ANTITOXINE IN THE TREATMENT 
OF DIPHTHERIA. 
By JOHN H. McCOLLOM, M.D. 
OF BOSTON. 
Head at the Annual Meeting of the Massachusetts Medical Society, 
June 9, 1896. ANTITOXINE IX THE TREATMENT OF 
DIPHTHERIA. 
It is the generally conceived opinion that physicians are 
exceptionally conservative in accepting any new remedy for 
the treatment of any special disease, and it is well that it 
should he so ; for only by careful investigation of the re- 
sults of any special mode of treatment can we hope to ar- 
rive at the truth. Statistics of the result of any method 
of treatment of a special disease, to be of value, must be 
based on a large number of cases and must continue for a 
very considerable period of time. It is also important that 
the cases should be observed until absolute recovery takes 
place. Antitoxine has now been in use something over 
three years, and the consensus of opinion is that it is a 
remedy of great value in the treatment of diphtheria. It 
has not, however, proved of advantage in far advanced 
septic cases of this disease, neither has it been shown to be 
of any value in the later symptoms characterized by failure 
of the heart’s action and a general degeneration of the 
nerves. While it is not claimed that antitoxine will cure 
every case of diphtheria, it is claimed, and an analysis of 
the following statistics proves, that the serum of horses 
rendered immune to the toxine of diphtheria is one of the 
most valuable agents in the treatment of diphtheria. In 
the Boston City Hospital in 1891 there were 237 cases of 
diphtheria treated, with 105 deaths. In 1892-3 there were 
387 cases treated, with 185 deaths. In 1893-4 there were 
438 cases treated, with 203 deaths. In 1894-5, when anti- 4 
ANTITOXINE IN THE 
toxine was used only in a comparatively small proportion 
of cases, there were 698 cases treated, with 266 deaths, 
making a total of 1760 cases with 759 deaths, with a per- 
centage of 43, which was about the average death-rate of 
diphtheria in hospital cases both in this country and in 
Europe. In private practice the death-rate as a rule is not 
quite so high as in hospital cases, simply from the fact that 
the severe cases only are sent to the hospital. In Bos- 
ton, from 1878 to 1894, the average death-rate in the city 
was 30.7. The lowest death-rate was 27.18 and the 
highest 35.7. As this comprises 24,813 cases, the average 
fatality of the disease can be readily seen. In the South 
Department of the Boston City Hospital, from the first of 
September, 1895, to the first of May, 1896, when every 
case was treated with antitoxine, there were 1359 cases of 
diphtheria treated, with 170 deaths, giving a percentage of 
12.50. In the year 1895 throughout the whole city there 
were 4059 cases reported to the Board of Health, with 588 
deaths and a percentage of 14.48. These cases reported 
to the Board of Health include many mild cases and there- 
fore cannot give a proper idea of the death-rate of this 
disease. Some of these cases were without doubt treated 
with antitoxine, but how many it is impossible to state. 
The cases in the South Department of the Boston City 
Hospital, on the other hand, were nearly all of them severe 
cases and in many instances the membrane covered the 
tonsils, the uvula and nearly the whole of the roof of the 
mouth, with extensive swelling of the cervical glands. As 
a rule patients are not sent to a hospital unless they are 
seriously ill, and for this reason statistics based on hospital 
cases give a much better idea of the benefit of any pre- 
scribed method of treatment than can be obtained from 
cases in private practice. It is claimed, and with truth, 
that in the first year of life diphtheria is an extremely fatal 
disease, the majority of patients succumbing to it. TREATMENT OF DIPHTHERIA. 
5 
An analysis of the cases at the hospital shows that in eight 
months there were 17 cases admitted under one year of age 
with three deaths, giving a percentage of 17.6. The number 
of patients from one to two years old admitted was 74 with 
20 deaths, giving a percentage of 27 ; from two to three 
years of age there were 136 patients admitted with 37 
deaths, giving a percentage of 27 ; from three to five 
years of age 329 patients were admitted with 55 deaths, a 
percentage of 16.7 ; from five to ten years there were 410 
patients admitted with 39 deaths, giving a percentage of 
9.5; from ten to twenty years 187 patients with 9 deaths, 
giving a percentage of 4.8 ; and from twenty years and up- 
wards 206 patients with 7 deaths, a percentage of 3.4. All 
of these cases were treated with antitoxine, and it would 
seem that these statistics should convince any one of the 
beneficial effects of this agent. If we take the hio-hest 
death-rates occurring in any of these ages, namely that from 
one to two years, and also from two to three years, chil- 
dren of these ages being particularly susceptible to the dis- 
ease, and in whom diphtheria plays the greatest havoc, we 
find that the death-rate is 27 as compared with 43 before 
antitoxine was used—a marked diminution. 
In the epochs of life from five to ten years, from ten to 
twenty years, and from twenty years upwards, there is an 
extremely low death-rate, being respectively 9.5, 4.8 and 
3.4. There would seem to be only one explanation of this low 
death-rate. In all of these cases antitoxine was administered 
within a very short time after the admission of the patients. 
Bacteriological examinations were made in every instance, 
but it was not deemed advisable to wait for the result of the 
cultures before administering the serum. In order to ob- 
tain the best results from the use of the anti-diphtheritic 
serum, it is important to administer the agent early in the 
disease. A delay of 24 hours after the appearance of the 
membrane frequently imperils the lives of the patients. In 6 
ANTITOXINE IN THE 
a case of well-marked clinical diphtheria the time necessary 
for the growth of the organism in the culture tube is lost, 
but it is very important that cultures should be made in 
each and every case of diphtheria in order that statistics 
may be based on a scientific foundation. The failure to 
obtain a positive result has occurred so seldom as not to be 
a factor of the slighest value, as this failure has been due 
to some error in technique. The importance of the early 
administration of antitoxine is shown by an examination of 
the statistics of the hospital. Of the 1,359 cases admitted 
53 died within 24 hours of admission, and of these 53 
quite a large number died within two or three hours. If 
we eliminate these 53 cases we have 1,306 cases and 117 
deaths, a percentage of 8.9. If we eliminate the 74 deaths 
that occurred within 48 hours of admission, we have a 
percentage of 7.4. 
Table of the number of cases of diphtheria, treated at 
the Boston City Hospital, with the deaths, by ages, from 
Sept. 1, 1895, to May 1, 1896:— 
Ages. 
Cases. 
Deaths. 
1 year 
17 . 
... 3 
1-2 years 
74 . 
... 20 
2-3 
. 136 . 
... 37 
3-5 “ 
. 329 . 
... 55 
5-10 “ 
. 410 . 
... 39 
10-20 “ 
. 187 . 
... 9 
20 years and 
upwards 
. 206 . 
. . . 7 
Cases in which antitoxine was used :— 
1359 with 170 deaths, percent. 12.50. 
Cases from February, 1891, to February, 1894, in which 
antitoxine was not used :— 
1062 with 493 deaths, per cent. 46. TREATMENT OF DIPHTHERIA. 
7 
Chart of the Percentage of Deaths from Diphtheria, isy ages, at the South Department of the 
Boston City Hospital, from Sept. 1, 1895, to May 1, 1896. 8 
ANTITOXINE IN THE 
It is manifestly evident that moribund cases should not 
be used as an argument against the administration of anti- 
toxine, and therefore in studying the use of this remedy 
these cases should be omitted. If a death-rate of 8.9 in 
hospital cases when antitoxine was employed is compared 
with a death-rate of 27.06, the lowest death-rate in the city at 
large, from 1878 to 1894, a period of 17 years, it would 
seem that there could be no other explanation than that this 
result was due to antitoxine. The effect of antitoxine, not only 
in the operative cases but in those in which an operation was 
impending, is very marked. Many cases have been observed 
at the hospital in which an operation before the days of anti- 
toxine would have been necessary, but after 18 to 24 hours 
the laryngeal stenosis was relieved, and large pieces of 
membrane were coughed up. In the operative cases the 
relief in many instances has been very marked. In the 
Boston City Hospital for the year ending January 31st, 
1895, there were 89 intubations and 74 deaths, giving a 
percentage of 83. In the South department of the Boston 
City Hospital for eight months there were 136 intubations 
and 63 deaths, giving a percentage of 46, a diminution of 
37, nearly one half. It seems reasonable to suppose that 
this diminution is due to the use of antitoxine. 
The antitoxine that has been used is that prepared by 
Prof. H. C. Ernst. From 5 to 10 c.c., varying according 
to the strength of the preparation and the age of the 
patient, have been administered. If at the end of twenty- 
four hours there was not a marked improvement in the 
general condition of the patient and in the appearance of 
the membrane, a second dose was administered. If there 
was no amelioration of the symptoms 24 to 32 hours 
after the second dose was administered, a third dose was 
given, and in certain instances a fourth dose. The 
appearance of the membrane in favorable cases caused by 
the action of the antitoxine is very characteristic. The TREATMENT OF DIPHTHERIA. 
9 
membrane commences to be detached at the edges, is 
undermined and begins to roll up. This appearance is so 
characteristic that when it has occurred a second dose has 
not been given. In no instance has the membrane ever 
re-formed to any considerable extent. In septic cases the 
septic odor in the majority of instances has been less ap- 
parent after the administration of antitoxine. The stronger 
the antitoxine is, the better ; because it is necessary to inject 
a less quantity, as can be readily understood. An injec- 
tion of 20 c.c. into the cellular tissue causes quite a per- 
ceptible tumor, and is a source of annoyance to the patient, 
therefore a preparation in which the requisite dose is from 
5 to 10 c.c. is better than one in which the dose is 20 c.c. 
The method of estimating the dose of antitoxine by normal 
units is perhaps the better one. An antitoxine unit is an 
amount of serum required to protect a guinea pig weighing 
500 grammes from the minimum fatal dose of the toxine 
of diphtheria. The number of immunity units per c.c. 
would give the strength of the serum; for example, one 
one-hundredth of a c.c. would protect a guinea pig weigh- 
ing 500 grammes, and for a person weighing 120 pounds, or 
about 50,000 grammes, 1 c.c. would be required for pro- 
curing immunity. For the cure of the disease, however, 
fifteen or twenty times as large a dose is required, namely, 
1,500 to 2,000 units. 
In no instance has any serious effect followed the use of 
antitoxine at the hospital. In a few instances abscesses 
have appeared at the point of injection. Cultures made 
from the contents of these abscesses showed a pure growth 
of streptococci, and as abscesses are not infrequently con- 
comitants of diphtheria, it is reasonable to suppose that the 
injection of antitoxine was only an exciting cause of a pre- 
disposing condition of the system. As illustrating this 
point, two sisters with severe attacks of diphtheria were in- 
jected at the same time with the same specimen of anti- 10 
ANTITOXIXE IX THE 
toxine. One had a large cervical abscess from which a 
pure culture of streptococci was taken, the other had a small 
abscess at the point of inoculation which also gave a pure 
growth of streptococci. The injection of antitoxine had 
certainly nothing to do with the cervical abscess and it is at 
least doubtful if the injection was the direct and immediate 
cause of the second abscess. It is a significant fact that 
pure cultures of streptococci have been obtained from all 
the cervical abscesses at the hospital occurring in the 
course of diphtheria. 
Severe joint pains have been noticed in five instances. 
These attacks have generally lasted from twenty-four to 
forty-eight hours, and have been a source of annoyance to 
the patients, but in no instance have they been an element 
of danger. 
Urticaria has occurred in quite a number of cases, and 
although this has been a cause of discomfort to the patient, 
it has never been a grave symptom. Dermatitis resem- 
bling the eruption of a severe attack of scarlet fever in which 
the diagnosis for the first twenty-four hours was impossible, 
has been noticed in a few instances. The moderate rise in 
the temperature, the absence of vomiting and the subse- 
quent history of the case confirmed the diagnosis of anti- 
toxine rash. An eruption resembling measles has been 
noticed a few times. From the appearance of this eruption 
it would be impossible to make a differential diagnosis, but 
the absence of constitutional symptoms has been an aid in 
deciding upon the nature of the eruption. 
In the mixed cases of scarlet fever and diphtheria, anti- 
toxine has had a beneficial effect upon the diphtheritic mem- 
brane, but of course has had no effect on the attack of scar- 
let fever. In addition to the use of antitoxine, alcoholic 
stimulation has been very freely used; digitalis, strychnia 
and atropia have been used in suitable cases. Milk has 
been the principal article of diet, and has been given in as TREATMENT OF DIPHTHERIA. 
11 
large quantities as the patient could be induced to take. 
In certain cases where the patients absolutely refused to 
take food and stimulants, nasal feeding has been tried, and 
in some instances this seemed to be the turning point, and 
the patient’s life was apparently saved by this procedure. It 
is not sufficient to simply give antitoxine and do nothing 
else for the relief of the patient. In no disease are food 
and stimulants more imperatively demanded than in diph- 
theria, and an attempt has been made to give food and 
stimulants in any way in which they could be absorbed. A 
word may be said regarding nasal feeding. It is less an- 
noyance to the patient, it causes less strain on the nervous 
system in some instances to give food by the nasal tube 
than by the mouth. The constant endeavor to make a 
patient take food by the mouth is a much greater injury to 
him than the passage of a small rubber catheter through 
the nose into the stomach. The beneficial effects of this 
method of feeding have been illustrated in so many instances 
at the hospital, that I may be pardoned for alluding to it in 
somewhat strong terms. The less you annoy a patient ill 
with diphtheria the better for him. There is no doubt in 
my mind that many a diphtheria patient has been harried 
to death by over zealous attempts to induce him to take 
nourishment. 
Irrigation with a hot saline solution, and in some cases a 
solution of corrosive sublimate one part to ten thousand, 
has been the application that has been used for the nose 
and throat, and the relief experienced by patients from this 
has been very marked. The less one interferes with the 
membrane the better for the patient. The irrigation re- 
moves all particles of membrane that are easily detached, 
and does not leave an abraded surface to serve as a focus 
for the extension of the membrane. The forcible detach- 
ment of the membrane by forceps cannot be too strongly 
deprecated. The use of caustics is of no advantage. 12 
ANTITOXINE IN THE 
The experiments of Roux and Yersin show conclusively 
that diphtheritic membrane is less likely to extend on intact 
mucous membrane than on abraded surfaces, and therefore 
when the mucous membrane is in anyway injured an oppor- 
tunity is given for the extension of the disease. 
Albuminuria has not been increased to any considerable 
extent by the use of antitoxine. An analysis of eighty- 
three cases at the hospital, in which the urine was examined 
before and after antitoxine was administered, showed that 
in thirty-eight cases albumen was absent; that in thirty 
cases there was the same amount of albumen before and 
after antitoxine was given ; that in eleven cases albumen 
was diminished after the injection, and that in four cases 
albumen was increased. Of these four cases, in two the 
amount of the increase was from nothing to the slightest 
possible trace, and in two the amount was increased from a 
trace to a large trace. In no instance have renal compli- 
cations given rise to serious symptoms. Albuminuria is 
such a frequent complication in diphtheria that any statistics, 
to be of value regarding the action of antitoxine on this 
condition, must embrace a great number of cases, and the 
examination of the urine must be made before and after the 
administration of the agent. Observers who have claimed 
that antitoxine causes albuminuria in diphtheria have in 
many instances failed to test the urine before antitoxine 
was used, and many of these observers lose sight of the 
fact that albuminuria is one of the most constant symptoms 
in severe cases of diphtheria. 
No cases of anuria have been observed at the hospital. 
Paralyses have been observed in a comparatively small 
number of cases, the percentage being somewhat less than 
was noted before the days of antitoxine. When the cases 
have been received early in the history of the attack, before 
the growth of the organism was sufficient to generate a 
great amount of toxine, paralysis has not as a rule occurred. 13 
TREATMENT OF DIPHTHERIA. 
If, on the other hand, the case was received late in the 
course of the disease and the membrane was extensive, par- 
alysis more or less marked has occurred in the majority of 
cases. Cases of sudden death so common in the convales- 
cence of diphtheria have not occurred, but there have 
been a few cases in which after apparent convalescence 
there would be an attack of vomiting and the patient 
rapidly lose strength and gradually sink and die in from 
24 to 72 hours from the commencement of the attack. 
Broncho-pneumonia has been one of the most frequent 
causes of death, and no one claims that antitoxine has any 
remedial power in this condition. If all the cases of death 
from broncho-pneumonia were eliminated, the death-rate 
from diphtheria pure and simple, when antitoxine is used, 
would be much lower than that that has been previously 
given. 
In the laryngeal cases intubation has been the operation 
generally selected, as this operation has in every instance 
relieved the stenosis. The advantages of intubation are 
first, a minimum amount of shock, and second, there are no 
cut surfaces to afford soil for the growth of not only the 
diphtheria baccilli but of other bacteria, for no matter how 
carefully you may carry out aseptic precautions it is impos- 
sible to keep a tracheotomy wound aseptic as can be done 
in other surgical operations. There can be no doubt that 
the fatal issue in cases of tracheotomy is due in most in- 
stances to an infection either through the wound or through 
the orifice of the tube itself. In the few cases of trache- 
otomy at the hospital, death was caused by this very in- 
fection. Another advantage of the intubation tube is the 
fact that the air that enters the lungs passes through the 
natural channels and therefore is less likely to irritate these 
organs. One argument that has been used against intuba- 
tion is that the patient is unable to take the requisite 
amount of food; but this is obviated by the use of nasal 14 
ANTITOXINE IN THE 
feeding, which lias been a very important factor in reducing 
the death-rate. That antitoxine has also been a very im- 
portant factor no one can reasonably doubt who has ob- 
served intubation cases before antitoxine was used and since 
its adoption. 
The site of the injection has been in some instances the 
outer aspect of the middle third of the thigh, the lumbar 
region and the upper third of the thorax near the posterior 
axillary line. After a careful consideration of these various 
positions, it seems to me that the last situation is the best, 
for the reason that any irritation and swelling in this local- 
ity causes less annoyance to the patient than in either of 
the other localities. One very important advantage is also 
that in this place the nervous distribution is comparatively 
limited, and therefore the amount of pain is diminished to 
a minimum. The technique of the operation is as follows : 
First, the parts are rendered aseptic by washing with corro- 
sive sublimate ; second, the syringe and needle are carefully 
sterilized by boiling. The antitoxine is strained into the 
barrel of the syringe through sterile gauze. A fold of the 
skin is taken up by the thumb and fore finger, and the 
needle plunged deeply into the cellular tissue. The injec- 
tion is then made slowly and carefully with only a limited 
amount of force. After the needle is removed the opening 
in the skin is sealed with gauze and collodion. If the in- 
jection is properly given there should be no tumor and 
therefore no necessity of rubbing the parts in order to cause 
the disappearance of the tumor as is recommended by cer- 
tain observers. Williams’s syringe, which consists of a 
glass barrel and a glass piston with asbestos packing, is 
the instrument that has been used. Koch’s syringe, which 
consists of a glass barrel with a detachable rubber bulb, is a 
very good instrument for this purpose. Liier manufactures 
a very good syringe. One advantage of Llier’s syringe is, 
that there is no packing to become worn, as the piston is TREATMENT OF DIPHTHERIA. 
15 
carefully ground to fit the barrel. The only objection to 
this syringe is its high cost. As a matter of fact it makes 
very little difference what kind of a syringe is used so long 
as each and every part can be thoroughly and absolutely 
sterilized by heat without injury. A small needle should 
always be used, for with a minute puncture the danger of 
infection is diminished. 
The preparation of antitoxine, and its use in the treat- 
ment of diphtheria, are the results of careful and laborious 
work of bacteriologists, and whatever advantage has been 
gained in the treatment of diphtheria is due to the science 
of bacteriology. It has been claimed that the use of anti- 
toxine is unscientific, but any one who has carefully read 
the reports of Roux, Yersin, Aronson and many others 
cannot fail to be struck with the eminently scientific nature 
of their work. As the preparation of antitoxine requires 
great scientific knowledge and an unlimited amount of time 
and patience, it is evident that in order to be a success, from 
a commercial point of view, the price must be so high as to 
place it out of the reach of the poorer classes, and therefore 
it is incumbent on State and City Boards of Health to make 
arrangements whereby the serum can be distributed gratui- 
tously or sold at a nominal price. As has been before 
stated, all the antitoxine used at the hospital has been pre- 
pared by Dr. Ernst, and there can be no doubt that the 
satisfactory results obtained have been due to the excellence 
of this preparation and the careful manner in which it has 
been prepared. 
In this paper a short and imperfect account of the work in 
the diphtheria wards of the hospital has been outlined, and 
certainly a diminution of the death-rate from 46 per cent, 
when antitoxine was not used, to one of 12.50 when it 
was used, can only be explained by the remedial power of 
this agent. If many cases of death occurring in persons ill 
of diphtheria, but in whom the cause of death was other 16 
ANTITOXINE IN DIPHTHERIA. 
than diphtheria, had been eliminated, the death-rate would 
have been much lower; but as it has been the object ot 
this paper to show the true value of antitoxine, in the treat- 
ment of diphtheria, it has been deemed advisable to err 
against antitoxine rather than for it.