471LEADING ARTICLES

Hypersensitivity and the Lung

THE LANCET

LONDON 26 FEBRUARY 1966

CLINICAL immunology is now one of the most

exciting activities in medicine. It has developed froma rapprochement between somewhat disparate elements.Of these, laboratory immunology, originally concernedwith the defence reactions of the animal body to foreignsubstances and especially micro-organisms and soonevolving quantitative techniques, and " allergology ",concerned with the study of asthma and other hyper-sensitivity diseases in man, usually by only qualitativeand sometimes almost subjective techniques, may beregarded as the extremes. Lately the study of auto-immune factors, both in disease and in relation to organtransplantation, has added to the range of clinical

specialties to which immunology is making an essentialcontribution. These events will provide muchmaterial for the new journal, Clinical and ExperimentalImmunology, to which we refer in an annotation on

p. 476.Nowhere are these developments more evident than

in respiratory disease. The role of hypersensitivity,associated with circulating reaginic antibodies and withimmediate skin reactions, in some cases of asthma haslong been known; these cases are often termed " extrin-sic " to emphasise their dependence on external sub-stances, to which the subject is specifically hypersensitive.In such subjects the specific reaction causes paroxysmalnarrowing of airways. Study of clinical syndromesassociated in man with the common mould Aspergillusfumigatus has shown reactions of other sorts. This workstarted with the clinical descriptions of the mycetoma,aspergilloma, or " fungus ball ", and of transient pul-monary infiltration associated with eosinophilia.1 Muchis now known about the immunology of these twosyndromes.2 3 The fungus ball generally develops in apre-existing air-containing space in the lung, of whichthe majority are open cavities left after chemotherapyfor tuberculosis has successfully eliminated the infection.In patients with this syndrome precipitins are usuallyfound, and immunoelectrophoretic tests reveal a largenumber of well-formed arcs 4; characteristically, thesepatients have symptoms referable only to the localeffects of the fungus ball. Patients with transient

pulmonary infiltrations and eosinophilia associated with1. Hinson, K. F. W., Moon, A. J., Plummer, N. S. Thorax, 1952, 7, 317.2. Pepys, J., Riddell, R. W., Citron, K. M., Clayton, Y. M., Short, E. I.

Am. Rev. resp. Dis. 1959, 80, 167.3. Longbottom, J. L., Pepys, J. J. Path. Bact. 1964, 88, 141.4. Longbottom, J. L., Pepys, J., Clive, F. T. Lancet, 1964, i, 588.

aspergillus are generally extrinsic asthmatics. A fewasthmatics with no special clinical features show skinsensitivity to aspergillus antigens. In those withinfiltrations associated with aspergillus such sensitivityis the rule, and a high proportion (70-80%) also haveprecipitins; some of those with precipitins show dualskin reactions, in which an immediate weal is followedafter several hours by a longer reaction. It seems

possible that the presence of both types of sensitivityis responsible for the full picture of transient infiltra-tion with eosinophilia, and that the bronchial dilatationwhich often follows resolution of such an infiltration maybe associated with damage to bronchial walls by anArthus-type reaction. Thus, these syndromes associatedwith aspergillus cover a’ wide range of clinical types,which can be correlated with variations in detectable

immunological reactions. In all of them, it is the conduct-ing part of the bronchopulmonary tree that is principallyinvolved; apart from its incidental involvement in thesegmental inflammatory change in the transient infiltra-tion syndrome, the peripheral gas-exchanging part ofthe lung is not affected.

" Farmer’s lung " exemplifies a type of hyper-sensitivity reaction involving predominantly the peri-pheral gas-exchanging part of the lung. Constitutional

symptoms, often with fever, and a feeling of tightnessin the chest but no wheezing, appearing several hoursafter exposure, are the features of the acute episode,rather than an immediate asthmatic reaction. Fine

mottling may be evident in the chest radiograph,especially after an acute episode. Typically, precipitinsto mouldy hay are present 5 6 and the antigens are

derived from certain thermophilic actinomycetes.7 8These are the commonest moulds in hay which hasoverheated in going mouldy; Thermopolyspora polysporain particular has been identified as a potent sourceof farmer’s-lung antigens. Histologically, the reactionis a characteristically granulomatous one which fromits situation interferes with gas exchange and diminishescompliance of the lung.10 11 Not surprisingly, somefarmers develop also reaginic sensitivity to antigenspresent in mouldy hay, with asthmatic symptoms; butthis is not the typical farmer’s lung reaction.That this type of reaction-involving the periphery of

the bronchopulmonary tree, with delayed symptomsafter exposure, and accompanied by the appearance ofprecipitins in the blood-may follow the inhalation of avariety of organic dusts is now becoming clear. Naturally,there are minor differences in the clinical picture accord-ing to the causal dust. Pigeon-breeders have beenshown to suffer from a clinical syndrome which is

apparently associated with such a reaction.12 13 In the

5. Pepys, J., Riddell, R. W., Citron, K. M., Clayton, Y. M. Thorax, 1962,17, 366.

6. Kobayashi, M., Stahmann, M. A., Rankin, J., Dickie, H. A. Proc. Soc.exp. Biol. Med. 1963, 113, 472.

7. Pepys, J., Jenkins, P. A., Festenstein, G. N., Gregory, P. H., Lacey,M. E., Skinner, F. A. Lancet, 1963, ii, 607.

8. Pepys, J., Jenkins, P. A. Thorax, 1965, 20, 21.9. Dickie, H. A., Rankin, J. J. Am. med. Ass. 1958, 167, 1069.

10. Bishop, J. M., Melnick, S. C., Raine, J. L. Q. Jl Med. 1963, 32, 257.11. Williams, J. Thorax, 1963, 18, 182, 255.12. Barboriak, J. J., Sosman, A. J., Reed, C. E. J. Lab. clin. Med. 1965, 65,

600.13. Reed, C. E., Sosman, A., Barbee, R. A. J. Am. med. Ass. 1965, 193, 261.

472

first article of this week’s issue Dr. PEPYS and his

colleagues confirm and extend these observations. Theyreport the cases of 7 pigeon fanciers and 5 budgerigarfanciers who developed symptoms and signs resemblingthose of farmer’s lung, characterised by dyspnoea withrales at the bases of the lungs in some, but with no otherabnormal physical signs; chest radiographs either werenormal or showed fine mottling, and, functionally, therewas evidence of a restrictive ventilatory defect and adefect in gas transfer. Those exposed to pigeons gavehistories of episodes of fever, malaise, dyspnoea, andcough starting five or more hours after exposure,the attacks resembling those in farmer’s lung syndrome.In the budgerigar fanciers these acute episodes wereless constant, and most of them presented with evidenceof established lung damage. In both groups, abundant

precipitins against antigens in avian serum-proteins,excreta, and egg-yolks, but not egg-whites, were demon-strated in the blood. Skin tests in all patients but 2 gavedual reactions. Inhalation tests provoked a responseafter six hours or more, resembling that produced inaffected farmers by similar tests with mouldy hay orthermophilic actinomycete antigens. At least one of thebudgerigar fanciers had additional asthmatic symptoms;and, in one pigeon fancier and one budgerigar fancier,inhalation tests produced immediate reactions withevidence of airway obstruction relieved by isoprenaline.The " typical " late reactions were not affected by iso-prenaline. 4 healthy control subjects showed no reactionto skin or inhalation tests. All the affected pigeonfanciers and 3 of the budgerigar fanciers were improvedby avoiding contact with their birds. Precipitins werenot found in any of a large number of sera from normalsubjects and from patients with various respiratorydiseases not known to be exposed to pigeons or budgeri-gars. They were found in some sera from bird fanciers,including some with respiratory disease not apparentlyof the farmer’s lung type; this is comparable withthe observation that specific precipitins may appearin the blood of subjects exposed to various vegetabledusts 14 even though there may be no respiratorysymptoms.

PEPYS et al. 15 have also observed pulmonary reactionsof farmer’s-lung type in subjects taking pituitary snuffon account of diabetes insipidus. Thus there is now clearevidence that a variety of dusts of vegetable and animalorigin can cause illnesses characterised by changes inthe peripheral gas-exchanging part of the lung. Namingthese is difficult. For the time being, the easy way outis to use such terms as " farmer’s lung " or " pigeonfancier’s " or " budgerigar fancier’s " lung-though"

pituitary-snuff-taker’s lung " seems rather cumber-some. Sooner or later, a generic name must be found forillnesses associated with reactions in the gas-exchangingpart of the lung caused by organic dusts to which thesubject has become specifically hypersensitive. Thereis now good evidence that precipitins are an essentialelement in the pathogenesis of this type of reaction.14. Pepys, J., Longbottom, J. L., Jenkins, P. A. Am. Rev. resp. Dis. 1963,

89, 84215. Pepys, J., Lachmann, P. H., Mahon, W. B. J. Endocr. 1965, 33, viii.

Early Diagnosis ofUpper Gastrointestinal Bleeding

PROMPT investigation of patients with haematemesisand melaena is now accepted as safe and capable ofsupplying information of diagnostic valued In Great

Britain, where peptic ulcer is the chief cause of acuteupper gastrointestinal bleeding, barium meal and

gastroscopy are standard measures; but in othercountries oesophageal varices may account for an

important proportion of bleeding episodes, and in theUnited States up to a third of patients admitted tohospital with haemorrhage have been reported 2 to haveoesophageal varices. Such patients do not alwayshave obvious clinical signs of liver disease, and testsof liver function must be used. McDERMOTT 3 sug-gested a simple qualitative test for raised blood-ammonia levels, which he found to be better than theestimation of bromsulphalein retention in the diagnosisof liver disease and oesophageal varices, though it hassince been claimed that blood-ammonia and bromsul-

phalein retention taken together gives better results.4The situation is complicated, however, by the commonassociation of cirrhosis, varices, and bleeding ulcer.sSince barium-meal examination is reasonably successfulin demonstrating varices even during examinationsin the ward, then it may well be that barium meal andendoscopy are still a satisfactory combination in areaswhere cirrhosis is common.

Various other methods of investigation have beendescribed. CHANDLER and WATKINSON found that

hourly sampling of gastric juice showed patterns ofnocturnal hyperacidity indicating duodenal ulcer, inter-mittent nocturnal neutralisation in chronic gastriculcer, and constant relative achlorhydria in acute gastriculcer. But this test, though simple to perform, is uncom-fortable for the patient because of the intubation, and italso needs careful supervision to ensure regular sampling,particularly at night. HAYNES and PITTMAN 9 found thatthe fluorescein string test was a satisfactory method forlocalising gastrointestinal bleeding. A fluorescein dye isinjected intravenously after a cotton tape, marked atintervals with a radioopaque thread, has been passed bymouth. The string is retrieved within five minutes ofthe injection and examined under ultraviolet light forevidence of dye staining. The exact site of staining, andtherefore bleeding, is determined by comparison with aradiograph taken at the time of the examination.Patients find the string hard to swallow, however, and ina modification 10 a rapid-entry tube makes it easier toswallow the string; but the usefulness of the test is stilllimited by the fact that bleeding must be taking place atthe time the dye is injected. The test is perhaps of

1. Avery Jones, F., Gummer, J. W. P. Clinical Gastroenterology. Oxford,1960.

2. Welch, C. E., Allen, A. W., Donaldson, G. A. New Engl. J. Med. 1955,252, 921.

3. McDermott, W. V. ibid. 1957, 257, 1161.4. Belkin, G. A., Conn, H. O. ibid. 1959, 260, 530.5. Lipp, W. F., Lipsitz, M. H. Gastroenterology, 1952, 22, 181.6. Schatzki, S. C., Blade, W. R. New Engl. J. Med. 1958, 259, 910.7. Cantwell, D. F. Clin. Radiol. 1960, 11, 60.8. Chandler, G. N., Watkinson, G. Q. Jl Med. 1959, 28, 371.9. Haynes, W. F., Pittman, F. E. Gastroenterology, 1960, 38, 690.

10. Pittman, F. E. Lancet, 1965, i, 1308.