. Bull. Georgetown Univ. med. Cent., 3, 77.

Assmann, H. (1934). Die klinische Rontgendiagnostik der innereniErkrankungen, 5th ed. Vogel, Leipzig.

Blumgart, H. L., and McMahon, H. E. (1929). Bronchiolitis fibrosaobliterans; a clinical and pathologic study. Med. Clin. N. Amer.,13, 197.

Darke, C. S., and Warrack, A. J. N. (1958). Bronchiolitis fromnitrous fumes. Thorax, 13, 327.

Ehrich, W., and McIntosh, J. F. (1932). The pathogenesis of bronchio-litis obliterans. Arch. Path., 13, 69.

Hubschmann, P. (1916). thber Influenzaerkrankungen der Lungeund ihre Beziehungen zur Bronchiolitis obliterans. Beitr. path.Anat., 63, 202.

LaDue, J. S. (1941). Bronchiolitis fibrosa obliterans. Arch. intern.Med., 68, 663.

Lange, W. (1901). Ueber eine eigenthumliche Erkrankung derkleinen Bronchien und Bronchiolen. Dtsch. Arch. klin. Med.70, 342.

Loblich, H. F. (1952). Primare Bronchiolitis obliterans. Frankfurt.Z. Path., 63, 350.

McAdams, A. J., Jr. (1955). Bronchiolitis obliterans. Amer. J. Med.,19, 314.

Wegelin, C. (1908). t'ber Bronchitis obliterans nach Fremdkorper-aspiration. Beitr. path. Anat., 43, 438.

Winternitz, M. C. (1920). Collected Studies on the Pathology of W1'al-Gas Poisoning. Yale University Press, New Haven.

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Bronchiolitis fibrosa obliterans - Thorax · Bronchiolitis fibrosa obliterans enlarged, 410 g. in weight, with particularly marked hypertrophy of the right ventricle, which had a