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Allergic shock following administration of anti-diphtheritic serum
98 there was carried out u n d e r the auspices of the Carnegie U n i t e d K i n g d o m T r u s t a survey of the experience o v e r a period of three years of young m e n between the ages of 18 and 25, especially of those w h o were unemployed. T h e T r u s t wished to know what services, statutory and voluntary, were effectively available for these young men, the extent to which the m e n resorted to t h e m and the measure of success which they achieved. A considerable part of this work was carried out in the Glasgow area, where in July, 1937, 11"9% of y o u n g m e n between the ages of 18 and 20 were u n e m p l o y e d ; and the Report on the Survey, published in 1943, u n d e r the title " Disinherited Y o u t h , " provides a unique storehouse of information on a major social p r o b l e m and a suitable j u m p i n g - o f f point for further work. T h e s e are exciting days in which we live, alike in relation to developments in the field of medical treatment and in the organisation of medical services. Almost everywhere things are m o v i n g and almost everywhere there is m u c h of interest. I n some directions there is urgent need for basic research ; in others scientific knowledge is ahead of administration. Advances in medical science are constantly opening up great possibilities, and it is a legitimate complaint of the scientist that often a long time is allowed to elapse before the fruits of his labours are m a d e generally available. J u s t before the outbreak of war Sir Edward Mellanby wrote that it was difficult to avoid the conclusion that the d o m i n a n t factor in deciding health legislation has often a political rather than a scientific basis. H e felt that the whole position of State action in health matters required clarification; that sentiment and " public appeal " associated with particular lines of action ought to be eliminated, and each proposition considered only from the point of view of results to be expected f r o m administrative schemes in terms of saving life and affording increased efficiency to citizens. T h e s e considered opinions are w o r t h y of recall w h e n we seek to formulate an approach to the health problems of to-morrow, for n e v e r was there greater need to discriminate between experiments and stunts, between what is based on scientific knowledge and what on political expediency : one is t e m p t e d to recall Juvenal's observation that plenty of bread a n d diverting shows are the most effectual means to keep the people to their duty. I have touched lightly on some of the public health problems of our time. Furtherance of national health involves first and foremost the creation of a healthy environment, good living and working conditions, education and encouragement in the art of living, and an appreciation of the essential u n i t y of health and of health s e r v i c e s - - t h e inseparability of curative and preventive medicine. Criteria of a Health Service
T h e r e are certain criteria by which, in the long run, the value of any health service m u s t be judged. Will it produce healthier citizens ? Is it a comprehensive service ? Is it balanced ? Are its elements integrated ? T h e p r o b l e m of tuberculosis, in Scotland at all events, is as m u c h the p r o b l e m of the t w o - r o o m e d house as the p r o b l e m of sanatorium care. E v e n such an important aspect of social medicine as the supervision of industrial health is, it appears, to be expressly excluded f r o m the G o v e r n m e n t ' s n e w scheme, though in this m a t t e r the Minister would probably claim Credit for good intentions. I believe it to be imperative to forge a stronger link between the work of the Medical Officer of H e a l t h and that of other elements in health and social services. It m a y be that in t i m e the evolution of health centres will help to break d o w n artificial barriers, and in any case it will certainly be a challenge to the genius of individual health officers to forge these links as best they can in the light of local circumstances, for without such links they m u s t inevitably be frustrated in their work and the Service be the poorer. But I think it would be extremely valuable if something could be done in framing the new service to secure practical recognition of the need for real unity in these matters. A n d what of the quality of the Service ? Sir George Buchanan, at the end of his long and distinguished association with the Health Organisation of the League of Nations, doubted if the world would gain by having a stock pattern of administration forced upon nations by any central a u t h o r i t y : he felt
PUBLIC HEALTH, April, 1946 sure it would not benefit by stock patterns of national administration in medicine or hygiene. T h e wisdom of this observation on rigidity of structure and approach is not wholly confined to essays in international health : e v e n within particular countries, health services seldom lend themselves to absolute uniformity. I t is inevitably difficult for the State to look with enthusiasm on that measure of individuality and freedom which is the v e r y essence of the practice of medicine. T h o s e of us w h o have seen at close quarters the working of State departments, necessarily politically minded, cannot fail to appreciate the difficulties u n d e r which professional m e n labour in their service. W e m u s t do everything possible to secure that t h r o u g h time the n e w service does not produce a standardised, flat l u m p without leaven. T h r e e h u n d r e d years ago J o h n Milton was troubled by somewhat similar qualms about official control, and the danger has certainly not become any less since his time : - " Another sort there be who w h e n they hear that all things shall be ordered, all thing§ regulated and settled; nothing written but what passes through the custom-house of certain Publicans that have the tunaging and p o u n d i n g of all freespoken truth . . . . H o w goodly and how to be wisht were such an obedient unanimity as this, what a fine conformity w o u l d it starch us all u n t o . " Conformity goes ill w i t h the practice of medicine; and it may be hard to keep the Publicans in check.
ALLERGIC SHOCK FOLLOWING OF ANTI-DIPHTHERITIC
ADMINISTRATION SERUM*
By I. M. LIBRACH, M.B., CH.B., B.A.O., D.P.H.,
Medical Superintendent, City Isolation Hospital, Nottingham Anaphylactie or allergic shockf in the h u m a n subject is fortunately, not a c o m m o n condition. I t is difficult, however, to make a p r o p e r appraisal of its incidence f r o m the personal experience of any individual physician, because that can n e v e r be wide enough. A review of the literature would indicate that severe allergic shock and death are extremely infrequent. Park estimated in 1928, that 1 in 20,000 s e r u m injections is followed by alarming symptoms, and 1 in 50,000 is fatal. T h e literature records few accounts of clinical anaphylactic shock. Vaughan (1939) states that it seems that one hears of more cases of severe shock and death than are recorded, perhaps because the average physician is loath to put such records on paper. Gottstein in 1896 gives 12 cases ; Rosenau and A n d e r s o n in 1906, 19 cases ; Gillette (1909), 16 fatal cases. Lamson, in 1924, reviewed the literature f r o m 1895 to 1923, and recorded 41 cases, while f r o m 1924 to 1936, Vaughan and others recorded 69 cases, of which 52% were due to serum. In view of the relative paucity of recorded accounts of this dangerous condition, it m i g h t be of interest to record and discuss the following two cases : CASE RECORDS Case I.--R. R., a schoolgirl aged 17 years, first complained of some headache, sore throat and earache, with pain in back and limbs, on 17.5.45. She was seen by her doctor who, suspecting diphtheria, swabbed her throat. The swab was returned positive and she was admitted to hospital on 19.5.45. Her previous history included measles, whooping cough and " fainting fits at the periods." She was vaccinated and had been immunised against diphtheria by her own doctor five years ago in two shots, probably A.P.T., but the doctor was not certain of this. No history of allergy was given by patient or family. On examination she was a strapping girl; temperature, pulse and respiration were normal. Both tonsils were swollen and stippled with white specks of exudare. The fauces were injected and the cervical glands were small and not tender. There was nothing of note in any other system. In view of the previous history of * Paper read to the East Midland Branch, February 14th, 1946. "~The term hyper-sensitivity as employed immunologically can be divided into (1) Anaphyliaxis, (2) Allergy. The former has now come to be used for cases of induced (i.e., non-spontaneous) hypersensitivity, while the latter comprises all other forms exclusive of anaphylaxis, namely, hereditary, bacterial, contact and drug allergies, and finally Serum Diseases, including shock. This latter definition will be adhered to in this paper, namely, Allergic Shock (or A.S.).
PUBLIC HEALTH, April, 1946 immunisation, a Schick test was done at 5.45 p.m. 19.5.45. A t 2.30 a.m. (eight hours later) 20.5.45, this was followed by the intramuscular administration of 80,000 units A.D.S. together with 3,000 units A.S.S. Adrenaline m.v was given in accordance with our normal ro~tine. Nepenthe, m.xv was ordered to be given if necessary. At 4.0 a.m. (one and a half hours afterwards) the patient suddenly collapsed. She was cold and clammy and sweating; with an imperceptible pulse and frothing at the month. Adrenaline m.x and coramine t c.cm. were ordered immediately, to be ft>llowed at 4.30 p.m. by a further 2 c.cm. coramine. The end of her bed was raised on blocks. Morphia g. one-sixth and radiant heat were also ordered. Adrenaline m . x was then instituted. At 6.45 a.m. she was much better, but there was an urticarial rash over her trunk, face and arms. The B.P. was 130/80; the pulse 88 and of good volume. The heart sounds were regular but muffled. The adrenaline and coramine were kept on eighthourly for a further 24 hours. On 26.5.45, a marked papulo-vesicular rash with conjunctival involvement appeared, which lasted for 24 hours. The heart sounds were still muffled and the blood pressure had fallen to 95/60. Despite warning, the patient was discharged, against advice, at this stage. The Schiek test proved to be a doubtful positive, but a virulence test showed the diphtheria bacillus to be of modified virulence, i.e., failing to kill a guinea-pig in four days, but producing a marked local lesion. Though she gave a history of horse riding, the patient was negative to a skin test of horse-dander. I subsequently discovered six weeks later that the patient made a perfect recovery. Case 2.--J. B., a boy aged I8 years, was admitted on 24.7.45, having complained of headache, vomiting and sore throat for two days previously. He had no allergic history, personal or familial. He had never been immunised. He had had mumps, measles and chicken-pox. He was non-vaccinated. He was a typical case with bull neck and severe faucial involvement, and had a suspicious urticarial rash on his skin. The ward sister was therefore told to watch for signs of allergic shock. At 6.15 p.m. he was given 100,000 units A.D.S. and Adrenaline m.x was ordered two-hourly for two further doses. At 7.20 p.m. (one hour later, before next dose of adrenaline was due), he suddenly became restless, cyanotic and confused and attempted to g e t out of bed. The pulse was rapid and soft, and he was clammy with perspiration. He improved with coramine and adrenaline by 9.20 p.m. Next day he had marked urticaria. He was put on penicillin in an attempt to expedite his recovery, and was given 212,000 units, but he developed nasal speech on 24.8.45, and accommodation disturbance on 27.8.45, together with triple rhythm. After 88 days in hospital he was discharged--an E.C.G. showed a low voltage in all leads and there was a rough systolic bruit at the pulmonary area which could not be accounted for. He was told to report in six weeks for a+ re-examination, but ne'~er did so. Discussion As defined originally b y Schick a n d v o n P i r q u e t in 1905, an i m m e d i a t e s e r u m reaction is one o c c u r r i n g w i t h i n 24 h o u r s of injection, a n d a n accelerated reaction f r o m t h e s e c o n d to the sixth day. R a t h e r (1943), h o w e v e r , divides t h e s y m p t o m s o f a n a p h y laxis in m a n into : - 1. M i l d - - u n e a s i n e s s , a p p r e h e n s i o n , urticaria, i t c h i n g o r pricking. 2. S e v e r e - - d y s p n o e a , cyanosis, generalised urticaria, erythema, o e d e m a of face, t o n g u e a n d t h r o a t , h a c k i n g cough, frothy e x p e c t o r a t i o n a n d collapse. H e does n o t define t h e 'time of t h e reaction, b u t says t h a t symptoms m a y c o m e o n explosively, e v e n b e f o r e t h e i n j e c t i n g needle is w i t h d r a w n , or after a l a t e n t p e r i o d o f 30 m i n u t e s o r longer. A e c o r d i n g to h i m , d e a t h m a y o c c u r in a few m i n u t e s or after several h o u r s d u e to ( I ) o e d e m a o f glottis ; (2) s p a s m of bronchioles ( g u i n e a - p i g t y p e of anaphylaxis) ; (3) s p a s m of hepatic v e n u l e s (canine t y p e ) ; (4) s p a s m of p u l m o n a r y arterioles ( r a b b i t t y p e ) ; (5) s p a s m of adrenal vessels. H o w these types are d i s t i n g u i s h e d clinically is n o t m e n t i o n e d ! D e a t h m a y e n s u e following i n t r a d e r m a l , s u b c u t a n e o u s , intramuscular or i n t r a v e n o u s injection, a n d t h o u g h t h e rate of absorption, w h i c h d e p e n d s o n t h e route, is said to influence the s u d d e n n e s s of death, t h e degree of h y p e r s e n s i t i v i t y of t h e patient is t+he d o m i n a n t factor. R a t h e r considers t h a t to " a t t r i bute the A r t h u s p h e n o m e n o n , a n a p h y l a c t i c shock a n d d e a t h to the mild sensitisation p r o d u c e d b y t o x i n - a n t i t o x i n , is n o t
99 c o n s o n a n t w i t h t h e facts detailed i n t h e literature, t h o u g h it u n d o u b t e d l y p r o d u c e s skin sensitivity lasting for years." H e says t h a t t h e i n c i d e n c e of generalised a n d p r o f o u n d reaction is g r e a t e r w h e n large doses h a v e previously b e e n given, t h a n w h e n small doses are given. T h e y are m o r e c o m m o n in h o r s e asthmatics. T h e first p a t i e n t of m i n e (R. R.) rode horses, b u t gave n o specific h i s t o r y of h o r s e - h a i r allergy : a n i n t r a d e r m a l test of h o r s e - d a n d e r was negative. H i l d a D a v i s (1938) analysed 4,835 cases of d i p h t h e r i a t r e a t e d w i t h c o n c e n t r a t e d s e r u m , a n d n o case o f severe o r fatal reaction o c c u r r e d in t h e series. L o u i s T u f t (1931-32), o n t h e o t h e r h a n d , c o n c l u d e d f r o m a s t u d y of 100 p a t i e n t s i m m u n i s e d against d i p h t h e r i a w i t h e q u i n e t o x i n - a n t i t o x i n , t h a t this sensitised 2 8 % to h o r s e - s e r u m , s u c h sensitisation i n c l u d i n g b o t h skin a n d b o d y t i s s u e s - - t h e t e n d e n c y to acquire t h i s was distinctly influenced b y a p e r s o n a l or familial allergic c o n s t i t u tion. H e t h e r e f o r e advises t h e u s e of goat s e r u m - - s e n s i t i v e n e s s to this being, a p p a r e n t l y , v e r y rare. H e says t h a t i n d o u b t f u l cases t h e s i m u l t a n e o u s a d m i n i s t r a t i o n of a d r e n a l i n is always a wise a n d safe p r o c e d u r e , a n d as far as is k n o w n does n o t e x e r t any d e t r i m e n t a l influence o n t h e s e r u m . O u r p a t i e n t s b o t h h a d a d r e n a l i n w i t h t h e i r s e r u m , as it is o u r r o u t i n e here, b u t it was insufficient to p r e v e n t t h e onset of shock. R. R. (Case 1) was also i m m u n i s e d w i t h A . P . T . , w h i c h does n o t c o n t a i n a n e q u i n e s e r u m . B u t to a r e c e n t q u e s t i o n (British Medical ffournal, 1945) r e g a r d i n g t h e reaction following A . P . T . especially in a s t h m a t i c s , it was s t a t e d in answer, t h a t cases m a y s h o w increased sensitivity to toxoid a n d t h a t A . P . T . or a n y d i p h t h e r i t i c a n t i g e n m a y evoke severe reactions. T . A . F . i n c l u d e s some foreign p r o t e i n s , a n d t h e r e fore s h o u l d n o t b e u s e d i n asthmatics. ( C o m p a r e this w i t h R a t n e r ' s opinion.) I t is u n i v e r s a l l y c o n c e d e d t h a t t h e largest n u m b e r of severe allergic or a n a p h y l a c t i c shock reactions a n d fatalities results f r o m a p r i m a r y injection. P i r q u e t a n d S c h i c k a d m i t t e d t h e y could n o t explain t h e cause o f sensitiveness in a n i n d i v i d u a l w h o h a d n e v e r b e e n t r e a t e d w i t h s e r u m before. T h e m o s t valid e x p l a n a t i o n n o w a d v a n c e d is t h a t h y p e r s e n s i t i v e n e s s h a s b e e n s p o n t a n e o u s l y a c q u i r e d as a result o f a sensitisation to h o r s e - d a n d e r inhalation, m e a t ingestion, or i n t r a - u t e r i n e t r a n s placental sensitisation from the mother. M o s t a u t h o r s agree t h a t n o m a t t e r h o w sensitivity is acquired, t h e fact t h a t t h e r e is a familial a n d p e r s o n a l h i s t o r y of.allergy is a m o s t i m p o r t a n t factor in c a u s i n g d e a t h f r o m allergic shock. T o q u o t e f r o m t h e l i t e r a t u r e : T w o cases w h o r e c o v e r e d are d e s c r i b e d b y K e r (1929), b o t h i n y o u n g child+~n r+ho h a d n o p r e v i o u s s e r u m . H e a t t r i b u t e d t h e cause t o a n a t u r a l h y p e r - s e n s i t i v i t y to s e r u m . E. L. H u n t (1943) describes a w o m a n of 24 years w i t h a n allergic family history, w h o died following a n i n t r a d e r m a l injection of g u i n e a p i g H b for e x p e r i m e n t a l p u r p o s e s ; a relative of hers died in 1895 following T . A . M . , a n d h e r m o t h e r a n d b r o t h e r h a d a s t h m a a n d h a y fever. F r e e d m a n (1935) cites t h e case of a b o y of six years w i t h t h e a s t h m a - e c z e m a s y n d r o m e , w h o d i e d following i n t r a d e r m a l injection of 0-05 c.cm. of h o r s e - s e r u m h a v i n g h a d T . A . M . t h r e e weeks before. C a l d e r (1941) r e p o r t s a b o y of 18 years w i t h h a y fever a n d p r o v e n sensitivity to pollen, s a l m o n a n d p o i s o n ivy (whose m o t h e r , b r o t h e r a n d sister h a d h a y fever, too), w h o developed A.S. after a S c h u l t z C h a r l t o n T e s t (0.2 c.cm. A.S.S.). T h e b o y was i m m u n i s e d against d i p h t h e r i a at 12 years, a n d C a l d e r t h o u g h t it possible t h a t this was t h e sensitising dose. H e m e n t i o n s t h e fact t h a t delayed reactions are m u c h c o m m o n e r t h a n i m m e d i a t e ones. H e t h i n k s allergic s h o c k is a b e t t e r t e r m t h a n acute anaphylaxis, since t h e latter t e r m implies p r e v i o u s s e r u m i n d u c e d sensitivity. T h o u g h o u r second case h a d a d o u b t f u l urticaria before a d m i n i s t r a t i o n of serum, h e was n o t tested for sensitivity to h o r s e s e r u m , n o r was h e desensitised b y gradually increasing doses. T h e n o n - a l l e r g i c h i s t o r y was c o n s i d e r e d s o u n d e n o u g h to rule o u t sensitisation to h o r s e s e r u m . A s c a n b e seen f r o m t h e a b o v e cases, e v e n small doses s u c h as o n e uses in desensitisation m a y p r o v o k e reactions. V a u g h a n (1939) r e c o m m e n d s t h e r o u t i n e use of t h e c o n j u n c t i v a l test, b u t this is often inaccurate and, m a y b e , dangerous. Again, t h e fact t h a t this b o y
100
PUBLIC HEALTH, April, 1946
never had any previous injections of serum also mitigated against shock supervening. It may be convenient here to add a final note on dermal tests in the diagnosis of allergy. Harley (1945) states that as a general rule it should be emphasised that the importance of any allergen as a specific causal factor should not be adduced from a positive skin rea tion alone. It is the correlation of skin reactions with clinical sensitivity that is the basis of diagnosis and treatment. A considerable n u m b e r of positive reactions occur in presumably normal people with no family or personal allergic history by the use of concentrated allergens (Pearson, 1937). In the absence of a dear-cut allergic history in my patients, skin tests were, therefore, not done, except the one for horse-dander. I n conclusion' there may have been some obscure sensirising protein factor in the batch of serum used, but this would obviously be difficult to discover. One could perhaps even postulate such a fraction in every case of spontaneous serum induced allergic shock. Witte's peptone has been described as the responsible agent in a case due to tetanus toxoid (Cunningham, 1940). Treatment and Prevention There appears to be no guaranteed anti-specific therapy, and it must be remembered that the presence of allergy should not deter one from administering serum in any case of diphtheria-theoretically, penicillin, to which C. diphtheriae is sensitive, could be used to replace or reinforce antitoxin. T h e average case, however, has already had a liberal dose of exotoxin before treatment is instituted, and so to withhold antitoxin in these cases because of the fear of allergic shock is most unwise. Penicillin could help by reducing the numbers of organisms and so diminishing the supply of lethal exotoxin. I n the second case I gave 212,000 units of penicillin, together with 140,000 units A.D.S., but it did not prevent the onset of complications. I n the presence of known allergy (personal and familial) desensitisation should, of course, be attempted. I n giving adrenaline care must be taken not to give too liberal a dosage, otherwise " adrenaline shock "* may ensue, and so make treatment as bad as the disease itself. Each case should be judged carefully on its merits. I hope that I shall not be accused of labouring the point by emphasising that immunisation is the only real safeguard, but it must be pushed to its logical conclusion by demanding that every child should be compulsorily done at one year of age, and thereafter receive boosting doses throughout its school life, until adolescence. T h e real prophylaxis of allergic shock in diphtheria is the wiping out of the disease itself. Finally, I wish to thank Dr. Banks (M.O.H., Nottingham) for his kindness and help in writing this paper, and for permission to publish it. ]~.EFERENCES
Brit. Med. 1. (1945). 2, t71. Calder, R. M. (I941). Brit. Meal. ]., 2, 198. Cunningham, A. A. (1940). Brit. Med. 1, 2, 522. Davis, Hilda M. (1938). Lancet, 1, 4, 193. Freedman, H . J . (1935). New England 1. Med., 212, 1, 10. Harley, D. (1945). Practitioner, 155, 313. Hunt, E. L (1943). N e w England 1. Med., 228, 16, 502. Ker's "Infectious Diseases." (1929). P. 441. Kohn et al. (1938). Amer. I. Dis. Children. 55, 3, 1018. Pearson, R. S. B. (1937). Quart. 1. Med., 6, 165. Ramer, B. (1943). "Allergy, Anaphylaxis and Immunotherapy." Louis Tuft. (1931-32). 1. Allergy, 235. Vaughan's " Practice of Allergy." (1939). * As shown by tachycardia, pallor and in extreme cases ventricular fibrillation and death.
T. F. Macrae, Esq., O.B.E., n.sc., PH.D., has been appointed Head of Research to the Glaxo Laboratories, and will direct and coordinate the work of the Research Departments at Greenford.
• AN
OUTBREAK
OF
SONNE
DYSENTERY
By C. B. HoGo, M.D., D.P.H., Medical Officer of Health, Borough of Kettering T h e acute symptoms of Sonne dysentery are often nonexistent or are so slight and pass off so quickly that many people ignore them and do not consult a doctor: such cases may remain for a time potential ~ources of infection to others. Many public health departments, owing perhaps to the difficulties of ascertainment of cases brought about by the mildness of the condition and to the shortage of staff due to the war, have not taken very active steps to deal with the disease. Collecting Information During the period September, 1943, to September, 1944, an outbreak of Sonne dysentery occurred in the Borough of Kettering, which has a population of approximately 36,000, temporarily increased by another 2-3,000 evacuated persons. I n all, 281 cases came to notice~ of which only 79 were notified by medical practitioners. Immediately information regarding a case was received a visit was paid by a sanitary inspector, who investigated the home conditions, gave instructions regarding cleanliness, protection of food'and utensils, and handwashing before meals and after defaecation, and arranged for specimens of faeces from the patient and from each of the home contacts to be sent to the bacteriological laboratory. Advice was also given regarding the calling in, if that had not already been done, of the private medical attendant. Arrangements were made when despatching the specimens of faeces to the laboratory for copies of the reports to be sent to the private doctor ; this practice was continued with subsequent specimens. All children and staff in the same nursery school or nursery class as a proved case .were regarded as contacts necessitating the examination of specimens of faeces unless, as occurred in some instances, there was no d o u b t that the child had been infected at home, where other members of the family were suffering from dysentery. I n elementary schools, apart from the nursery classes, children in the same class as a case of dysentery were not considered to be contacts unless there was some special reason for so doing. Where close contact between one family having dysentery and another family was found, specimens of faeces from all the members of the second family were examined. All definite and suspected cases in children were immediately excluded from nurseries or schools, and food-handlers suffering from or in contact with the disease were kept off work. At first three negative specimens were required from definite cases unless they were children attending nurseries, n u r s e r / schools or infant schools, or were adults engaged in foodhandling, when six successive negative specimens' were considered necessary before return to nursery, school or work. For suspected cases three negative specimens were obtained before they were dismissed as not having dysentery. From negative contacts two negative specimens were taken. Treatment Although in each definite or suspected case the patient was advised to consult his private doctor, treatment did not result in every instance, because some practitioners did not in the early part of the outbreak consider that medication was necessary, while others thought that sutphaguanidine was too expensive a drug for club patients, with some of whom the agreement was apparently for " no expensive drugs to be used in treatment." Therefore, six weeks after the commencement of the outbreak a letter was sent to the medical practitioners in the town pointing out that of the 37 cases which had then come to notice only three had been cleared of dysentery bacilli, that secondary cases had occurred in some of the affected families, and that consequently several mothers who were war workers were being kept at home to attend to their children. It was also emphasised that the treatment of cases should be early and should continue after subsidence of the acute symptoms. T h e response to this appeal was that of the total 281 cases 179 received early treatment, 41 repeated treatment, 22 delayed treatment, and 39 no treatment. By
T h e r e are certain criteria by which, in the long run, the value of any health service m u s t be judged. Will it produce healthier citizens ? Is it a comprehensive service ? Is it balanced ? Are its elements integrated ? T h e p r o b l e m of tuberculosis, in Scotland at all events, is as m u c h the p r o b l e m of the t w o - r o o m e d house as the p r o b l e m of sanatorium care. E v e n such an important aspect of social medicine as the supervision of industrial health is, it appears, to be expressly excluded f r o m the G o v e r n m e n t ' s n e w scheme, though in this m a t t e r the Minister would probably claim Credit for good intentions. I believe it to be imperative to forge a stronger link between the work of the Medical Officer of H e a l t h and that of other elements in health and social services. It m a y be that in t i m e the evolution of health centres will help to break d o w n artificial barriers, and in any case it will certainly be a challenge to the genius of individual health officers to forge these links as best they can in the light of local circumstances, for without such links they m u s t inevitably be frustrated in their work and the Service be the poorer. But I think it would be extremely valuable if something could be done in framing the new service to secure practical recognition of the need for real unity in these matters. A n d what of the quality of the Service ? Sir George Buchanan, at the end of his long and distinguished association with the Health Organisation of the League of Nations, doubted if the world would gain by having a stock pattern of administration forced upon nations by any central a u t h o r i t y : he felt
PUBLIC HEALTH, April, 1946 sure it would not benefit by stock patterns of national administration in medicine or hygiene. T h e wisdom of this observation on rigidity of structure and approach is not wholly confined to essays in international health : e v e n within particular countries, health services seldom lend themselves to absolute uniformity. I t is inevitably difficult for the State to look with enthusiasm on that measure of individuality and freedom which is the v e r y essence of the practice of medicine. T h o s e of us w h o have seen at close quarters the working of State departments, necessarily politically minded, cannot fail to appreciate the difficulties u n d e r which professional m e n labour in their service. W e m u s t do everything possible to secure that t h r o u g h time the n e w service does not produce a standardised, flat l u m p without leaven. T h r e e h u n d r e d years ago J o h n Milton was troubled by somewhat similar qualms about official control, and the danger has certainly not become any less since his time : - " Another sort there be who w h e n they hear that all things shall be ordered, all thing§ regulated and settled; nothing written but what passes through the custom-house of certain Publicans that have the tunaging and p o u n d i n g of all freespoken truth . . . . H o w goodly and how to be wisht were such an obedient unanimity as this, what a fine conformity w o u l d it starch us all u n t o . " Conformity goes ill w i t h the practice of medicine; and it may be hard to keep the Publicans in check.
ALLERGIC SHOCK FOLLOWING OF ANTI-DIPHTHERITIC
ADMINISTRATION SERUM*
By I. M. LIBRACH, M.B., CH.B., B.A.O., D.P.H.,
Medical Superintendent, City Isolation Hospital, Nottingham Anaphylactie or allergic shockf in the h u m a n subject is fortunately, not a c o m m o n condition. I t is difficult, however, to make a p r o p e r appraisal of its incidence f r o m the personal experience of any individual physician, because that can n e v e r be wide enough. A review of the literature would indicate that severe allergic shock and death are extremely infrequent. Park estimated in 1928, that 1 in 20,000 s e r u m injections is followed by alarming symptoms, and 1 in 50,000 is fatal. T h e literature records few accounts of clinical anaphylactic shock. Vaughan (1939) states that it seems that one hears of more cases of severe shock and death than are recorded, perhaps because the average physician is loath to put such records on paper. Gottstein in 1896 gives 12 cases ; Rosenau and A n d e r s o n in 1906, 19 cases ; Gillette (1909), 16 fatal cases. Lamson, in 1924, reviewed the literature f r o m 1895 to 1923, and recorded 41 cases, while f r o m 1924 to 1936, Vaughan and others recorded 69 cases, of which 52% were due to serum. In view of the relative paucity of recorded accounts of this dangerous condition, it m i g h t be of interest to record and discuss the following two cases : CASE RECORDS Case I.--R. R., a schoolgirl aged 17 years, first complained of some headache, sore throat and earache, with pain in back and limbs, on 17.5.45. She was seen by her doctor who, suspecting diphtheria, swabbed her throat. The swab was returned positive and she was admitted to hospital on 19.5.45. Her previous history included measles, whooping cough and " fainting fits at the periods." She was vaccinated and had been immunised against diphtheria by her own doctor five years ago in two shots, probably A.P.T., but the doctor was not certain of this. No history of allergy was given by patient or family. On examination she was a strapping girl; temperature, pulse and respiration were normal. Both tonsils were swollen and stippled with white specks of exudare. The fauces were injected and the cervical glands were small and not tender. There was nothing of note in any other system. In view of the previous history of * Paper read to the East Midland Branch, February 14th, 1946. "~The term hyper-sensitivity as employed immunologically can be divided into (1) Anaphyliaxis, (2) Allergy. The former has now come to be used for cases of induced (i.e., non-spontaneous) hypersensitivity, while the latter comprises all other forms exclusive of anaphylaxis, namely, hereditary, bacterial, contact and drug allergies, and finally Serum Diseases, including shock. This latter definition will be adhered to in this paper, namely, Allergic Shock (or A.S.).
PUBLIC HEALTH, April, 1946 immunisation, a Schick test was done at 5.45 p.m. 19.5.45. A t 2.30 a.m. (eight hours later) 20.5.45, this was followed by the intramuscular administration of 80,000 units A.D.S. together with 3,000 units A.S.S. Adrenaline m.v was given in accordance with our normal ro~tine. Nepenthe, m.xv was ordered to be given if necessary. At 4.0 a.m. (one and a half hours afterwards) the patient suddenly collapsed. She was cold and clammy and sweating; with an imperceptible pulse and frothing at the month. Adrenaline m.x and coramine t c.cm. were ordered immediately, to be ft>llowed at 4.30 p.m. by a further 2 c.cm. coramine. The end of her bed was raised on blocks. Morphia g. one-sixth and radiant heat were also ordered. Adrenaline m . x was then instituted. At 6.45 a.m. she was much better, but there was an urticarial rash over her trunk, face and arms. The B.P. was 130/80; the pulse 88 and of good volume. The heart sounds were regular but muffled. The adrenaline and coramine were kept on eighthourly for a further 24 hours. On 26.5.45, a marked papulo-vesicular rash with conjunctival involvement appeared, which lasted for 24 hours. The heart sounds were still muffled and the blood pressure had fallen to 95/60. Despite warning, the patient was discharged, against advice, at this stage. The Schiek test proved to be a doubtful positive, but a virulence test showed the diphtheria bacillus to be of modified virulence, i.e., failing to kill a guinea-pig in four days, but producing a marked local lesion. Though she gave a history of horse riding, the patient was negative to a skin test of horse-dander. I subsequently discovered six weeks later that the patient made a perfect recovery. Case 2.--J. B., a boy aged I8 years, was admitted on 24.7.45, having complained of headache, vomiting and sore throat for two days previously. He had no allergic history, personal or familial. He had never been immunised. He had had mumps, measles and chicken-pox. He was non-vaccinated. He was a typical case with bull neck and severe faucial involvement, and had a suspicious urticarial rash on his skin. The ward sister was therefore told to watch for signs of allergic shock. At 6.15 p.m. he was given 100,000 units A.D.S. and Adrenaline m.x was ordered two-hourly for two further doses. At 7.20 p.m. (one hour later, before next dose of adrenaline was due), he suddenly became restless, cyanotic and confused and attempted to g e t out of bed. The pulse was rapid and soft, and he was clammy with perspiration. He improved with coramine and adrenaline by 9.20 p.m. Next day he had marked urticaria. He was put on penicillin in an attempt to expedite his recovery, and was given 212,000 units, but he developed nasal speech on 24.8.45, and accommodation disturbance on 27.8.45, together with triple rhythm. After 88 days in hospital he was discharged--an E.C.G. showed a low voltage in all leads and there was a rough systolic bruit at the pulmonary area which could not be accounted for. He was told to report in six weeks for a+ re-examination, but ne'~er did so. Discussion As defined originally b y Schick a n d v o n P i r q u e t in 1905, an i m m e d i a t e s e r u m reaction is one o c c u r r i n g w i t h i n 24 h o u r s of injection, a n d a n accelerated reaction f r o m t h e s e c o n d to the sixth day. R a t h e r (1943), h o w e v e r , divides t h e s y m p t o m s o f a n a p h y laxis in m a n into : - 1. M i l d - - u n e a s i n e s s , a p p r e h e n s i o n , urticaria, i t c h i n g o r pricking. 2. S e v e r e - - d y s p n o e a , cyanosis, generalised urticaria, erythema, o e d e m a of face, t o n g u e a n d t h r o a t , h a c k i n g cough, frothy e x p e c t o r a t i o n a n d collapse. H e does n o t define t h e 'time of t h e reaction, b u t says t h a t symptoms m a y c o m e o n explosively, e v e n b e f o r e t h e i n j e c t i n g needle is w i t h d r a w n , or after a l a t e n t p e r i o d o f 30 m i n u t e s o r longer. A e c o r d i n g to h i m , d e a t h m a y o c c u r in a few m i n u t e s or after several h o u r s d u e to ( I ) o e d e m a o f glottis ; (2) s p a s m of bronchioles ( g u i n e a - p i g t y p e of anaphylaxis) ; (3) s p a s m of hepatic v e n u l e s (canine t y p e ) ; (4) s p a s m of p u l m o n a r y arterioles ( r a b b i t t y p e ) ; (5) s p a s m of adrenal vessels. H o w these types are d i s t i n g u i s h e d clinically is n o t m e n t i o n e d ! D e a t h m a y e n s u e following i n t r a d e r m a l , s u b c u t a n e o u s , intramuscular or i n t r a v e n o u s injection, a n d t h o u g h t h e rate of absorption, w h i c h d e p e n d s o n t h e route, is said to influence the s u d d e n n e s s of death, t h e degree of h y p e r s e n s i t i v i t y of t h e patient is t+he d o m i n a n t factor. R a t h e r considers t h a t to " a t t r i bute the A r t h u s p h e n o m e n o n , a n a p h y l a c t i c shock a n d d e a t h to the mild sensitisation p r o d u c e d b y t o x i n - a n t i t o x i n , is n o t
99 c o n s o n a n t w i t h t h e facts detailed i n t h e literature, t h o u g h it u n d o u b t e d l y p r o d u c e s skin sensitivity lasting for years." H e says t h a t t h e i n c i d e n c e of generalised a n d p r o f o u n d reaction is g r e a t e r w h e n large doses h a v e previously b e e n given, t h a n w h e n small doses are given. T h e y are m o r e c o m m o n in h o r s e asthmatics. T h e first p a t i e n t of m i n e (R. R.) rode horses, b u t gave n o specific h i s t o r y of h o r s e - h a i r allergy : a n i n t r a d e r m a l test of h o r s e - d a n d e r was negative. H i l d a D a v i s (1938) analysed 4,835 cases of d i p h t h e r i a t r e a t e d w i t h c o n c e n t r a t e d s e r u m , a n d n o case o f severe o r fatal reaction o c c u r r e d in t h e series. L o u i s T u f t (1931-32), o n t h e o t h e r h a n d , c o n c l u d e d f r o m a s t u d y of 100 p a t i e n t s i m m u n i s e d against d i p h t h e r i a w i t h e q u i n e t o x i n - a n t i t o x i n , t h a t this sensitised 2 8 % to h o r s e - s e r u m , s u c h sensitisation i n c l u d i n g b o t h skin a n d b o d y t i s s u e s - - t h e t e n d e n c y to acquire t h i s was distinctly influenced b y a p e r s o n a l or familial allergic c o n s t i t u tion. H e t h e r e f o r e advises t h e u s e of goat s e r u m - - s e n s i t i v e n e s s to this being, a p p a r e n t l y , v e r y rare. H e says t h a t i n d o u b t f u l cases t h e s i m u l t a n e o u s a d m i n i s t r a t i o n of a d r e n a l i n is always a wise a n d safe p r o c e d u r e , a n d as far as is k n o w n does n o t e x e r t any d e t r i m e n t a l influence o n t h e s e r u m . O u r p a t i e n t s b o t h h a d a d r e n a l i n w i t h t h e i r s e r u m , as it is o u r r o u t i n e here, b u t it was insufficient to p r e v e n t t h e onset of shock. R. R. (Case 1) was also i m m u n i s e d w i t h A . P . T . , w h i c h does n o t c o n t a i n a n e q u i n e s e r u m . B u t to a r e c e n t q u e s t i o n (British Medical ffournal, 1945) r e g a r d i n g t h e reaction following A . P . T . especially in a s t h m a t i c s , it was s t a t e d in answer, t h a t cases m a y s h o w increased sensitivity to toxoid a n d t h a t A . P . T . or a n y d i p h t h e r i t i c a n t i g e n m a y evoke severe reactions. T . A . F . i n c l u d e s some foreign p r o t e i n s , a n d t h e r e fore s h o u l d n o t b e u s e d i n asthmatics. ( C o m p a r e this w i t h R a t n e r ' s opinion.) I t is u n i v e r s a l l y c o n c e d e d t h a t t h e largest n u m b e r of severe allergic or a n a p h y l a c t i c shock reactions a n d fatalities results f r o m a p r i m a r y injection. P i r q u e t a n d S c h i c k a d m i t t e d t h e y could n o t explain t h e cause o f sensitiveness in a n i n d i v i d u a l w h o h a d n e v e r b e e n t r e a t e d w i t h s e r u m before. T h e m o s t valid e x p l a n a t i o n n o w a d v a n c e d is t h a t h y p e r s e n s i t i v e n e s s h a s b e e n s p o n t a n e o u s l y a c q u i r e d as a result o f a sensitisation to h o r s e - d a n d e r inhalation, m e a t ingestion, or i n t r a - u t e r i n e t r a n s placental sensitisation from the mother. M o s t a u t h o r s agree t h a t n o m a t t e r h o w sensitivity is acquired, t h e fact t h a t t h e r e is a familial a n d p e r s o n a l h i s t o r y of.allergy is a m o s t i m p o r t a n t factor in c a u s i n g d e a t h f r o m allergic shock. T o q u o t e f r o m t h e l i t e r a t u r e : T w o cases w h o r e c o v e r e d are d e s c r i b e d b y K e r (1929), b o t h i n y o u n g child+~n r+ho h a d n o p r e v i o u s s e r u m . H e a t t r i b u t e d t h e cause t o a n a t u r a l h y p e r - s e n s i t i v i t y to s e r u m . E. L. H u n t (1943) describes a w o m a n of 24 years w i t h a n allergic family history, w h o died following a n i n t r a d e r m a l injection of g u i n e a p i g H b for e x p e r i m e n t a l p u r p o s e s ; a relative of hers died in 1895 following T . A . M . , a n d h e r m o t h e r a n d b r o t h e r h a d a s t h m a a n d h a y fever. F r e e d m a n (1935) cites t h e case of a b o y of six years w i t h t h e a s t h m a - e c z e m a s y n d r o m e , w h o d i e d following i n t r a d e r m a l injection of 0-05 c.cm. of h o r s e - s e r u m h a v i n g h a d T . A . M . t h r e e weeks before. C a l d e r (1941) r e p o r t s a b o y of 18 years w i t h h a y fever a n d p r o v e n sensitivity to pollen, s a l m o n a n d p o i s o n ivy (whose m o t h e r , b r o t h e r a n d sister h a d h a y fever, too), w h o developed A.S. after a S c h u l t z C h a r l t o n T e s t (0.2 c.cm. A.S.S.). T h e b o y was i m m u n i s e d against d i p h t h e r i a at 12 years, a n d C a l d e r t h o u g h t it possible t h a t this was t h e sensitising dose. H e m e n t i o n s t h e fact t h a t delayed reactions are m u c h c o m m o n e r t h a n i m m e d i a t e ones. H e t h i n k s allergic s h o c k is a b e t t e r t e r m t h a n acute anaphylaxis, since t h e latter t e r m implies p r e v i o u s s e r u m i n d u c e d sensitivity. T h o u g h o u r second case h a d a d o u b t f u l urticaria before a d m i n i s t r a t i o n of serum, h e was n o t tested for sensitivity to h o r s e s e r u m , n o r was h e desensitised b y gradually increasing doses. T h e n o n - a l l e r g i c h i s t o r y was c o n s i d e r e d s o u n d e n o u g h to rule o u t sensitisation to h o r s e s e r u m . A s c a n b e seen f r o m t h e a b o v e cases, e v e n small doses s u c h as o n e uses in desensitisation m a y p r o v o k e reactions. V a u g h a n (1939) r e c o m m e n d s t h e r o u t i n e use of t h e c o n j u n c t i v a l test, b u t this is often inaccurate and, m a y b e , dangerous. Again, t h e fact t h a t this b o y
100
PUBLIC HEALTH, April, 1946
never had any previous injections of serum also mitigated against shock supervening. It may be convenient here to add a final note on dermal tests in the diagnosis of allergy. Harley (1945) states that as a general rule it should be emphasised that the importance of any allergen as a specific causal factor should not be adduced from a positive skin rea tion alone. It is the correlation of skin reactions with clinical sensitivity that is the basis of diagnosis and treatment. A considerable n u m b e r of positive reactions occur in presumably normal people with no family or personal allergic history by the use of concentrated allergens (Pearson, 1937). In the absence of a dear-cut allergic history in my patients, skin tests were, therefore, not done, except the one for horse-dander. I n conclusion' there may have been some obscure sensirising protein factor in the batch of serum used, but this would obviously be difficult to discover. One could perhaps even postulate such a fraction in every case of spontaneous serum induced allergic shock. Witte's peptone has been described as the responsible agent in a case due to tetanus toxoid (Cunningham, 1940). Treatment and Prevention There appears to be no guaranteed anti-specific therapy, and it must be remembered that the presence of allergy should not deter one from administering serum in any case of diphtheria-theoretically, penicillin, to which C. diphtheriae is sensitive, could be used to replace or reinforce antitoxin. T h e average case, however, has already had a liberal dose of exotoxin before treatment is instituted, and so to withhold antitoxin in these cases because of the fear of allergic shock is most unwise. Penicillin could help by reducing the numbers of organisms and so diminishing the supply of lethal exotoxin. I n the second case I gave 212,000 units of penicillin, together with 140,000 units A.D.S., but it did not prevent the onset of complications. I n the presence of known allergy (personal and familial) desensitisation should, of course, be attempted. I n giving adrenaline care must be taken not to give too liberal a dosage, otherwise " adrenaline shock "* may ensue, and so make treatment as bad as the disease itself. Each case should be judged carefully on its merits. I hope that I shall not be accused of labouring the point by emphasising that immunisation is the only real safeguard, but it must be pushed to its logical conclusion by demanding that every child should be compulsorily done at one year of age, and thereafter receive boosting doses throughout its school life, until adolescence. T h e real prophylaxis of allergic shock in diphtheria is the wiping out of the disease itself. Finally, I wish to thank Dr. Banks (M.O.H., Nottingham) for his kindness and help in writing this paper, and for permission to publish it. ]~.EFERENCES
Brit. Med. 1. (1945). 2, t71. Calder, R. M. (I941). Brit. Meal. ]., 2, 198. Cunningham, A. A. (1940). Brit. Med. 1, 2, 522. Davis, Hilda M. (1938). Lancet, 1, 4, 193. Freedman, H . J . (1935). New England 1. Med., 212, 1, 10. Harley, D. (1945). Practitioner, 155, 313. Hunt, E. L (1943). N e w England 1. Med., 228, 16, 502. Ker's "Infectious Diseases." (1929). P. 441. Kohn et al. (1938). Amer. I. Dis. Children. 55, 3, 1018. Pearson, R. S. B. (1937). Quart. 1. Med., 6, 165. Ramer, B. (1943). "Allergy, Anaphylaxis and Immunotherapy." Louis Tuft. (1931-32). 1. Allergy, 235. Vaughan's " Practice of Allergy." (1939). * As shown by tachycardia, pallor and in extreme cases ventricular fibrillation and death.
T. F. Macrae, Esq., O.B.E., n.sc., PH.D., has been appointed Head of Research to the Glaxo Laboratories, and will direct and coordinate the work of the Research Departments at Greenford.
• AN
OUTBREAK
OF
SONNE
DYSENTERY
By C. B. HoGo, M.D., D.P.H., Medical Officer of Health, Borough of Kettering T h e acute symptoms of Sonne dysentery are often nonexistent or are so slight and pass off so quickly that many people ignore them and do not consult a doctor: such cases may remain for a time potential ~ources of infection to others. Many public health departments, owing perhaps to the difficulties of ascertainment of cases brought about by the mildness of the condition and to the shortage of staff due to the war, have not taken very active steps to deal with the disease. Collecting Information During the period September, 1943, to September, 1944, an outbreak of Sonne dysentery occurred in the Borough of Kettering, which has a population of approximately 36,000, temporarily increased by another 2-3,000 evacuated persons. I n all, 281 cases came to notice~ of which only 79 were notified by medical practitioners. Immediately information regarding a case was received a visit was paid by a sanitary inspector, who investigated the home conditions, gave instructions regarding cleanliness, protection of food'and utensils, and handwashing before meals and after defaecation, and arranged for specimens of faeces from the patient and from each of the home contacts to be sent to the bacteriological laboratory. Advice was also given regarding the calling in, if that had not already been done, of the private medical attendant. Arrangements were made when despatching the specimens of faeces to the laboratory for copies of the reports to be sent to the private doctor ; this practice was continued with subsequent specimens. All children and staff in the same nursery school or nursery class as a proved case .were regarded as contacts necessitating the examination of specimens of faeces unless, as occurred in some instances, there was no d o u b t that the child had been infected at home, where other members of the family were suffering from dysentery. I n elementary schools, apart from the nursery classes, children in the same class as a case of dysentery were not considered to be contacts unless there was some special reason for so doing. Where close contact between one family having dysentery and another family was found, specimens of faeces from all the members of the second family were examined. All definite and suspected cases in children were immediately excluded from nurseries or schools, and food-handlers suffering from or in contact with the disease were kept off work. At first three negative specimens were required from definite cases unless they were children attending nurseries, n u r s e r / schools or infant schools, or were adults engaged in foodhandling, when six successive negative specimens' were considered necessary before return to nursery, school or work. For suspected cases three negative specimens were obtained before they were dismissed as not having dysentery. From negative contacts two negative specimens were taken. Treatment Although in each definite or suspected case the patient was advised to consult his private doctor, treatment did not result in every instance, because some practitioners did not in the early part of the outbreak consider that medication was necessary, while others thought that sutphaguanidine was too expensive a drug for club patients, with some of whom the agreement was apparently for " no expensive drugs to be used in treatment." Therefore, six weeks after the commencement of the outbreak a letter was sent to the medical practitioners in the town pointing out that of the 37 cases which had then come to notice only three had been cleared of dysentery bacilli, that secondary cases had occurred in some of the affected families, and that consequently several mothers who were war workers were being kept at home to attend to their children. It was also emphasised that the treatment of cases should be early and should continue after subsidence of the acute symptoms. T h e response to this appeal was that of the total 281 cases 179 received early treatment, 41 repeated treatment, 22 delayed treatment, and 39 no treatment. By