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TREATMENT AND PROPHYLAXIS OF SCARLET FEVER WITH SPECIFIC ANTITOXIC SERUM.
DR. J. C. B. CRAIG: ANTITOXIC SERUM IN SCARLET FEVER.
1123
Type of Serum and Methods of Standardisation. The preparation used was a concentrated scarlet SCARLET FEVER WITH SPECIFIC fever streptococcus antitoxin supplied by (1) Messrs. Parke, Davis and Co. (P., D. and Co.) ; (2) Messrs. ANTITOXIC SERUM.* Burroughs Wellcome and Co. (B. W. and Co.). These sera, before they are put on the market, have their B. BY JAMES C. CRAIG, M.D., D.P.H. EDIN., antitoxic titre tested, and 10 c.cm. or less of the SENIOR MEDICAL ASSISTANT, EDINBURGH CITY FEVER HOSPITAL. P., D. and Co. preparation is said to contain an efficient therapeutic dose, able to neutralise 500,000 skin-test doses of scarlet fever toxin. The potency of the THE setiological relationship between scarlet fever is likewise B. W. and Co. and the and certain specific strains of the haemolytic strepto- recommended preparation doses are : tested, 10 c.cm. for therapeutic coccus has been established through the work of mild cases, 20 c.cm. for severe cases, and 20-50 c.cm. Tunnicliff, Gordon, Dochez, Dick and Dick, Zingher, for cases of a very severe type. and others, and their work has changed the views of To corroborate these statements the potency of on of the treatment and control this investigators disease. The injection into horses of these specific samples of the sera were tested by the Schultzstrains and their toxic products has been shown to Charlton blanching test and the toxin-antitoxin test. In the former method an intraproduce an antitoxic serum, for which various workers1 neutralisation have claimed favourable therapeutic results. Park, cutaneous injection of a fixed quantity of serum in of New York, in his observations upon the use of an varying dilutions was performed on patients exhibiting antitoxic serum in the treatment of scarlet fever, a typical scarlatiniform eruption of under 48 hours’ duration. An attempt is thereby made to determine emphasises the necessity of giving a sufficient dose the smallest amount of serum which will show local at the earliest possible moment. He agrees with of the rash. The results obtained varied, blanching that antitoxin has little effect previous investigators on septic complications already developed, but that but out of a total of 18 patients tested, definite before their onset the serum appears to be of service blanching occurred in four cases with 0-2 c.cm. of in preventing them. Gardner Robb,2 Harries,s and 1 in 16,000 dilution, in rashes of under 24 hours’ Benson and MacIver4 report satisfactory results duration. In all cases blanching was obtained with from the use of serum in the prompt neutralisation of 0-2 c.cm. of dilutions up to 1 in 4000 of the serum in the specific togaemia of the disease, and a beneficial question. The results were similar for both types of effect in lessening the incidence of subsequent com- serum. The rationale of the second method is to find the plications. Cushing5 reviews the antitoxin treatment TREATMENT AND PROPHYLAXIS OF
of 500
cases
smallest amount of antitoxin which will neutralise
of scarlet fever at the Alexandra Fever
Hospital, Montreal. He found that the acti on of vari ous one skin-test dose of a standard scarlet fever toxin in preparations of serum differed only in degree, the a strongly Dick-positive individual. From this effects varying according to strength and concentra- quantity we can establish a unit of antitoxin (i.e., tion. Antitoxic serum was given to every definite case the amount which neutralises 100 skin-test doses of of scarlet fever, and the findings were controlled by toxin), and can thus calculate how many units of studying the hospital statistics for the previous year antitoxin are contained in a given amount-e.g., 1 c.cm. of the antitoxin. Thirty-four Dick-positive, of cases of the same clinical type. diphtheria-convalescent children were tested, and from the results in 14 of these cases the serum was Method Adopted. calculated to be able to neutralise 50,000 skin-test I had the the 1926-27, October, During period of toxin per c.cm. Again the findings were not doses in the opportunity of treating with antitoxic serum, consistent in all the patients tested and, taking the City Fever Hospital, Edinburgh, 500 cases of simpleI results as a whole, the potency of the samples of sera, scarlet fever, 10 cases of septic scarlet fever, and in terms of the ability to neutralise scarlet fever toxin, 2 cases of the toxic type of the disease. The followed was to administer serum, on the day of seemed to vary between 10,000 and 50,000 skin-test admission to hospital, to every definite case of scarlet doses per c.cm. fever of the simple type within the first three days of disease. Included in the series are a few cases to ’, Prophylactic and Therapeutic Dosage of Serum. whom serum was given on the fourth day of disease. There are many difficulties in the methods of These cases were of more than average severity, and of scarlet fever antitoxic serum, and it was thought advisable to give them the benefit of standardisation of these preparations is therefore somewhat the dosage serum therapy, although it is generally admitted that uncertain. The method employed in the prophylaxis by this time patients have passed the stage at which of scarlet fever by antitoxin is the production of antitoxin treatment proves beneficial. Cases of a passive immunity, which is expressed in terms of the very mild type or of doubtful diagnosis were not smallest amount of antitoxin which will render all included. Dick-positive reactors negative and keep them so for It was not possible to secure adequate control cases a period of time beyond the longest incubation period admitted during the same months, as I wanted to study of the disease. the results of serum therapy on as large a number of A batch of 20 children, all of whom showed positive cases as possible within the prescribed period. For conDick tests, received an intramuscular injection of 2c.cm. trols, therefore, I studied the clinical course of a similar of B. W. and Co. concentrated antitoxin (A. 4488F). Of these,
practice
’
number of
cases
of definite scarlet fever admitted to
hospital during the preceding year, October, 1925-26. The cases selected from the hospital records were of the same age-period and the same clinical type, and had been admitted to hospital on the same day of disease and on a corresponding date to those in the serum-treated series. Though it is recognised that scarlet fever varies considerably in its severity from year to year, the control cases were selected so as to be comparable in every detail with those treated by serum. This method of comparing and contrasting results in serum and non-serum treated cases is reliable one, provided the number of cases is large.
a
* The contents of this paper form a résumé of the work embodied in a thesis which was accepted for the degree of M.D. of the University of Edinburgh.
50 per cent. became Dick-negative within 24 hours of the injection, and, taking seven days as the longest incubation period of scarlet fever, it was found that 30 per cent. remained Dick-negative for that length of time (Dick toxin X 48, B. W. and Co.). A dose of 5 c.cm. of the same type of serum (A. 4488F) was next employed on 25 Dick-
positive reactors :
48 per cent. became Dick-negative 24 hours later and 56 per cent. within 48 hours of receiving the injection. They all remained negative for seven days (Dick toxin X 48, B. W. and Co.). A further series of 20 children were given 5 c.cm. of P., D. and Co. concentrated antitoxin (079761B). Of these, 70 per cent. showed a negative Dick test 24 hours later and 95 per cent. within 48 hours ; subsequent tests proved that 95 per cent. of this series remained Dick-negative for the required seven days. (Dick toxin B. 3015, B. W. and Co.) The material used for performing the Dick tests in the last two series of cases differed, as shown by the control
1124
DR. J. C. B. CRAIG: ANTITOXIC SERUM IN SCARLET FEVER. 1
that this might partly account for the variation in results obtained. Finally I administered 5 c.cm. of B. W. and Co. concentrated antitoxin (A. 4608A, A. 4608c) to 22 children and used toxins (B. 3782 and B. 3812, B. W. and Co.) for the Dick tests. In this group 60 per cent. became Dick-negative 24 hours later, but only 50 per cent. remained so for seven days. All these tests were performed upon diphtheria-convalescent patients, and the serum and Dick toxin employed was always used shortly after receipt from the makers.
numbers,
and it
was
thought
admitted to hospital. All patients received on the day of admission. The control cases were treated on purely symptomatic lines. In evaluating the effects of antitoxic serum I wish to draw particular attention to the following salient points in the clinical course of the disease : (1) temwere
their
injection
perature
curve ;
(2)
nervous
manifestations; (3) dura-
tion of rash and degree of desquamation; (4) serum reactions ; (5) incidence of subsequent complications; duration of stay in hospital ; (7) incidence of An opportunity to employ scarlet fever antitoxic (6) and second attacks ; (8) case-mortality. relapses serum prophylactically was afforded on two occasions when a case of scarlet fever developed in a diphtheria Temperature Curve.-In cases of simple scarlet ward. The procedure adopted was to Dick-test all fever the temperature normally falls on the third to the contacts, and on the next day to give to those fifth days of disease, irrespective of serum treatment, showing a positive Dick test and negative control an and so it is difficult to ascribe reduction of pyrexia, intramuscular injection of 5 c.cm. of concentrated unless very dramatic, to the effects of serum. Table II. shows the course of the temperature in the serumscarlet fever streptococcus antitoxin. CASE 1.—Out of a total of 17 contacts 11 were Dick- treated and control cases. positive (Dick toxin B. 3888. B. W. and Co.). Of these only two showed a negative Dick-test 24 hours after the injection TABLE II. of serum (A. 4654s, B.W. and Co.) One of the children who received serum and who remained Dick-positive developed scarlet fever ten days after the primary case had been isolated. This case, developing beyond the longest incubation period of scarlet fever, cannot be regarded as having been infected from the primary source.
CASE 2.-Amongst 15 contacts there were seven Dickpositive reactors (Dick toxin B. 4084, B. 4126, B.W. and Co.), and these were given 5 c.cm. of antitoxic serum (A. 4661D, B. W. and Co.). All of them showed a negative Dick test 24 hours later, and the test remained negative for ten days. No secondary cases of scarlet fever developed. As the infecting cases in these two outbreaks were promptly isolated the absence of secondary cases is not surprising, and therefore the serum must not
given too much credit. Nervous ll2anifestations.-The toxin of scarlet fever The views of various workers on the efficient acts as an exciting factor to the nervous apparently of of dose antitoxin for cases therapeutic simple that of diphtheria is a depressant. whereas system, scarlet fever have differed. The general opinion all the cases to whom serum was given on seems to be that an amount of antitoxin equivalent to Practically 200,000-1.000,000 skin-test doses of scarlet fever the evening of admission to hospital showed marked toxin fulfils the requirements for cases of average improvement in the toxæmic manifestations of the disease within 12 hours. This was most easily judged severity. Each patient in the series of 500 cases of simple in adult patients, who invariably admitted that they scarlet fever received the recommended dose of felt much more comfortable and relatively well within 10 c.cm. (B. W. and Co. antitoxin being administered a short time of receiving treatment. to 293 cases and P., D. and Co. serum to the remaining Effects on Rash and Desquamation.-The rash is 207). The injection was, in every case, intramuscular regarded as due to the toxin of the causal organism, into the lateral aspect of the thigh. The ten cases of and so it is to be expected that the prompt adminisseptic scarlet fever were treated by an intramuscular tration of the specific antitoxin will cause a blanching injection of 10 c.cm of concentrated scarlet fever of the exanthem before its normal time of disappearstreptococcus antitoxin followed by 50-100 c.cm. of ance. This phenomenon is most strikingly seen in the polyvalent antistreptococcal serum (B. W. and Co.). early rashes of under 48 hours’ duration : complete The therapeutic dose of 10 c.cm. was repeated 12 hours blanching occurred in 60 per cent. of cases within later in both the cases of toxic scarlet fever. 24 hours. In some cases the rash showed little or no blanching beyond normal limits. This fact may be Results of Serum Treatment. ascribed to inadequate dosage or to lack of specificity I propose to summarise separately the results of on the part of the antitoxin towards the toxin elaborated by the particular strain of hæmolytic serum treatment in the three types of the disease under consideration-viz., simple, septic, and toxic streptococcus. Moreover, rashes of over 48 hours’ duration become stained into the tissues of the skin scarlet fever. and cannot be blanched by the antitoxin. As was to TABLE I. be expected, the cases showing complete or modified blanching of the rash had an almost imperceptible be
desquamation. Serum Reactions.-According
S
=
Serum-treated
case.
C = Control
case.
to previous observers the introduction of concentrated preparations of serum has resulted in diminished frequency and severity of reactions. Out of the total of 500 cases receiving serum, 41 per cent. showed reactions at periods varying from 4 to 16 days after the injection. In no case did the symptoms give rise to alarm. In 25 per cent. of these cases there was only a rash-usually urticarial in nature-which lasted from a few hours to three davs in the most severe cases. The remaining 16 per cent. showed definite signs of serum disease : slight pyrexia, adenitis, fleeting joint pains, and an urticarial
eruption. of
Simple Scarlet Fever.-Table 1. shows the age-groups
the serum- and non-serum-treated or cases and the day of disease on which the
control
patients
Calcium chloride was given orally for ten days after the serum injection in doses of grs. 5 to children and grs. 10 to adults thrice daily. It was found to have no
DR. J. C. B. CRAIG : ANTITOXIC SERUM IN SCARLET FEVER.
effect at all in reducing the number or intensity of the reactions. Incidence of Subsequent Complications.-The power which an antitoxic serum possesses of preventing or reducing the various complications associated with scarlet fever forms the main line of investigation of Most the therapeutic value of such a measure. workers agree that serum, even when given on the first day of disease, is not an absolute safeguard against complications. A comparison of the incidence of complications in 500 cases treated with serum and a similar number of control cases is given in Table III. TABLE III.
1125
Arthritis occurred chiefly in adult female patients, and the likelihood of its being a serum phenomenon The was, as far as possible, carefully excluded. nephritis was an extremely mild type and occurred in a female aged 12 who received serum on the third day of disease. Duration of Stay in Hospital.—The usual quarantine period of four weeks for simple, uncomplicated cases of scarlet fever was not altered for serum-treated patients, and if there were complications the cases were detained in hospital until clear of infection. Fresh complications developed after the fourth week of disease in 14 serum-treated patients who had already shown complications, except one who was discharged as a clean case at the end of the fourth week and who was readmitted one week later with a purulent rhinitis and otitis media. The number of weeks in hospital beyond the usual quarantine period was 485 for the 500 serum-treated cases, while for the control series the figure was 680 weeks. Incidence of Relapses and Second Attacks.—The serum-treated cases showed three genuine relapses during the fourth week of the disease, an incidence of less than 1 per cent., which cannot be regarded as exceeding normal limits. Second attacks of scarlet fever, though rare, do occur, and a girl of 5 who received her injection on the second day of disease had a second mild but quite definite attack nine months later. The Dick test on the second day of disease was negative, which suggests that the particular strain of hæmolytic streptococcus causing the second attack differed from that causing the primary disease. Case-mortality.—The case-mortality for simple scarlet fever is at present very low, owing to the mild type prevalent in this country. It is therefore difficult to imagine that serum therapy will cause any dramatic change in this. One death occurred in the serum-treated cases, and was attributable to an intercurrent tuberculous peritonitis. There was also one fatal case in the control series.
Septic Scarlet Fever. It was hoped, by the combined administration of the two types of serum-concentrated scarlet fever streptococcus antitoxin and polyvalent antistreptococcal serum-to bring about improvement simultaneously in the two aspects of infection—viz., the specific hæmolytic streptococcus of scarlet fever and the secondary invading organisms. The effects have been observed on ten cases of septic scarlet fever. The number is too limited for definite conclusions, but the opinion formed of its efficacy is favourable. The cases were all of a very severe type with marked constitutional symptoms and exaggeration of the condition, together with cervical adenitis and purulent rhinitis. Six, after a febrile period varying from 3-12 days after the injection of serum, experienced an uninterrupted convalescence and were discharged from hospital during the fifth week of disease. Three developed otitis media, and in one of these the condition proceeded to mastoiditis requiring operation. They were discharged from hospital at the end of 9, 9, and 15 weeks respectivelv. The remaining child developed broncho-pneumonia during the fifth week of disease and remained in hospital until the end of the ninth week of disease. There were no deaths.
faucial cases not until the fourth day of disease were more numerous than in the control series, and the best results were obtained amongst cases treated on the first day of disease. The table shows that the number .of multiple complications in the control cases was
As the table
receiving
shows, the complications in
serum
TABLE IV.
twice that in those treated with serum. The incidence - of arthritis, nephritis, and otitis media in cases treated with serum during the first three days of disease and in a corresponding number of control cases is shown in Table IV.
l’o:ric 8carlet Fever. It is in this type of the disease that we look for the most dramatic results of specific serum therapy, if given in sufficient dosage and early enough in the course of the disease, when the patient ha the power to respond. The two following cases, which may be regarded as genuine examples of toxic scarlet fever, were treated with concentrated scarlet fever streptococcus antitoxin. CASE 1.—Female, aged 7, admitted to hospital on second
day of disease. Three more cases of scarlet fever from same family. Temperature, 103° F. ; pulse-rate, 168 ; respirations, 36. Pulse soft and thready. Rash poorly developed.
1126
CLINICAL AND LABORATORY NOTES.
Fauces congested. Severe vomiting and diarrhoea. Extreme restlessness. 10 c.cm., P.. D. and Co., antitoxic serum given intramuscularly on admission. Very little improvement in general condition 12 hours later. 10 c.cm. of same type of serum given intravenously in half a pint of warm sterile normal saline. Very marked improvement 12 hours later. Vomiting and diarrhoea Restlessness gone. Temperature and pulse-rate ceased. reached normal 24 hours after second injection. No serum reaction. Convalescence uneventful. Discharged from hospital on the thirty-seventh day of disease. CASE 2.-Female, aged 10, admitted to hospital on the third day of disease. Temperature, 103° F. ; pulse-rate, 156 ; respirations, 32. Poorly developed punctate erythema over trunk. Tongue and fauces typical of scarlet fever. Slight cyanosis of lips. Pulse rapid and soft. Extreme restlessness. Marked diarrhoea. No vomiting. 10 c.cm., B. W. and Co., antitoxic serum given intramuscularly on admission. No definite improvement 12 hours later. 10 c.cm. of same type of serum given intramuscularly (attempt at intravenous administration failed). Marked improvement 24 hours after second injection. Restlessness and diarrhoea ceased. Temperature and pulse-rate normal 48 hours after second injection. No serum reaction. Convalescence uneventful. Discharged from hospital on the thirty-fourth day of disease.
Lips cyanosed.
Clinical and
Laboratory Notes. A CASE OF
CONGENITAL VALVULAR OBSTRUCTION OF THE URETHRA. BY HELENA B. KING, M.B.
LOND.,
MEDICAL OFFICER TO MATERNITY AND CHILD WELFARE
CENTRE,
BRENTFORD ; AND
W. P. H. SHELDON, M.D., M.R.C.P. LOND., JUNIOR PHYSTCIAN TO THE CHILDREN’S DEPARTMENT, KING’S COLLEGE HOSPITAL ; LATE MEDICAL REGISTRAR, HOSPITAL FOR SICK CHILDREN, GREAT ORMOND-STREET.
THE condition of congenital bilateral hydronephrosis together with dilatation of both ureters is comparatively well known, but any example which helps to shed a light upon the pathogenesis of this condition is worth recording and considering from every available aspect. The following case is one of the youngest Conclusions. recorded, and the facts noted during the 20 days of 1. The potency of different samples of scarlet fever life were checked and correlated at the post-mortem streptococcus antitoxin has, up to the present time, examination. varied considerably as shown by the methods in use A primipara, aged 34, had a normal pregnancy until the for testing its antitoxic titre. 2. A minimum of thirty-fourth week, when slight oedema of the lower 5 c.cm. of the average serum at present on the market extremities developed and the urine contained a trace of
should be administered as a prophylactic dose. albumin. The oedema was progressive until delivery, 3. The administration of antitoxic serum within the although no signs of toxaemia could be found, and the first three days of disease produces a favourable FIG. 1. effect in counteracting the specific toxaemia. 4. The reactions following the administration of a reliable concentrated antitoxin are not severe. 5. An amount ’, of antitoxin sufficient to neutralise 500,000 skin-test doses of scarlet fever toxin should be regarded as the minimum therapeutic dose for simple scarlet fever. 6. The full therapeutic dose should be given at the earliest possible moment to obtain the best results. 7. When given within the first three days of disease it lessens the incidence and reduces the severity of subsequent complications. 8. The therapeutic efficacy of the serum diminishes with each day of delay in its administration, the third day of disease it seems to have little effect in influencing the incidenceI of subsequent complications. 9. From the results obtained it does not seem advisable to reduce the quarantine period to less than four weeks in cases treated with antitoxin, but the total period of hospitalisation is reduced because the serum therapy lowers the incidence and severity of complications. 10. Antitoxin treatment of scarlet fever does not appear to increase the incidence of relapses beyond normal limits. 11. There is reason to believe that the treatment of septic scarlet fever by a combination of specific antitoxic serum and polyvalent antistreptococcal serum cuts short the course of disease and lessens the liability to the development of subsequent septic complications. 12. Specific antitoxic serum, if given early and in large doses, is an extremely efficacious treatment for toxic scarlet fever. Intravenous administration is more advantageous than intraShowing the whole urinary apparatus. Both kidneys are hydronephrotic, the ureters are dilated and muscular, as it ensures a more rapid maximum tortuous, the bladder wall is hypertrophied, and the action.
and beyond
prostatic urethra is dilated.
I wish to take this
opportunity
of
expressing
my
grateful thanks to Dr. W. T. Benson, medical systolic blood pressure remained steady at 130 mn2. of superintendent, Edinburgh City Fever Hospital, for mercury. The presentation was a persistent breech with his kind permission to carry out these investigations extended legs, and delivery was by Cæsarean section at full and for much useful
term.
help.
Bibliography.—1. Park, W. H. : Jour. Amer. Med. Assoc., 1925, lxxxv., 1180. 2. Robb, A. Gardner : Brit. Med. Jour., 1926, i., 11. 3. Harries, E. H. R. : Public Health, 1925-26, xxxix., 104. 4. Benson, W. T., and MacIver, D. P. : Edin. Med. Jour., 1926, xxxiii., 701. 5. Cushing, H. B.: Canad. Med. Assoc. Jour., 1926, xvi., 936. WEST END HOSPITAL
FOR
NERVOUS DISEASES.-
About ;BSOOO was raised at the jubilee dinner of the hospital held at Grosvenor House last week in response to an appeal for £10,000 for development work.
The mother had no pyrexia, and convalescence was At the time of the operation it was noticed that there was practically no liquor amnii. Although the membranes had ruptured earlier in the day only a normal quantity of liquor had been lost during the few hours of labour that preceded delivery. The child was a well-developed male, weighing 81 lb. The scrotum and penis were very cedematous. and there was a well-marked right-sided torticollis, and a linear discoloration amounting almost to an abrasion of the skin of the subclavicular region where the head appeared to have been pressed closely against the chest wall. The child cried well, but from the first he seemed lethargic and took the breast
uneventful.
1123
Type of Serum and Methods of Standardisation. The preparation used was a concentrated scarlet SCARLET FEVER WITH SPECIFIC fever streptococcus antitoxin supplied by (1) Messrs. Parke, Davis and Co. (P., D. and Co.) ; (2) Messrs. ANTITOXIC SERUM.* Burroughs Wellcome and Co. (B. W. and Co.). These sera, before they are put on the market, have their B. BY JAMES C. CRAIG, M.D., D.P.H. EDIN., antitoxic titre tested, and 10 c.cm. or less of the SENIOR MEDICAL ASSISTANT, EDINBURGH CITY FEVER HOSPITAL. P., D. and Co. preparation is said to contain an efficient therapeutic dose, able to neutralise 500,000 skin-test doses of scarlet fever toxin. The potency of the THE setiological relationship between scarlet fever is likewise B. W. and Co. and the and certain specific strains of the haemolytic strepto- recommended preparation doses are : tested, 10 c.cm. for therapeutic coccus has been established through the work of mild cases, 20 c.cm. for severe cases, and 20-50 c.cm. Tunnicliff, Gordon, Dochez, Dick and Dick, Zingher, for cases of a very severe type. and others, and their work has changed the views of To corroborate these statements the potency of on of the treatment and control this investigators disease. The injection into horses of these specific samples of the sera were tested by the Schultzstrains and their toxic products has been shown to Charlton blanching test and the toxin-antitoxin test. In the former method an intraproduce an antitoxic serum, for which various workers1 neutralisation have claimed favourable therapeutic results. Park, cutaneous injection of a fixed quantity of serum in of New York, in his observations upon the use of an varying dilutions was performed on patients exhibiting antitoxic serum in the treatment of scarlet fever, a typical scarlatiniform eruption of under 48 hours’ duration. An attempt is thereby made to determine emphasises the necessity of giving a sufficient dose the smallest amount of serum which will show local at the earliest possible moment. He agrees with of the rash. The results obtained varied, blanching that antitoxin has little effect previous investigators on septic complications already developed, but that but out of a total of 18 patients tested, definite before their onset the serum appears to be of service blanching occurred in four cases with 0-2 c.cm. of in preventing them. Gardner Robb,2 Harries,s and 1 in 16,000 dilution, in rashes of under 24 hours’ Benson and MacIver4 report satisfactory results duration. In all cases blanching was obtained with from the use of serum in the prompt neutralisation of 0-2 c.cm. of dilutions up to 1 in 4000 of the serum in the specific togaemia of the disease, and a beneficial question. The results were similar for both types of effect in lessening the incidence of subsequent com- serum. The rationale of the second method is to find the plications. Cushing5 reviews the antitoxin treatment TREATMENT AND PROPHYLAXIS OF
of 500
cases
smallest amount of antitoxin which will neutralise
of scarlet fever at the Alexandra Fever
Hospital, Montreal. He found that the acti on of vari ous one skin-test dose of a standard scarlet fever toxin in preparations of serum differed only in degree, the a strongly Dick-positive individual. From this effects varying according to strength and concentra- quantity we can establish a unit of antitoxin (i.e., tion. Antitoxic serum was given to every definite case the amount which neutralises 100 skin-test doses of of scarlet fever, and the findings were controlled by toxin), and can thus calculate how many units of studying the hospital statistics for the previous year antitoxin are contained in a given amount-e.g., 1 c.cm. of the antitoxin. Thirty-four Dick-positive, of cases of the same clinical type. diphtheria-convalescent children were tested, and from the results in 14 of these cases the serum was Method Adopted. calculated to be able to neutralise 50,000 skin-test I had the the 1926-27, October, During period of toxin per c.cm. Again the findings were not doses in the opportunity of treating with antitoxic serum, consistent in all the patients tested and, taking the City Fever Hospital, Edinburgh, 500 cases of simpleI results as a whole, the potency of the samples of sera, scarlet fever, 10 cases of septic scarlet fever, and in terms of the ability to neutralise scarlet fever toxin, 2 cases of the toxic type of the disease. The followed was to administer serum, on the day of seemed to vary between 10,000 and 50,000 skin-test admission to hospital, to every definite case of scarlet doses per c.cm. fever of the simple type within the first three days of disease. Included in the series are a few cases to ’, Prophylactic and Therapeutic Dosage of Serum. whom serum was given on the fourth day of disease. There are many difficulties in the methods of These cases were of more than average severity, and of scarlet fever antitoxic serum, and it was thought advisable to give them the benefit of standardisation of these preparations is therefore somewhat the dosage serum therapy, although it is generally admitted that uncertain. The method employed in the prophylaxis by this time patients have passed the stage at which of scarlet fever by antitoxin is the production of antitoxin treatment proves beneficial. Cases of a passive immunity, which is expressed in terms of the very mild type or of doubtful diagnosis were not smallest amount of antitoxin which will render all included. Dick-positive reactors negative and keep them so for It was not possible to secure adequate control cases a period of time beyond the longest incubation period admitted during the same months, as I wanted to study of the disease. the results of serum therapy on as large a number of A batch of 20 children, all of whom showed positive cases as possible within the prescribed period. For conDick tests, received an intramuscular injection of 2c.cm. trols, therefore, I studied the clinical course of a similar of B. W. and Co. concentrated antitoxin (A. 4488F). Of these,
practice
’
number of
cases
of definite scarlet fever admitted to
hospital during the preceding year, October, 1925-26. The cases selected from the hospital records were of the same age-period and the same clinical type, and had been admitted to hospital on the same day of disease and on a corresponding date to those in the serum-treated series. Though it is recognised that scarlet fever varies considerably in its severity from year to year, the control cases were selected so as to be comparable in every detail with those treated by serum. This method of comparing and contrasting results in serum and non-serum treated cases is reliable one, provided the number of cases is large.
a
* The contents of this paper form a résumé of the work embodied in a thesis which was accepted for the degree of M.D. of the University of Edinburgh.
50 per cent. became Dick-negative within 24 hours of the injection, and, taking seven days as the longest incubation period of scarlet fever, it was found that 30 per cent. remained Dick-negative for that length of time (Dick toxin X 48, B. W. and Co.). A dose of 5 c.cm. of the same type of serum (A. 4488F) was next employed on 25 Dick-
positive reactors :
48 per cent. became Dick-negative 24 hours later and 56 per cent. within 48 hours of receiving the injection. They all remained negative for seven days (Dick toxin X 48, B. W. and Co.). A further series of 20 children were given 5 c.cm. of P., D. and Co. concentrated antitoxin (079761B). Of these, 70 per cent. showed a negative Dick test 24 hours later and 95 per cent. within 48 hours ; subsequent tests proved that 95 per cent. of this series remained Dick-negative for the required seven days. (Dick toxin B. 3015, B. W. and Co.) The material used for performing the Dick tests in the last two series of cases differed, as shown by the control
1124
DR. J. C. B. CRAIG: ANTITOXIC SERUM IN SCARLET FEVER. 1
that this might partly account for the variation in results obtained. Finally I administered 5 c.cm. of B. W. and Co. concentrated antitoxin (A. 4608A, A. 4608c) to 22 children and used toxins (B. 3782 and B. 3812, B. W. and Co.) for the Dick tests. In this group 60 per cent. became Dick-negative 24 hours later, but only 50 per cent. remained so for seven days. All these tests were performed upon diphtheria-convalescent patients, and the serum and Dick toxin employed was always used shortly after receipt from the makers.
numbers,
and it
was
thought
admitted to hospital. All patients received on the day of admission. The control cases were treated on purely symptomatic lines. In evaluating the effects of antitoxic serum I wish to draw particular attention to the following salient points in the clinical course of the disease : (1) temwere
their
injection
perature
curve ;
(2)
nervous
manifestations; (3) dura-
tion of rash and degree of desquamation; (4) serum reactions ; (5) incidence of subsequent complications; duration of stay in hospital ; (7) incidence of An opportunity to employ scarlet fever antitoxic (6) and second attacks ; (8) case-mortality. relapses serum prophylactically was afforded on two occasions when a case of scarlet fever developed in a diphtheria Temperature Curve.-In cases of simple scarlet ward. The procedure adopted was to Dick-test all fever the temperature normally falls on the third to the contacts, and on the next day to give to those fifth days of disease, irrespective of serum treatment, showing a positive Dick test and negative control an and so it is difficult to ascribe reduction of pyrexia, intramuscular injection of 5 c.cm. of concentrated unless very dramatic, to the effects of serum. Table II. shows the course of the temperature in the serumscarlet fever streptococcus antitoxin. CASE 1.—Out of a total of 17 contacts 11 were Dick- treated and control cases. positive (Dick toxin B. 3888. B. W. and Co.). Of these only two showed a negative Dick-test 24 hours after the injection TABLE II. of serum (A. 4654s, B.W. and Co.) One of the children who received serum and who remained Dick-positive developed scarlet fever ten days after the primary case had been isolated. This case, developing beyond the longest incubation period of scarlet fever, cannot be regarded as having been infected from the primary source.
CASE 2.-Amongst 15 contacts there were seven Dickpositive reactors (Dick toxin B. 4084, B. 4126, B.W. and Co.), and these were given 5 c.cm. of antitoxic serum (A. 4661D, B. W. and Co.). All of them showed a negative Dick test 24 hours later, and the test remained negative for ten days. No secondary cases of scarlet fever developed. As the infecting cases in these two outbreaks were promptly isolated the absence of secondary cases is not surprising, and therefore the serum must not
given too much credit. Nervous ll2anifestations.-The toxin of scarlet fever The views of various workers on the efficient acts as an exciting factor to the nervous apparently of of dose antitoxin for cases therapeutic simple that of diphtheria is a depressant. whereas system, scarlet fever have differed. The general opinion all the cases to whom serum was given on seems to be that an amount of antitoxin equivalent to Practically 200,000-1.000,000 skin-test doses of scarlet fever the evening of admission to hospital showed marked toxin fulfils the requirements for cases of average improvement in the toxæmic manifestations of the disease within 12 hours. This was most easily judged severity. Each patient in the series of 500 cases of simple in adult patients, who invariably admitted that they scarlet fever received the recommended dose of felt much more comfortable and relatively well within 10 c.cm. (B. W. and Co. antitoxin being administered a short time of receiving treatment. to 293 cases and P., D. and Co. serum to the remaining Effects on Rash and Desquamation.-The rash is 207). The injection was, in every case, intramuscular regarded as due to the toxin of the causal organism, into the lateral aspect of the thigh. The ten cases of and so it is to be expected that the prompt adminisseptic scarlet fever were treated by an intramuscular tration of the specific antitoxin will cause a blanching injection of 10 c.cm of concentrated scarlet fever of the exanthem before its normal time of disappearstreptococcus antitoxin followed by 50-100 c.cm. of ance. This phenomenon is most strikingly seen in the polyvalent antistreptococcal serum (B. W. and Co.). early rashes of under 48 hours’ duration : complete The therapeutic dose of 10 c.cm. was repeated 12 hours blanching occurred in 60 per cent. of cases within later in both the cases of toxic scarlet fever. 24 hours. In some cases the rash showed little or no blanching beyond normal limits. This fact may be Results of Serum Treatment. ascribed to inadequate dosage or to lack of specificity I propose to summarise separately the results of on the part of the antitoxin towards the toxin elaborated by the particular strain of hæmolytic serum treatment in the three types of the disease under consideration-viz., simple, septic, and toxic streptococcus. Moreover, rashes of over 48 hours’ duration become stained into the tissues of the skin scarlet fever. and cannot be blanched by the antitoxin. As was to TABLE I. be expected, the cases showing complete or modified blanching of the rash had an almost imperceptible be
desquamation. Serum Reactions.-According
S
=
Serum-treated
case.
C = Control
case.
to previous observers the introduction of concentrated preparations of serum has resulted in diminished frequency and severity of reactions. Out of the total of 500 cases receiving serum, 41 per cent. showed reactions at periods varying from 4 to 16 days after the injection. In no case did the symptoms give rise to alarm. In 25 per cent. of these cases there was only a rash-usually urticarial in nature-which lasted from a few hours to three davs in the most severe cases. The remaining 16 per cent. showed definite signs of serum disease : slight pyrexia, adenitis, fleeting joint pains, and an urticarial
eruption. of
Simple Scarlet Fever.-Table 1. shows the age-groups
the serum- and non-serum-treated or cases and the day of disease on which the
control
patients
Calcium chloride was given orally for ten days after the serum injection in doses of grs. 5 to children and grs. 10 to adults thrice daily. It was found to have no
DR. J. C. B. CRAIG : ANTITOXIC SERUM IN SCARLET FEVER.
effect at all in reducing the number or intensity of the reactions. Incidence of Subsequent Complications.-The power which an antitoxic serum possesses of preventing or reducing the various complications associated with scarlet fever forms the main line of investigation of Most the therapeutic value of such a measure. workers agree that serum, even when given on the first day of disease, is not an absolute safeguard against complications. A comparison of the incidence of complications in 500 cases treated with serum and a similar number of control cases is given in Table III. TABLE III.
1125
Arthritis occurred chiefly in adult female patients, and the likelihood of its being a serum phenomenon The was, as far as possible, carefully excluded. nephritis was an extremely mild type and occurred in a female aged 12 who received serum on the third day of disease. Duration of Stay in Hospital.—The usual quarantine period of four weeks for simple, uncomplicated cases of scarlet fever was not altered for serum-treated patients, and if there were complications the cases were detained in hospital until clear of infection. Fresh complications developed after the fourth week of disease in 14 serum-treated patients who had already shown complications, except one who was discharged as a clean case at the end of the fourth week and who was readmitted one week later with a purulent rhinitis and otitis media. The number of weeks in hospital beyond the usual quarantine period was 485 for the 500 serum-treated cases, while for the control series the figure was 680 weeks. Incidence of Relapses and Second Attacks.—The serum-treated cases showed three genuine relapses during the fourth week of the disease, an incidence of less than 1 per cent., which cannot be regarded as exceeding normal limits. Second attacks of scarlet fever, though rare, do occur, and a girl of 5 who received her injection on the second day of disease had a second mild but quite definite attack nine months later. The Dick test on the second day of disease was negative, which suggests that the particular strain of hæmolytic streptococcus causing the second attack differed from that causing the primary disease. Case-mortality.—The case-mortality for simple scarlet fever is at present very low, owing to the mild type prevalent in this country. It is therefore difficult to imagine that serum therapy will cause any dramatic change in this. One death occurred in the serum-treated cases, and was attributable to an intercurrent tuberculous peritonitis. There was also one fatal case in the control series.
Septic Scarlet Fever. It was hoped, by the combined administration of the two types of serum-concentrated scarlet fever streptococcus antitoxin and polyvalent antistreptococcal serum-to bring about improvement simultaneously in the two aspects of infection—viz., the specific hæmolytic streptococcus of scarlet fever and the secondary invading organisms. The effects have been observed on ten cases of septic scarlet fever. The number is too limited for definite conclusions, but the opinion formed of its efficacy is favourable. The cases were all of a very severe type with marked constitutional symptoms and exaggeration of the condition, together with cervical adenitis and purulent rhinitis. Six, after a febrile period varying from 3-12 days after the injection of serum, experienced an uninterrupted convalescence and were discharged from hospital during the fifth week of disease. Three developed otitis media, and in one of these the condition proceeded to mastoiditis requiring operation. They were discharged from hospital at the end of 9, 9, and 15 weeks respectivelv. The remaining child developed broncho-pneumonia during the fifth week of disease and remained in hospital until the end of the ninth week of disease. There were no deaths.
faucial cases not until the fourth day of disease were more numerous than in the control series, and the best results were obtained amongst cases treated on the first day of disease. The table shows that the number .of multiple complications in the control cases was
As the table
receiving
shows, the complications in
serum
TABLE IV.
twice that in those treated with serum. The incidence - of arthritis, nephritis, and otitis media in cases treated with serum during the first three days of disease and in a corresponding number of control cases is shown in Table IV.
l’o:ric 8carlet Fever. It is in this type of the disease that we look for the most dramatic results of specific serum therapy, if given in sufficient dosage and early enough in the course of the disease, when the patient ha the power to respond. The two following cases, which may be regarded as genuine examples of toxic scarlet fever, were treated with concentrated scarlet fever streptococcus antitoxin. CASE 1.—Female, aged 7, admitted to hospital on second
day of disease. Three more cases of scarlet fever from same family. Temperature, 103° F. ; pulse-rate, 168 ; respirations, 36. Pulse soft and thready. Rash poorly developed.
1126
CLINICAL AND LABORATORY NOTES.
Fauces congested. Severe vomiting and diarrhoea. Extreme restlessness. 10 c.cm., P.. D. and Co., antitoxic serum given intramuscularly on admission. Very little improvement in general condition 12 hours later. 10 c.cm. of same type of serum given intravenously in half a pint of warm sterile normal saline. Very marked improvement 12 hours later. Vomiting and diarrhoea Restlessness gone. Temperature and pulse-rate ceased. reached normal 24 hours after second injection. No serum reaction. Convalescence uneventful. Discharged from hospital on the thirty-seventh day of disease. CASE 2.-Female, aged 10, admitted to hospital on the third day of disease. Temperature, 103° F. ; pulse-rate, 156 ; respirations, 32. Poorly developed punctate erythema over trunk. Tongue and fauces typical of scarlet fever. Slight cyanosis of lips. Pulse rapid and soft. Extreme restlessness. Marked diarrhoea. No vomiting. 10 c.cm., B. W. and Co., antitoxic serum given intramuscularly on admission. No definite improvement 12 hours later. 10 c.cm. of same type of serum given intramuscularly (attempt at intravenous administration failed). Marked improvement 24 hours after second injection. Restlessness and diarrhoea ceased. Temperature and pulse-rate normal 48 hours after second injection. No serum reaction. Convalescence uneventful. Discharged from hospital on the thirty-fourth day of disease.
Lips cyanosed.
Clinical and
Laboratory Notes. A CASE OF
CONGENITAL VALVULAR OBSTRUCTION OF THE URETHRA. BY HELENA B. KING, M.B.
LOND.,
MEDICAL OFFICER TO MATERNITY AND CHILD WELFARE
CENTRE,
BRENTFORD ; AND
W. P. H. SHELDON, M.D., M.R.C.P. LOND., JUNIOR PHYSTCIAN TO THE CHILDREN’S DEPARTMENT, KING’S COLLEGE HOSPITAL ; LATE MEDICAL REGISTRAR, HOSPITAL FOR SICK CHILDREN, GREAT ORMOND-STREET.
THE condition of congenital bilateral hydronephrosis together with dilatation of both ureters is comparatively well known, but any example which helps to shed a light upon the pathogenesis of this condition is worth recording and considering from every available aspect. The following case is one of the youngest Conclusions. recorded, and the facts noted during the 20 days of 1. The potency of different samples of scarlet fever life were checked and correlated at the post-mortem streptococcus antitoxin has, up to the present time, examination. varied considerably as shown by the methods in use A primipara, aged 34, had a normal pregnancy until the for testing its antitoxic titre. 2. A minimum of thirty-fourth week, when slight oedema of the lower 5 c.cm. of the average serum at present on the market extremities developed and the urine contained a trace of
should be administered as a prophylactic dose. albumin. The oedema was progressive until delivery, 3. The administration of antitoxic serum within the although no signs of toxaemia could be found, and the first three days of disease produces a favourable FIG. 1. effect in counteracting the specific toxaemia. 4. The reactions following the administration of a reliable concentrated antitoxin are not severe. 5. An amount ’, of antitoxin sufficient to neutralise 500,000 skin-test doses of scarlet fever toxin should be regarded as the minimum therapeutic dose for simple scarlet fever. 6. The full therapeutic dose should be given at the earliest possible moment to obtain the best results. 7. When given within the first three days of disease it lessens the incidence and reduces the severity of subsequent complications. 8. The therapeutic efficacy of the serum diminishes with each day of delay in its administration, the third day of disease it seems to have little effect in influencing the incidenceI of subsequent complications. 9. From the results obtained it does not seem advisable to reduce the quarantine period to less than four weeks in cases treated with antitoxin, but the total period of hospitalisation is reduced because the serum therapy lowers the incidence and severity of complications. 10. Antitoxin treatment of scarlet fever does not appear to increase the incidence of relapses beyond normal limits. 11. There is reason to believe that the treatment of septic scarlet fever by a combination of specific antitoxic serum and polyvalent antistreptococcal serum cuts short the course of disease and lessens the liability to the development of subsequent septic complications. 12. Specific antitoxic serum, if given early and in large doses, is an extremely efficacious treatment for toxic scarlet fever. Intravenous administration is more advantageous than intraShowing the whole urinary apparatus. Both kidneys are hydronephrotic, the ureters are dilated and muscular, as it ensures a more rapid maximum tortuous, the bladder wall is hypertrophied, and the action.
and beyond
prostatic urethra is dilated.
I wish to take this
opportunity
of
expressing
my
grateful thanks to Dr. W. T. Benson, medical systolic blood pressure remained steady at 130 mn2. of superintendent, Edinburgh City Fever Hospital, for mercury. The presentation was a persistent breech with his kind permission to carry out these investigations extended legs, and delivery was by Cæsarean section at full and for much useful
term.
help.
Bibliography.—1. Park, W. H. : Jour. Amer. Med. Assoc., 1925, lxxxv., 1180. 2. Robb, A. Gardner : Brit. Med. Jour., 1926, i., 11. 3. Harries, E. H. R. : Public Health, 1925-26, xxxix., 104. 4. Benson, W. T., and MacIver, D. P. : Edin. Med. Jour., 1926, xxxiii., 701. 5. Cushing, H. B.: Canad. Med. Assoc. Jour., 1926, xvi., 936. WEST END HOSPITAL
FOR
NERVOUS DISEASES.-
About ;BSOOO was raised at the jubilee dinner of the hospital held at Grosvenor House last week in response to an appeal for £10,000 for development work.
The mother had no pyrexia, and convalescence was At the time of the operation it was noticed that there was practically no liquor amnii. Although the membranes had ruptured earlier in the day only a normal quantity of liquor had been lost during the few hours of labour that preceded delivery. The child was a well-developed male, weighing 81 lb. The scrotum and penis were very cedematous. and there was a well-marked right-sided torticollis, and a linear discoloration amounting almost to an abrasion of the skin of the subclavicular region where the head appeared to have been pressed closely against the chest wall. The child cried well, but from the first he seemed lethargic and took the breast
uneventful.