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ALLERGY IN SKIN DISEASEBy C. D. CALNAN, M.B., M.R.C.P.

Consultant Dermatologist, St. _'ohn's Hospital for Diseases of the Skin, LondonPhysician, Skin Department, Royal Free Hospital, London

The skin has considerable importance in relationto allergy. Many allergic disorders have mani-festations which can be seen in the skin, apart fromthose in which the skin itself is the shock organ.And because the skin is so easily accessible, itcan be used for various allergy test procedures,either clinically or experimentally. Notableadvances have been made in the whole field ofallergy and immunology in recent years, parti-cularly in relation to the skin; and some of themsubsequent to the review six years ago of thebasic mechanisms and the role of allergy inclinical medicine in this journal by Pepys (I953).In spite of this, however, much controversyremains and many problems are still unsolved.

UrticariaUrticaria is the clinical prototype of the allergic

reaction in the skin. Sir Henry Dale's discovery ofH substance or histamine was the starting pointfor numerous investigations; the fact that hista-mine could produce vasodilatation and increasedcapillary permeability-in fact, all the elementsof Sir Thomas Lewis' triple response of ery-thema, wheal, and local axon flare-tended for along time to identify this amine as the chemicalmediator of the allergic reaction. The demon-stration by Riley and West (i953) of the mastcells in the skin and other tissues as the principalstore of histamine, came after the dominant roleof histamine was being challenged by 5-hydroxy-tryptamine (5-HT or serotonin), proteolyticenzymes, and kinins. The use of histamineliberating substances, antihistamine drugs, andother blocking agents have shown the problemto be much more complex than was originallysuspected (Inderbitzen, 1955).From the clinician's point of view, urticaria is

best divided into acute and chronic forms, theacute cases consisting of one or more relativelybrief episodes, and the chronic cases being thosewhich persist with only short intervals of freedombeyond an arbitary period of about three to sixmonths. Many, but not all, of the acute cases canbe traced to causative agents, such as a food,

inhalant, or other foreign protein allergen. Theymay be shown to be dependent on the presence of acirculating antibody in the serum by means ofskin tests (prick, scratch, or intradermal) withthe appropriate antigen, or by the passive transfertechnique. The latter method is not now recom-mended because of the very real risk of serumhepatitis, which may be severe and sometimesfatal. Most of the patients who have circulatingantibodies to food antigens give such a precisehistory of urticarial swelling of the mouth andlips, with or without vomiting, only and on everyoccasion when they eat that particular food, thatskin testing is not normally required for diagnosis.Patients, however, vary enormously in theirsensitivity; some may react to raw or lightlycooked eggs but not to eggs used in cakes, pastries,and so on, whilst others react to eggs in anyform; some patients may be so sensitive to fishprotein that they cannot handle paper or plateswhich have been in contact with fish, withoutdeveloping urticarial swelling of their hands (butnever an eczematous reaction, even in atopicsubjects). Not infrequently there is some dis-parity between a patient's clinical history and theskin tests with food antigens, since allergic sensi-tivities can be subclinical. Important, on the otherhand, is the fact that hydrolysates of some shell-fish, fruits and possibly other foods can liberatehistamine. This may be the explanation of someanomalous and irregular skin test results. Experi-mental work has shown that a wide variety ofdifferent substances can release histamine withoutany antigen-antibody reaction taking place (Paton,1956). Some examples are snake venoms andanimal toxins, proteolytic enzymes like trypsin,tween 20 and bile salts, egg white, dextran, horseserum, and polyvinyl pyrollidone, alkylamines andcompound 48/80. In addition numerous drugshave this property to some degree, for example,morphine, pilocarpine, codeine, atropine, quinine,curare, stilbamidine, apresoline, and aspirin(Winkelmann, I957, Pepys, I95I). It is note-worthy that in chronic urticaria, a specific antigenis rarely found to be the cause, and skin testing is

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unrewarding. It is possible that one of thenumerous histamine release mechanisms is operat-ing. Penicillin is an important cause of urticaria,and it tends to persist for a period of a few weeksor even months after the drug has been stopped.Skin testing is unhelpful and antibodies canrarely be demonstrated. Patients may be soextremely sensitive to it as to react to the smallamounts present in milk, consequent upon theuse of the drug for treatment of mastitis in cows(Zimmerman, I959). Considerable benefit hasbeen derived from penicillinase preparations,although there is the risk of such agents themselvesbeing antigenic. In both acute and chronicurticaria drug sensitivity should always be con-sidered as a possible cause. It is said to accountfor io% of cases. Aspirin can be allergenic, butin the writer's experience it appears to act morefrequently as a histamine liberator only therebyaggravating many instances of chronic urticaria.Serum sickness is infrequently seen with.the

diminished use of specific sera and with the specialtreatment of foreign sera, but a number ofexamples were encountered last year following thewidespread inoculations with Asian influenzavaccine prepared from virus grown on eggs. Nodescription of the condition can better the classicalmonograph by von Pirquet and Schick (I905),which was recently translated into English by thelatter author. Oedema and urticaria are theimportant cutaneous components of the syndromeand they may persist for some months. Penicillinmay produce it, in addition to the more severeand sometimes fatal anaphylactoid reaction, whichis normally only seen with protein antigens; itis more frequently encountered in patients withthe atopic diathesis.

For treatment, a wide variety of anti-histaminedrugs is available. The most suitable one mayhave to be found by trial and error for each patient,but it is important to prescribe adequate dosagewithout incapacitating side effects; to give thedrug at the times of day when the patient expectshis urticaria to be worse; and to continue the drugfor a few weeks after the urticaria has ceased.The itching of urticaria is associated with theerythematous flare rather than the wheal; thechemical mediator of the itch sensation is almostcertainly a proteolytic enzyme (Shelley andArthur, I955). But the precise inter-relationshipof the enzyme and histamine is, as yet, unclarified.Steroids are also effective when given orally orparenterally, but their use should be restricted tothe most severe cases, and they are best avoided inchronic urticaria.

Atopic DermatitisThe term atopic dermatitis was introduced by

Coca (I93I) to delineate a particular pattern ofeczema which was especially liable to be seen inassociation with a personal or a family history ofallergic asthma or hay fever. Its manifestationscan be very varied in infancy, childhood, ado-lescence and adult life. The term has proved auseful unifying concept, in this regard, from thedermatologist's point of view, although not uni-versally accepted. It has, however, been re-sponsible for a continuous controversy, whichremains unresolved. The subject was recentlydebated by Mayer (I957) and Jadassohn (I957) atthe Third International Collegium of Allergologyin London. The hypersensitivity basis of allergiccontact dermatitis is generally accepted as a causeand effect relationship. The simple chemicals ornon-protein substances involved behave as in-complete antigens, although the delayed type' antibodies ' to which they give rise, do notconform to the criteria of the classical type Qfprecipitation or agglutination- antibodies, and theyhave not been satisfactorily separated fromcellular elements. Nevertheless, these 'anti-bodies ' appear to be the effective means by whichthe contact dermatitis reaction is produced. Inthe case of atopic dermatitis, on the other hand,one finds that an appreciable proportion, thoughnot all, of the patients have immediate type anti-bodies in their serum similar to those found inasthma, hay fever, and urticaria. Their presencecan be demonstrated by the usual prick, scratch,intradermal, or passive transfer tests. The cruxof the matter is the relationship of these serumantibodies to the dermatitis. The usual dermato-logical viewpoint is that such antibodies relate tothe patient's asthma, hay fever, and urticarialtendencies only, and not to their dermatitis(Schnyder, 1957), while many allergists believethat there is a causal relationship. The issue hasbeen obscured by many observations. Sulzberger(I940) said ' we have never succeeded in pro-ducing the dermatosis de novo, and we know of noregularly successful production of the dermatosisby deliberate exposure to the presumptive allergenduring dermatosis-free periods.' In dietarystudies, Cooke (I944) was unable to detect anyexacerbation of eczema from the ingestion of food-stuffs to which the patient gave a positive whealreaction. Similar views are expressed by Adamsonand MacLeod (I926), O'Leary (I953), andRostenberg (955). Evidence to the contrary hasbeen cited by Engman, Weiss and Engman (1936),Tuft (I949) and Herrmann (1946). It must beemphasized, however, that the evidence advancedby these latter authors shows that exposure toatopic reagins may produce itching and thensecondarily exacerbate or aggravate existingdermatitis; but this is not comparable to the cause

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and effect relationship of allergic contact dermatitisor of hay fever. The various theories concerningthe pathogenesis of the atopic state have been wellreviewed by Rostenberg (1955). More recentlyStrauss and Kligman (I957) have producedexperimental data to show that there may be amechanism by which food and inhalant allergenscan provoke flares of an existing but aetiologicallyunrelated dermatitis. They found that the intra-nasal, subcutaneous, or surface application of suchreagins in sensitive patients influenced the be-haviour of areas of poison ivy dermatitis producedby known quantities of the specific allergen(pentadecylcatechol). The contact dermatitis wasshown to be aggravated, made to persist longer,and to produce lichenification, perhaps as a resultof scratching. It would appear, therefore, thatthe reagins occupy a secondary rather than aprimary role in atopic dermatitis.One must agree with Mayer (I957) when he

says that the disagreement between allergists anddermatologists is perpetuated primarily by mis-conceptions and misinterpretations. However,the writer is unable to support his contention thatatopic dermatitis and contact dermatitis are quiteclosely related, and that they are both of allergicorigin. It is accepted that simple chemicalcompounds such as paraphenylenediamine, picrylchloride or quinine, can induce the formation ofboth immediate and delayed type antibodies, withtheir appropriate clinical manifestations. Kligman(1958) has recently emphasised the not infrequentoccurrence of immediate type reactions in contactsensitization to poison ivy. Chase (1954) hasshowed that the type of antibody produceddepended in part on the route of administration,and Mayer (I957) believes it to be associated withwhether the chemical hapten links with a fibrousor globulin protein as a carrier. His view is thatif the chemical is applied to the skin it is mostlikely to combine with keratin or collagen proteinand so form delayed type antibodies; while if thechemical is injected intravenously, it wouldcombine with albumen or globulin protein and soform immediate type antibody. There is, how-ever, incomplete proof of this theory. It is in-disputable that one chemical substance may in-duce both types of antibody. The point at issueis that, while the delayed type antibodies are asine qua non for the development of allergic contactdermatitis, there is ample evidence that atopicdermatitis can occur in the absence of, and in-dependently of any demonstrable immediate typeantibodies. Atopic dermatitis, in fact, is notprimarily an allergic dermatitis at all. Theatopic state or diathesis is an inherited abnormalitymanifested as a syndrome of associated conditions-a particular clinical pattern of eczema, asthma,

hay fever, and urticaria (dependent on reagin anti-bodies in the plasma); certain physiologicalstigmata (Kierland, 1955) such as white der-mographism and abnormal sweat gland responses;and a special type of cataract. Gans (I956)believes it is linked to the leptosome type ofhuman physique.Contact Dermatitis

Contact dermatitis is a unique allergic responseof the skin. It is more highly developed in manthan in any other animal, perhaps as a defencemechanism compensating for the loss of a uni-versal hair covering. From the immunologicalstandpoint it is an example of the delayed type ofhypersensitivity, and is not normally associatedwith any demonstrable antibodies in the plasma.Our understanding of the allergic mechanisms in-volved in contact dermatitis has been advancedcommensurately with the increased biological andimmunological interest and research in delayedhypersensitivity reactions over the past decade.Most of the work has been done in animals,especially the guinea-pig, but recent attemptshave been made to study the reaction experi-mentally in man. The skin of guinea-pigs, whensensitized by contact with simple chemical com-pounds, does not react with the histologicalresponse of the dermatitis reaction found in man,except over the skin of the nipple. However, thisis due to an anatomical and not an immunologicaldifference. If the skin is thickened (i.e. madeacanthotic) by previous treatment with a suitableagent (such as lauryl sulphate) the guinea-pig' sskincan be made to produce analogous histologicalchanges (Jadassohn, 1957), but in most experi-mental work this procedure is unnecessary. Bloch,Mayer, Landsteiner, and many others have shownthat the guinea-pig can be readily sensitized by therepeated application to the skin of relativelysimple chemicals, such as primula extracts,paraphenylenediamine, dinitrochlorbenzene, picrylchloride and paranitrodimethylaniline. It hasbeen assumed that these chemicals are haptenswhich must be conjugated with protein to form acomplete antigen. Such a conjugation can be pro-duced in vitro and has been shown to occur in vivo.But the in vitro conjugated chemical is not a moreeffective antigen than the simple chemical alone,and when injected the conjugated chemical doesnot usually produce contact type sensitivity-it hasto be applied to the skin surface. As mentionedpreviously, Mayer (I957) feels that the chemicalmust be conjugated with a fibrous rather than aglobular protein in the skin in order to producedelayed as opposed to immediate type anti-bodies.Much recent interest in this field has centred

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round the role of the lymphocyte and the regionallymph nodes. Landsteiner and Chase (I942)originally showed that contact sensitization inguinea-pigs could be transferred by means oflymphocytes, and this important observation hasbeen amply confirmed whether the lymphocytesare obtained from circulating blood, thymus,lymph nodes, spleen, thoracic duct, or by para-biosis. The experiments of Haxthausen (I939)are particularly interesting. He transplanted skinfrom sensitized to non-sensitized animals and viceversa, and repeated the operation in identicalhuman twins. The results demonstrated' recipientdominance ' i.e. if a sensitized animal received agraft from a non-sensitized one, that graft showedsensitivity after it had become firmly established;and if a non-sensitized animal received a graftfrom a sensitive one, the graft ceased to show anyreactivity. Hence the skin was demonstrated tobe mainly important as a target organ and not toplay any part in the immunological process, apartfrom its still undefined role in initial sensitization.Frey and Wenk (1956) have studied the problemwith an ingenious skin explant which is connectedto the flank of the guinea-pig only by a neuro-vascular bundle, and by a slender bridge of skincontaining lymphatic channels. They found thatthe application of a suitable chemical to the mainskin of the animal could sensitize the explant onlywhen the direct vascular supply was intact;whereas, when the chemical was applied to theexplant, sensitization of the whole animal de-pended on the integrity of the lymphatic channelsand the regional lymph nodes.There is now little doubt that the lymph nodes

are the principal sites of manufacture of delayed-type antibodies, and their cells can transfer sensi-tivity to non-sensitive animals. Further, lymphnode cells can produce antibodies of delayed typehypersensitivity in vitro, as shown by Harris,Harris and Farber (1956) in rabbits using anti-genic material from Shigella paradysenteriae. Ifthis can be shown to be true of the contact der-matitis reaction in man, the dominating role of theregional lymph glands will be established. Thathuman contact dermatitis can be transferred bylymphocytes, has been confirmed by Epstein andKligman (1957). They emphasized that the im-portant requirements are (i) a very high degree ofsensitivity in the donor, (2) a large number oflymphocytes (probably about 200 million), (3) avery potent allergen, and (4) a recipient who isgenetically susceptible to being sensitized. Anintriguing aspect of sensitization by lymphocytetransfer is that some of the recipients remainedsensitive for several months-long after all thedonated cells must have been destroyed by thehomograft reaction. It would seem that some

form of active sensitization, as well as passivetransfer, had been achieved. The details of theprocess are not clear, but it is suggested that theintra-lymphocytic antibody protein is incompletelymetabolized when such cells die, and is taken upup by young cells and re-utilized by them asfunctioning antibody (Hamilton, I958). Becausesuch antibodies behave so differently fromclassical precipitating or agglutinating antibodies,some immunologists feel they should have aseparate designation and refer to them as ' transferfactors.' Pappenheimer (1958) has put forward atheoretical scheme for the way in which suchtransfer factors are released from lymphocyteswhich contain them and are then able to activatenew lymphocytes which take them up. Such ascheme may be useful as a working hypothesis,but it yet awaits the necessary proof.

Kligman's (1958) extensive clinical and experi-mental study with poison ivy (Rhus) has em-phasized important aspects of contact dermatitis.White persons are more readily sensitized than theNegro, Puerto Rican or Hawaiian. Pre-pubertalchildren are much more easily sensitized withi per cent. pentadecyl-catechol (one of the poisonivy allergens) than are adults. But this differencemay be due to previous (unknown) exposure inthe case of the latter. Prior exposure has an im-portant influence on later sensitization. Patientswith atopic eczema, asthma, or hay fever, are notmore prone to rhus dermatitis. All contactsensitivity has a natural tendency to diminish withage, and this is probably part of a general biologicalphenomenon, as illustrated by the diminution oftuberculin sensitivity with age. Contact sensi-tivity may be sub-clinical, as when patients thinkthey are immune after failure to develop dermatitisfrom a weak exposure to an allergen, although apatch test with a stronger concentration is positive.A significant difference from other types of allergyis that fresh exposure to the antigen does notordinarily increase the titre of sensitivity, whichappears to be determined mainly during the initialsensitization phase. The factors responsible dur-ing that period are unknown, but a genetic pre-disposition is probably one of them. A severeattack of dermatitis not infrequently makes the skinsupersensitive in a non-specific fashion (the so-called status eczematicus) and false positive patchtests can be elicited. The reverse condition alsooccurs, though rarely. The skin becomes re-fractory and may not react to the specific allergenwhich has caused the dermatitis, except in veryhigh concentrations. Whether the skin is tooexhausted to react or whether there is an im-munological change is uncertain.

There have been numerous discussions sinceCivatte described his 'vesiculette primordiale '

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as to whether the dermis or the epidermis is thesite of the initial reaction in contact dermatitis.It now seems clear that the process begins aroundthe blood vessels of the dermis and that all contactdermatitis is a combined dermal and epidermalreaction. Kligman has shown that the dermis willstill react to contact allergens after the epidermishas been removed. The terms dermal andepidermal sensitivity used by dermatologists todenote immediate and delayed type allergic re-actions are anachronisms. Epstein (I956) hasraised a further difficulty by coining the term' dermal contact dermatitis ' for cases in which thepatch test is negative, but an intradermal test givesa delayed positive result. Many such cases canbe explained by lack of penetration of the allergenthrough the epidermis, when present in lowconcentration, examples being neomycin (Calnanand Sarkany, 1958), and eosin (Calnan andSarkany, I957). Epstein (I958), however, main-tains that there is a different immunologicalmechanism involved.

Desensitization or hyposensitization againstcontact dermatitis can be achieved but it is rarelyindicated in practice, having regard to the time,care, and side effects involved. It may bejustified in certain circumstances such as withnurses suffering from streptomycin or penicillindermatitis (Wilson, 1958), or with NorthAmericans afflicted by rhus allergy. Kligman(I958) has evolved a satisfactory scheme forhyposensitization to poison ivy by means ofgraduated oral doses of cashew nut shell oil (whichcontains related allergens), and has demonstrated alowering of the patient's sensitivity titre. Herightly warns against accepting clinical improve-ment as evidence that a patient has been im-munologically desensitized. Once hyposensitiza-tion has been achieved, it unfortunately wanes, andthe original sensitivity slowly returns. This is incontrast with the difficulty of re-establishing acontact sensitivity in a person who has lost itnaturally with old age or over the passage of years.

Drug ReactionsThe commonest manifestations of drug sensi-

tivity are in the skin. There are many differentcausative mechanisms in drug reactions, but allergyis believed to be the basis of the largest group,although proof is frequently lacking. Evidence of aspecific serum antibody has been provided in thecase of sedormid thrombocytopenic purpura bythe work of Ackroyd (I949) and other drugs havebeen shown capable of linking with platelets toform a complete antigen. A notable dividend ofAckroyd's work is the diagnostic in vitro test forserum antibody. The claim of Hoigne et al.(1956) to be able to identify specific reacting factors

in the serum of patients with drug sensitivities,has not yet been satisfactorily confirmed, in spiteof attempts by several workers. Hoigne and hiscolleagues used a nephalometer to detect an in-crease in turbidity when the serum and a solutionof the drug were mixed in optimal concentrations.The presence of antibodies has not been confirmedin any other form of drug sensitivity exceptthrombocytopenic purpura and urticaria. Labora-tory tests would be particularly valuable in eluci-dating drug induced disease syndromes likeerythema multiforme, erythema nodosum, glan-dular fever (from anti-tuberculous drugs) andsystemic lupus erythematosus (from apresoline)-all presumably mediated by an allergicmechanism. In addition to the apresoline re-action, evidence of an immunological basis forlupus erythematosus is accumulating, especiallysince the finding of auto-antibodies to desoxyri-bosenucleic acid. But all the serological ab-normalities in this disease could still be onlysecondary effects produced by some undiscoveredcausal agent.

GranulomasRenewed interest in the allergic nature of the

sarcoid granuloma has been aroused by the ap-pearance of an unusual dermatosis. An eruptionof small papules with the histology of a sarcoidalgranuloma was found in the axillae of certainpatients who had used a new type of stick deodorantcontaining a zirconium salt (Shelley and Hurley,1958). More than 70 cases were described in-cluding one from England (Calnan and Sarkany,1958) before the products were withdrawn by themanufacturers. The condition was producedexperimentally and was shown to be due to specifichypersensitivity to the metal zirconium when in-jected intradermally in high dilution. Thepatients did not give a positive patch test. Theonly other metals known to produce sarcoid-likegranulomas are mercury, silicon and beryllium.There is no evidence as yet that the silica granu-loma, arising many years after silica had been ac-cidentally introduced into the skin, is an allergicprocess. But berylliosis or beryllium disease,whether it is manifest as pulmonary infiltration orcutaneous sarcoidal nodules, is dependent onhypersensitivity to the metal. It can be demon-strated by a positive patch test reaction with ai per cent. solution of a beryllium salt, andSneddon (1958) has shown that the eczematousresponse may merge after some weeks into a dermalgranuloma. Patients with idiopathic sarcoidosis,pulmonary anthraco-silicosis as well as controlsubjects do not show hypersensitivity to intra-dermal injections of the salts of any of the elementsin the periodic table (Shelley et al., 1958).

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450 POSTGRADUATE MEDICAL JOURNAL August I959

The differential diagnosis of a sarcoidal granu-loma in the skin may often be difficult because ofthe wide range of possible causes (Shelley andHurley, I958). The principal ones giving rise to thisproblem in England are tuberculosis, syphilis,leprosy, leishmaniasis, as well as silica, mercury,and other foreign bodies; most patients with asarcoid reaction, however, fall into the category ofidiopathic sarcoid, whose status as an independententity is not universally accepted although theKveim reaction specificity is strong evidence in itsfavour.

Physical and Vascular AllergyThere are a wide variety of dermatoses which

are usually regarded as being of allergic origin,although this cannot yet be regarded as proven.One example is hypersensitivity to physical agents,such as light, heat and cold, some of which may bedrug induced. In some instances of solar urticariaonly have antibodies been demonstrated by thepassive transfer technique. Substances such asrose bengal, eosin, and haematoporphyrin cangreatly increase the reaction of the skin to sunlightwithout any sign of an allergic mechanism. Adistinction has been made between phototoxic andphotoallergic reactions, although it is not alwayseasy to differentiate them, especially in the caseof some drug photosensitivities like sulphanilamide(Blum, I94I) and chlorpromazine (Calnan, I958).Although much work has been done to determinethe active wavelengths of light in photosensitivity,with the aid of filters or a monochromator, we arestill quite unable to define the nature of the allergenwhich is presumably formed in the skin by theincidcent light, if the reaction is to be regarded as agenuinely allergic one.A number of skin disorders in which the main

histological feature is inflammation and damageto small blood vessels, which cannot be explainedin any other way, are now thought to be allergic,and the concept of vascular allergy or allergicvasculitis has arisen. Examples are NodularDermal Allergide of Gougerot (I95I), arteriolitisallergica (Ruiter, 1953), cutaneous periarteritisrodosa (Miescher, 1956) and the median nasalgranuloma associated with renal lesions. Thechief evidence in favour of an allergic basis forthese conditions is the similarity of the histologicalfindings to known allergic lesions. Evidence of acausal allergen such as acute or focal bacterial in-

fection, or drugs is unconvincing, and the patientsare not usually responsive to treatment. Theseconditions are clinically recognizable, but theirallergic basis remains questionable.

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Med. Clin. N. Amer., 20, 65I.EPSTEIN, S. (x956), Dermatologica (Basel), 113, 19I.EPSTEIN, S. (1958), Ibid., 117, 287.EPSTEIN S. and KLIGMAN, A. (I957), Y. invest. Derm. 28, 291FREY, J. R., and WENK, P. (1956), Ibid., 112, 265.GANS, 0. (I956), Trans. St. 3ohn's Hosp. Derm. Soc., 37, I.GOUGEROT, H. (195s), Minerva Dermatoloftca, XXVI.HAMILTON, L. D. (I958), N.Y. Acad. Sci., 73 (I), 39.HARRIS, T. N., HARRIS, S., and FARBER, M. B. (I956),

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Press, New York.PATON, W. D. M. (I956), in 'Histamine' CIBA Foundation

Symposium, Little, Brown & Co., Boston, Mass.PEPYS, J. (isi), Int. Arch. Allergy, 2, 147.PEPYS, J. (I953), Postgrad. med. J., 29, 351, 564.RILEY, J. F., and WEST, G. B. (1953), J. Physiol. (Lond.), 120, 528.ROSTENBERG, A., Jr. (09ss), Amer. Practit. (Philad.), 6, I094.RUITER, M. (I953), Brit. J. Derm., 65, 77.SCHNYDER, U. W. (957), Int. Arch. Allergy, iI, 64.SHELLEY, W. B., and ARTHUR, R. P. (I95s), Arch. Derm. and

SYPh., 72, 399.SHELLEY, W. B., and HURLEY, H. J. (I958), Brit, J. Derm.,

70, 75.SHELLEY, W. B., et al. (1958), J. invest. Derm., 31, 301.SNEDDON, I. B. (I958), Postgrad. med. Y., 34, 262.STRAUSS, J. S., and KLIGMAN, A. M. (1957), Arch. Derm.,

75, 8o6.SULZBERGER, M. B. (I940), ' Dermatologic Allergy,' Charles C.

Thomas, Springfield, Ill.TUFT, L. (i949), J. invest. Derm., 12, 21 1.VON PIRQUET, C., and SCHICK, B. (I905), 'Die Serumkrank-

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