403 distinct from their toxic actions ; these tend to be characteristic of each individual drug, whereas allergic effects are common to a -number of drugs, and their character depends on the site of the reacting tissue. Thus the leucopbietic marrow reacts in an identical fashion to sensitisation-by sulphonamides, amidopyrine, arsphenamine and other benzene compounds. In the cases quoted other tissues besides the bone- marrow have shared in the allergic response, including the heat-regulating mechanisms (drug fever), the lymphatic glands (enlargement), and the blood-vessels (vasodilatation in the skin and conjunctivae, exanthe- matous eruptions and purpura). Many of the so-called " toxic " effects of sulphonamides, especially eruptions and fever, appear characteristically after an incubation of a week or more, and investigation of these might, reveal that they too are allergic. CONCLUSIONS In some people the administration of sulphonamides for more than about a week induces a dangerous form of drug allergy. As a working rule chemotherapy should not be prolonged beyond this period ; since most amenable infections - respond in a few days, longer administration is seldom necessary. ’ Sensitivity develops gradually, the first signs being a depression of neutrophils in the blood. It steadily rises, and the next effects are such constitutional symptoms as malaise and headache, which may go unnoticed in a patient already ill from an acute infection. Finally the neutrophils disappear completely from the blood, and the alarming syndrome of agranulocytosis appears, often suddenly supervening upon hitherto mild symptoms. If the drug has been given up to this stage, or even several days short of it, the prognosis is grave. In the few cases, therefore, where it is considered necessary to give sulphonamides for over a week, however small the amounts, daily leucocyte counts should be done, and at the first sign of neutropenia the drug should be stopped and its elimination encouraged by promoting diuresis. It cannot at present be indicated how long this allergic state lasts. In a report on sulphonamide sunlight eruptions, Platts and I (1942) observed that these rashes typically came on after 8-10 days’ therapy and that some patients received subsequent courses with no recurrence of their eruptions. If this was an allergic reaction it had disappeared in the course of a few weeks ; and sensitivity of the bone-marrow may also be short-lived. The occurrence of these delayed eruptions in cases of neutropenia suggests that they are a closely related form of allergy. Until this point is cleared up, however, a reasonable precaution in any victim of neutropenia requiring sulphonamide later would be to give it in ascending doses with extreme caution. . SUMMARY A case is reported where neutropenia from -sulpha- pyridine was clearly due to drug allergy., After three months’ observation the patient was desensitised. From an examination of reported cases and by analogy with neutropenia from other drugs, it seems probable that all such cases are allergic responses. Other toxic effects of sulphonamides are probably of the same nature. 1- wish to thank Captain C. P. Powles and his -laboratory staff for their help in the blood-counts in the case reported, and the Director of Medical Services, NZEF, for permission to publish this paper. REFERENCES Briggs, G. O. A. (1939) Lancet, ii, 739. Corr, P. and Root, R. H. (1939) J. Amer. med. Ass. 112, 1939. Gayus, I. K., Green-Armytage, V. D. and Baker, J. K. (1939) Brit. med. J. ii, 560. Hill, W. R. and Downing, J. G. (1942) Arch. Derm. Syph. 46, 139. Kracke, R. R. (1938) J. Amer. med. Ass. 111, 1255. Leftwich, P. (1940) S. Afr. med. J. 14, 142. Madison, F. W. and Squier, T. L. (1934) J. Amer. med. Ass. 102, 755. Nicol, H. and Freedman, B. (1939) Lancet, ii, 647. Park, R. G. and Platts, W. M. (1942) Brit. med. J. ii, 308. Pearson, M. E. S. (1939) Ibid, i, 1031. Rosenthal, N. and Vogel, P. (1939) J. Amer. med. Ass. 113, 584. Shirley, J. S. and Allday, L. E. (1940) Ann. int. Med. 13, 1241. Sulzberger, M. B. (1940) Dermatologic Allergy. Springfield, Illinois. Sutherland, M. E. (1939) Lancet, i, 1208. Medical Societies ROYAL SOCIETY OF MEDICINE ON March 14 the section of experimental medicine, with Dr. R. D. LAWRENCE in the chair, discussed the Etiology of Jaundice including infective hepatitis, homologous serum jaundice, arsenotherapy jaundice, and the type which follows vaccination. Dr. F. 0. MACCALLUM reviewed the attempts to isolate a causative agent from cases of infective hepa- titis and homologous serum jaundice by inoculation into various animals and man. A large number of experiments have been carried out in the different countries where infective hepatitis is prevalent, but only two groups of workers have claimed positive results. From Denmark Andersen and Tulinius reported trans- mission of the human disease by feeding duodenal juice from cases of infective hepatitis to young pigs on a quantitatively deficient diet. Liver changes were said to have been produced within 2-4 days of the feed- ing experiment. The value of these experiments is rather doubtful as there was an epizootic of hepatitis among the swine in Denmark at that time. The other positive transmissions were claimed by three groups of workers in Leipzig. It was said that inoculation of duodenal washings from cases of hepatitis in the pre- icteric stage on to the chorioallantoic membrane of developing chick embryos had resulted in the death of the embryos after 4-5 days, and that the toxic agent had been transmitted for 8 passages in the embryo. Negative results were obtained by inoculation of urine and blood from cases of infective hepatitis. The Leipzig workers had also reported infection and death of canaries inoculated with duodenal juice or urine. Symptoms appeared in the canaries about the 3rd day after inoculation, with death on the 4th or 5th day. Canaries inoculated with blood from cases of infective hepatitis remained well. In the present study being carried out at Cambridge for the Medical Research Council all attempts to repeat the results in pigs and canaries had so far been unsuccessful. Microscopic liver changes as described by Andersen had been seen in the control animals on the deficient diet at Cambridge. The human transmission experiments suggested that the causative agent of infective hepatitis was present in the duodenal juice and blood of patients before jaundice appeared and in the blood 2 days after jaundice had appeared. The results of animal experiments with material from cases of homologous serum jaundice and pools of human serum known to be icterogenic had been entirely -negative. Experiments in human volunteers had shown that the icterogenic agent was present in the blood of a presumed case of homologous serum jaundice 7 days after the appearance of the jaundice but not 66 days later. It had also been proved that a batch of supposedly normal human serum made from a pool from a number of blood-transfusion depots had contained an icterogenic agent which was responsible for the jaundice produced by a batch of yellow fever vaccine containing that serum. Dr. A. M. McFARLAN described some features of an outbreak of hepatitis in British Army recruits after intravenous inoculations of mumps convalescent plasma, studied by the American Red Cross Harvard Unit. A clinical comparison of 49 cases with 37 cases of infective hepatitis showed that vomiting was less frequent, and rashes and arthralgiawere more -frequent, in the plasma jaundice cases. Epidemiologically the outbreak was unlike infective hepatitis in the long interval between inoculation and development of symptoms (60-90 days in 87% of cases), the absence of a secondary batch of cases in uninoculated men, and the occurrence of jaun- dice in 8 of 11 inoculated men who gave a history of jaundice in childhood. It was clear that certain batches of human plasma or serum were icterogenic, but state- ments that jaundice had been caused by transfusion with whole blood were less well .founded. Reports of such cases should record the results of a search for cases of hepatitis in contacts, and the source of the suspected blood or blood product.
Transcript
403
distinct from their toxic actions ; these tend to becharacteristic of each individual drug, whereas allergiceffects are common to a -number of drugs, and theircharacter depends on the site of the reacting tissue.Thus the leucopbietic marrow reacts in an identicalfashion to sensitisation-by sulphonamides, amidopyrine,arsphenamine and other benzene compounds.
In the cases quoted other tissues besides the bone-marrow have shared in the allergic response, includingthe heat-regulating mechanisms (drug fever), thelymphatic glands (enlargement), and the blood-vessels(vasodilatation in the skin and conjunctivae, exanthe-matous eruptions and purpura). Many of the so-called" toxic " effects of sulphonamides, especially eruptionsand fever, appear characteristically after an incubationof a week or more, and investigation of these might,reveal that they too are allergic.
CONCLUSIONS
In some people the administration of sulphonamidesfor more than about a week induces a dangerous formof drug allergy. As a working rule chemotherapyshould not be prolonged beyond this period ; since mostamenable infections - respond in a few days, longeradministration is seldom necessary.
’
Sensitivity develops gradually, the first signs being adepression of neutrophils in the blood. It steadilyrises, and the next effects are such constitutionalsymptoms as malaise and headache, which may gounnoticed in a patient already ill from an acute infection.Finally the neutrophils disappear completely from theblood, and the alarming syndrome of agranulocytosisappears, often suddenly supervening upon hithertomild symptoms. If the drug has been given up to thisstage, or even several days short of it, the prognosis isgrave. In the few cases, therefore, where it is considerednecessary to give sulphonamides for over a week, howeversmall the amounts, daily leucocyte counts should bedone, and at the first sign of neutropenia the drugshould be stopped and its elimination encouraged bypromoting diuresis.It cannot at present be indicated how long thisallergic state lasts. In a report on sulphonamidesunlight eruptions, Platts and I (1942) observed thatthese rashes typically came on after 8-10 days’ therapy
and that some patients received subsequent courses
with no recurrence of their eruptions. If this was anallergic reaction it had disappeared in the course of afew weeks ; and sensitivity of the bone-marrow mayalso be short-lived. The occurrence of these delayederuptions in cases of neutropenia suggests that they area closely related form of allergy. Until this point iscleared up, however, a reasonable precaution in anyvictim of neutropenia requiring sulphonamide laterwould be to give it in ascending doses with extremecaution. .
SUMMARY
A case is reported where neutropenia from -sulpha-pyridine was clearly due to drug allergy., After threemonths’ observation the patient was desensitised.From an examination of reported cases and by analogy
with neutropenia from other drugs, it seems probablethat all such cases are allergic responses. Other toxiceffects of sulphonamides are probably of the same
nature.
1- wish to thank Captain C. P. Powles and his -laboratorystaff for their help in the blood-counts in the case reported,and the Director of Medical Services, NZEF, for permissionto publish this paper.
REFERENCES
Briggs, G. O. A. (1939) Lancet, ii, 739.Corr, P. and Root, R. H. (1939) J. Amer. med. Ass. 112, 1939.Gayus, I. K., Green-Armytage, V. D. and Baker, J. K. (1939)
Brit. med. J. ii, 560.Hill, W. R. and Downing, J. G. (1942) Arch. Derm. Syph. 46, 139.Kracke, R. R. (1938) J. Amer. med. Ass. 111, 1255.Leftwich, P. (1940) S. Afr. med. J. 14, 142.Madison, F. W. and Squier, T. L. (1934) J. Amer. med. Ass. 102, 755.Nicol, H. and Freedman, B. (1939) Lancet, ii, 647.Park, R. G. and Platts, W. M. (1942) Brit. med. J. ii, 308.Pearson, M. E. S. (1939) Ibid, i, 1031.Rosenthal, N. and Vogel, P. (1939) J. Amer. med. Ass. 113, 584.Shirley, J. S. and Allday, L. E. (1940) Ann. int. Med. 13, 1241.Sulzberger, M. B. (1940) Dermatologic Allergy. Springfield,
Illinois.Sutherland, M. E. (1939) Lancet, i, 1208.
Medical Societies
ROYAL SOCIETY OF MEDICINE
ON March 14 the section of experimental medicine,with Dr. R. D. LAWRENCE in the chair, discussed the
Etiology of Jaundice
including infective hepatitis, homologous serum jaundice,arsenotherapy jaundice, and the type which followsvaccination.
Dr. F. 0. MACCALLUM reviewed the attempts toisolate a causative agent from cases of infective hepa-titis and homologous serum jaundice by inoculationinto various animals and man. A large number ofexperiments have been carried out in the differentcountries where infective hepatitis is prevalent, but onlytwo groups of workers have claimed positive results.From Denmark Andersen and Tulinius reported trans-mission of the human disease by feeding duodenaljuice from cases of infective hepatitis to young pigson a quantitatively deficient diet. Liver changes weresaid to have been produced within 2-4 days of the feed-ing experiment. The value of these experiments israther doubtful as there was an epizootic of hepatitisamong the swine in Denmark at that time. The other
positive transmissions were claimed by three groupsof workers in Leipzig. It was said that inoculation ofduodenal washings from cases of hepatitis in the pre-icteric stage on to the chorioallantoic membrane ofdeveloping chick embryos had resulted in the death ofthe embryos after 4-5 days, and that the toxic agenthad been transmitted for 8 passages in the embryo.Negative results were obtained by inoculation of urineand blood from cases of infective hepatitis. TheLeipzig workers had also reported infection and death ofcanaries inoculated with duodenal juice or urine.Symptoms appeared in the canaries about the 3rd dayafter inoculation, with death on the 4th or 5th day.Canaries inoculated with blood from cases of infectivehepatitis remained well. In the present study beingcarried out at Cambridge for the Medical ResearchCouncil all attempts to repeat the results in pigs andcanaries had so far been unsuccessful. Microscopic liverchanges as described by Andersen had been seen in thecontrol animals on the deficient diet at Cambridge.The human transmission experiments suggested that thecausative agent of infective hepatitis was present in theduodenal juice and blood of patients before jaundiceappeared and in the blood 2 days after jaundice hadappeared. The results of animal experiments withmaterial from cases of homologous serum jaundice andpools of human serum known to be icterogenic had beenentirely -negative. Experiments in human volunteershad shown that the icterogenic agent was present in theblood of a presumed case of homologous serum jaundice7 days after the appearance of the jaundice but not 66days later. It had also been proved that a batch ofsupposedly normal human serum made from a poolfrom a number of blood-transfusion depots had containedan icterogenic agent which was responsible for thejaundice produced by a batch of yellow fever vaccinecontaining that serum.
Dr. A. M. McFARLAN described some features of anoutbreak of hepatitis in British Army recruits afterintravenous inoculations of mumps convalescent plasma,studied by the American Red Cross Harvard Unit. Aclinical comparison of 49 cases with 37 cases of infectivehepatitis showed that vomiting was less frequent, andrashes and arthralgiawere more -frequent, in the plasmajaundice cases. Epidemiologically the outbreak wasunlike infective hepatitis in the long interval betweeninoculation and development of symptoms (60-90 daysin 87% of cases), the absence of a secondary batch ofcases in uninoculated men, and the occurrence of jaun-dice in 8 of 11 inoculated men who gave a history ofjaundice in childhood. It was clear that certain batchesof human plasma or serum were icterogenic, but state-ments that jaundice had been caused by transfusion withwhole blood were less well .founded. Reports of suchcases should record the results of a search for cases ofhepatitis in contacts, and the source of the suspectedblood or blood product.
404
Major JAMES MARSHALL said that the hepatitis whichdeveloped-about 9 days after the beginning of arseno-therapy for syphilis was due to the arsenic and was morefrequent in patients receiving intensive therapy. Theincidence had been higher in a series of cases reportedfrom the Royal Navy than in an American series, perhapsbecause the American diet contained more liver-pro-tective substances. The hepatitis which developed12-17 weeks after the beginning of treatment was notdue to a recurrence of syphilis. Arsenic played somepart, but was not the prime factor. The incidence ofjaundice was lowered if the dose of arsenic was reducedbut not by the use ,of arsphenoxide in place of NAB.No particular batches of the drug were associated with ahigh incidence. The increased incidence of arseno-therapy jaundice was noted in districts south and south-west of London in 1941, in London itself in 1942, and inEssex in late 1942 and 1943. The incidence in variousclinics ranged from 20 to 50% ; it was higher in Armyclinics than in RAF and civilian clinics. Officers andother ranks were affected equally, whereas in peace-time private patients had practically never been affected.In women in Service clinics the incidence was only 5%.Experiments carried out with Prof. John Beattiehad shown that the administration of methionine or ofcystine alone or with a papain digest of casein delayedthe onset of hepatitis so -that 20 injections of arseniccould be given instead of 11. This was of great im-portance in treating syphilis. Major Marshall suggestedthat an icterogenic agent was transferred by the syringesused for arsenical inoculations. Of 6 cases treated withindividual sterilised syringes none had developed jaun-dice within 100 days of the first inoculation. There wasan incidence of jaundice of 50% in patients treated at thesame clinic with the usual syringe technique. Inindividual cases the interval between the first inoculationwith a possibility of infection and the development ofsymptoms had been 80 days. Cases of arsenotherapyjaundice had apparently been infected in hospital bypatients with infective hepatitis, which suggested thatthe’ " 100-day jaundice " of arsenotherapy was distinctfrom the " 30-day jaundice " of infective hepatitis. Intreatment he recommended a high protein and highcarbohydrate diet including 2 pints of dried or freshmilk and 1 dried or fresh egg daily.
Lieut.-Colonel T. BADGER (USA) reported on 1300cases of yellow fever vaccine jaundice seen in his hospital.The clinical picture was similar to that described byothers and differed little from ordinary infective hepatitisexcept that none of his patients had any fever. Therewas no evidence of any contact infection in groups ofindividuals who had not received the suspected vaccinebut were exposed to the cases of jaundice. The interval’between inoculation of vaccine and appearance ofjaundice varied from 12 to 18 weeks and this period wassimilar for groups inoculated with different batches ofvaccine. Laboratory experiments showed that thedisease was not a form of yellow fever, and the evidencesuggested that the supposedly normal human serumused for making the vaccine contained the responsibleicterogenic agent.Major M. H. SALAMAN described experiments made to
see if the recent increase in arsenotherapy jaundice wasdue to faulty technique in sterilisation of syringes. Ithad been suggested that using the methods generallypractised blood might be transferred from a patientincubating hepatitis to other patients in the clinic.Of 29 syphilitic patients who received arsenical injectionswith individual heat-sterilised syringes and special pre-cautions to ensure sterility, only 1 developed jaundicewithin four months of the first injection. In contrast,jaundice developed in 40% of patients (25 out of 67)receiving inoculations with the usual technique. Whenthe follow-up was extended to six months, only 1 of 12patients treated with individual syringes developed jaun-dice, as compared with 38 of 56 patients treated by theusual technique. He doubted whether boiling syringesbetween inoculations was a sufficient safeguard, and recom-mended the use of individual heat-sterilised syringes andscrupulous attention to the details of technique.
Dr. N. F. MACLAGAN said that the colloidal gold testshowed differences between obstructive jaundice, wherealmost all sera were negative, and infective hepatitis,where almost all were positive. In arsenotherapy
jaundice sera were less often positive. Hanger had noteda low percentage of positives in the cephalin cholesterolflocculation test applied to arsenotherapy jaundice cases.These biochemical findings indicated some differencebetween arsenotherapy jaundice and infective hepatitis.
Dr. J. F. LOUTIT. said that an icterogenic batch ofpooled serum had produced jaundice in 10 of 17 personswho received transfusions of quantities up to 1200c.cm. There had been an equally high incidence ofjaundice in persons who received intradermal injectionsof 01 c.cm. Homologous serum jaundice might there-fore result from very small amounts of serum, which-was an argument in favour of the syringe transmission ofarsenotherapy jaundice.
Sir HENRY TIDY recalled that when " catarrhaljaundice " was prevalent in 1928 it was noted that thedisease was more severe in older patients. Jaundicehad become a common complication of glandular fever(infectious mononucleosis) only in 1935. It was also acomplication of other infectious diseases. ’He thoughtthat the kidneys might be affected as well as the liver,and that the parenteral portal of entry in homologousserum jaundice as compared with the respiratory portalin infective hepatitis would account for the observeddifferences in infectivity.
Reviews of Books
Diseases of the Gastro- Intestinal TractASHER WINKELSTEIN, MD, associate in medicine andphysician in charge of the gastro-intestinal clinic MountSinai Hospital, New York. (Oxford University Press.Pp. 195. 12s. 6d.) )
A BOOK of 195 pages on gastro-intestinal diseasescould give a useful summary of the aetiology, pathology,symptoms, diagnosis and treatment, .useful alike forkeen senior students, general practitioners and consultingphysicians and surgeons, though hardly for specialistsin gastro-enterology ; and to hold their attention itshould be well written, and present the facts in aninteresting way. Dr. Winkelstein is a learned gastro-enterologist with an original mind, but his book consistsof terse statements divided into ten chapters, each with2-13 numbered subheadings, further subdivided untilthe smallest sections are single sentences. For thosewho like to have their mental food offered in the formof iron rations the method can be recommended ; thebook certainly contains the essential facts of gastro-enterology with few errors or omissions.
State of Medicine in IrelandW. R. F. COLLIS, MD CAMB., FRCP, FRCPI, physician tothe National Children’s Hospital, Dublin. (ParksidePress. Pp. 70. 2s. 6d.)
AT his death in 1849, Richard Carmichael, a distin-guished Dublin surgeon, bequeathed to the Royal Collegeof Surgeons in Ireland a sum of .E3000 to endow prizesfor essays dealing with medical education and with thecondition of the medical profession. The prize wasawarded in 1943 to Dr. Collis for a compact and carefulstudy, whose value lies, not so much in its facts, which arenot always - exact, as -in its constructive spirit. Dr.Collis covers the several branches of medical work, andhas criticisms and suggestions to make on nearly all.He has special qualifications for a task of this kind :Irish by birth, he was educated at Cambridge, andspent some years in specialist professional work in Londonbefore settling in Dublin. He therefore sees freshly.To those well accustomed to present conditions some ofhis suggestions may appear impracticable, while in thosewho have traditional rights they may rouse resentment.He recommends the establishment of a National Board ofHealth, to combine the Ministry of Health, the NationalHealth Insurance Society and the dispensary system-in fact all the official side of medicine. He recognisesthe practical value of the clinical education given inIrish medical schools, but emphasises the lack of trainingand opportunity for scientific investigation. His sug-gestions might redress the balance between these twotypes of medical education. His criticisms are generallywell based, and his positive suggestions sound, but hemay have underestimated the strength of custom andthe prejudice in favour of established ways.
