THE IMMUNIZING EFFECTS OF ANTITOXIN 
BY 
F. GORDON MORRILL, M. D. 
Visiting Physician to the Chi£K^n*s Hospital, Boston 
Reprinted from the Boston Medical and Surgical Journal of 
fune 2"], 1895 
BOSTON 
DAMRELL & UPHAM, Pubijshers 
283 Washington Street 
1895 3. J. PARKHILL & CO., PRINTERS 
BOSTON THE IMMUNIZING EFFECT# OF ANTITOXIN.1 
BY F. GORDON MORRILL, M.D., 
Visiting Physician to the ChitriTFn's Hospital, Boston. 
Before describing the results obtained from 438 
immunizing injections of antitoxin at the Children's 
Hospital, I will briefly explain the reasons which have 
rendered such an extensive use of the serum neces- 
sary. 
The policy of the institution has always been to 
decline to admit cases of such diseases as are gener- 
ally regarded as infectious ; and the building originally 
included but two small rooms for the isolation of such 
cases as might appear among the patients in the 
house. After a time (as might be naturally expected 
in any large congregation of children), endemics oc- 
curred, and larger, but (in the light of recently 
acquired experience) insufficient quarters were pro- 
vided. 
During the year 1894, cases of diphtheria occurred 
so frequently as to necessitate the closing of the hos- 
pital. and disinfection of the wards, on three separate 
occasions; to the great Inconvenience of all concerned, 
and with serious detriment to the usefulness of the 
institution. 
It was thought at first, that the infection was intro- 
duced by the parents or friends of the patients; and 
blouses and disinfectant washes for the faces and 
hands of all visitors were prescribed. But in spite of 
these precautions, fresh outbreaks occurred, and we 
were reluctantly forced to the conclusion that the 
Klebs-Lbfiler bacillus had installed itself as a perma- 
1 Read before the American Pediatric Society, Hot Springs of Vir- 
ginia, May 27, 1895. 2 
nent and most unwelcome guest within our walls, and 
stood in no need of an introduction. 
Furthermore we convinced ourselves that the chief 
source of trouble was confined to one ward, where 
grave defects of ventilation were discovered. Some 
time elapsed before this last conclusion was reached ; 
for while cases of diphtheria were more frequent in 
this ward than elsewhere, the fact that the majority of 
the children were in the habit of meeting in the play- 
room, had led to such a distribution of the infection as 
to give rise to cases in all parts of the hospital. The 
type which the disease assumed was seldom frank ; 
children with coryza or slight tonsillitis and scarcely 
any constitutional symptoms, would perhaps fatally 
infect others, and in many instances repeated bacterio- 
logical examinations of the secretions alone showed 
when the trouble began and ended - no membrane or 
other clinical evidence of diphtheria being present at 
any time. 
January 13, 1895, there were nine cases in the in- 
fectious wards, four or five of which had been trans- 
ferred from the house within forty-eight hours. 
The question of closing the hospital for the fourth 
time was discussed, and it was decided to first try 
immunization with antitoxin, in the hope that this 
course might enable us to maintain open doors and 
go on with our work. The staff was so kind as to 
give me carte blanche, so far as the diphtheria was 
concerned, and within thirty-six hours, thirty-nine 
patients who remained in the house, and three nurses 
who were on duty in the contagious wards, received 
each an injection of five cubic centimetres of the serum 
prepared at the Pasteur Institute of New York, ac- 
cording to the formula of Roux. 
The apparent result of this first attempt was to in- 
stantly arrest any further spread of the disease. Pa- 3 
tients in the contagious wards were disinfected and 
returned to the house as soon as negative reports of the 
cultures of two specimens taken forty-eight hours 
apart, were received from the bacteriological labora- 
tory of the Harvard Medical School. No patients 
were admitted with any suspicious symptoms in their 
noses or throats; and all new-comers received an in- 
jection of five cubic centimetres on entrance. Speci- 
mens were obtained frequently from all patients, and 
reports of the cultures were all negative until January 
29th, when a boy who had reacted perfectly well to 
an immunizing dose, was found guilty of harboring 
the Klebs-Lbffler bacillus, and was at once transferred 
to the contagious wards. The specimen from which 
this positive culture was obtained, was taken sixteen 
days after immunization; and while there was no cer- 
tainty that the bacillus had not been present for an 
indefinite time in this particular case (through an 
oversight, no previous culture having been made) it 
was thought best to inject antitoxin again in all cases 
which had not been immunized within ten days. Cult- 
ures were now made at the bacteriological labora- 
tory of the Harvard Medical School, of specimens 
from every nose and throat in the house, and negative 
reports obtained in every case but one - that of a boy 
who had been returned to the house from the infec- 
tious wards after two favorable bacteriological examin- 
ations. 
A rule was now made that all new patients should 
be injected in the bath-room before being allowed to 
enter the wards for the first time, and the dose of anti- 
toxin was increased to ten cubic centimetres for chil- 
dren ten years of age or over. I do not believe that 
the injections have been omitted or deferred a dozen 
times on account of the condition of any child's health, 
and I have seen but one instance in which danger was 4 
suggested by the use of the serum - a case which I 
shall refer to later on. The mere inspection of noses 
and throats was soon found to be a very slight safe- 
guard against the introduction of the bacillus, for 
children with apparently normal mucous membranes 
were frequently discovered to have bacteriological 
diphtheria a day or two after entering the hospital, 
and emergency cases were often found to be in the 
same plight. One of the latter developed diphthe- 
ritic membrane; and while all this went to prove the 
reliability of antitoxin as an immunizing agent, bitter 
experience had rendered us timid, and the rules for 
admission were amended so far as to exclude all ap- 
plicants until they had been reported as free from the 
bacillus, excepting cases of the greatest urgency. 
Meanwhile, all patients found guilty of secreting (and 
perhaps excreting) the Klebs-Loffler were transferred 
to the infectious wards, there to remain until negative 
reports of their cultures should set them free. 
No signs of the enemy were present again in any 
patient whose mucous membranes were free at the 
start, until February 15th, when a boy who had been 
twice immunized - the second time on January 29th 
- and whose cultures had always given negative re- 
sults, was found to be infected. Injections were at 
once given in all cases which had not been immunized 
within two weeks, and the rule established, to repeat 
them every fortnight. 
March 12th, a patient who through an oversight had 
been given no antitoxin since February 16th, was 
found to have the bacillus; but we had now become 
quite accustomed to its presence, and so long as it had 
not been detected in any child who had begun with a 
clean record, in a shorter space of time than seventeen 
days after immunization, we felt pretty safe so long as 
the injections were regularly given every two weeks. 5 
The next day, however, a positive culture was obtained 
in the case of a patient who had been injected Febru- 
ary 28th. This eclipsed any previous records, and 
showed that fourteen days could not be surely counted 
on, so the period allowed to intervene between the im- 
munizations was shortened to thirteen days. Mean- 
while an estimate of the applicants for admission 
whose cultures were positive, showed that over 20 per 
cent, had the bacillus in their throats or noses. 
Emergency cases came thick and fast (emergency is 
an elastic term from a surgical standpoint) and when 
the observation rooms in which such cases were kept 
(pending reports from the bacteriological laboratory) 
happened to be full, they went into the common wards. 
Some of these proved to have bacteriological diphthe- 
ria, and one developed clinical evidence of the disease. 
There is not the slightest doubt that many patients in 
the house were thoroughly exposed, aside from the 
infection present in the building itself. Our conta- 
gious wards were now full, and the question of continu- 
ing to admit patients, and allowing such patients as 
might present bacteriological but no clinical evidence 
of the disease to remain in the open wards (or even to 
be transfered to them from the contagious quarters) 
was discussed. I thought at the time, and I still 
think that this could have been done with safety so 
long as immunization was regularly kept up. There 
had been but few days during the past month when 
the wards had been free from the bacillus either alone, 
or as a companion to membrane. A large majority of 
the staff agreed with me; but we refrained from pur- 
suing a course which might injure the hospital by giv- 
ing rise to distorted rumors. 
So a vote was passed to the effect that every patient 
with the bacillus present, whose culture had not been 
tested by injecting a guinea-pig, should remain in the 6 
infectious wards, and admissions to the hospital sus- 
pended ; for if measles or scarlet fever broke out 
among the children we should find ourselves badly 
crippled. Everything considered, I am sure that the 
staff is entitled to the credit of showing a considerable 
degree of deference to the somewhat freely expressed 
opinion of outsiders, who know but little about the 
actual situation. Fortunately the bacilliary tide began 
to ebb at this time, and we were spared the guinea- 
pig test, which often consumes a fortnight's time, and 
may lead to no really definite conclusion in the end. 
Things now went along smoothly until March 25th, 
when an unmistakable break-down occurred in a child 
who had been antitoxined on the 10th, and again (by 
mistake) on the 16th. Negative cultures had been 
obtained on the 4th and 19th, but the girl had per- 
fectly well-marked clinical diphtheria, and the diag- 
nosis was confirmed by bacteriological examination. 
Within twenty-four hours bacilli, but no membrane, 
were found in two other cases which had been immu- 
nized on the 1 6th. But in spite of these exceptional 
cases (occurring as they did nine and ten days respec- 
tively after-being injected) it was not thought best to 
shorten the interval between the immunizations, as I 
had good reasons for doubting the reliability of the 
serum used in these instances. April 4th, but two 
patients remained in the infectious wards, and as the 
service was becoming less active we no longer made 
surgical patients wait for bacteriological examinations 
before admitting them to the house. Two or three 
proved to be infected (inasmuch as the bacillus was 
present in their throats and such cases must be re- 
garded as infectious no matter how robust their gen- 
eral health may be until their cultures have been 
proved benign by the guinea-pig test) and were 
allowed to remain in an open ward; the epidemic 7 
was on the wane, the infectious wards were quite 
empty, and we did not care to reopen them. In short, 
we did now what we might have safely done weeks 
before, and for better reasons. No bad results fol- 
lowed this course, and I am sorry it was not pursued- 
at an earlier date. Children who had the bacillus but 
no symptoms requiring special care, might far better 
have remained in the house and passed their time in 
being cured of the affections they entered the hospital 
for originally, than have gone to the infectious wards 
and increased the work of the staff and nurses. Cer- 
tainly nobody who is familiar with the conduct of 
children in hospitals - their close intimacies, the man- 
ner in which toys are used by all - can believe that 
the risk of infection would have been materially in- 
creased over what already existed if they had been 
allowed to remain. 
An analysis of all the cases, shows that of a total 
of 438 immunizing injections given between January 
13th and May 13th, 109 were of Gibier's serum; 104 
of Behring's; 74 of Aronson's; and 151 of the anti- 
toxin prepared by the Massachusetts State Board of 
Health. The largest number administered to one 
child was seven. Many of these patients were under 
treatment for acute diseases at the time of injection: 
croupous and broncho-pneumonia, grippe, tubercular 
peritonitis, empyema, typhoid, or such surgical trou- 
bles as naturally find their way to a children's hospi- 
tal. No special symptoms were noted as produced by 
the serum with regard to the existent diseases at the 
time of injection excepting in one or two suppurative 
hip cases, in which there was a temporary improve- 
ment in the appetite and general condition. In a few 
cases of desperate illness the antitoxin was omitted, or 
postponed until the patient's condition improved ; but as 
a rule, all fared alike. I have failed to observe any dan- 8 
gerous symptoms arise from immunization excepting 
one case-a boy, aged two, with leucocytosis and a large 
spleen, upon whom two preceding doses had produced 
no ill effect, had a temperature of 105.4° F. and con- 
siderable edema about the point of injection (given in 
the abdominal wall in this instance), and certainly ap- 
peared very sick. Cold baths and brandy soon made 
him better, however, much to my relief. Of course, 
the results of an analysis of our cases are by no means 
claimed to be conclusive. They are, however, suffi- 
ciently well based to permit their being regarded as 
suggestive. As a rule, the temperature goes up less 
than a degree a few hours after immunization, and in 
75 per cent, of all cases this is all there is to be seen. 
Erythema around the point of injection occurred in 
23 cases. In four it was very extensive, and closely 
resembled erysipelas - in one instance the child was 
isolated. The average duration of this symptom is 
three days; in some cases it lasts only a few hours. 
It usually appears on the first day after antitoxin, and 
never later than the eighth. Urticaria occurred 28 
times. The frequency, severity, time of appearance, 
and duration &f this symptom varies greatly with the 
brand of serum employed. That of Gibier (Pasteur 
Institute of New York), produced it in 22 per cent, 
on the (average) seventh day, and lasting (an average 
of) two and a half days. Behring's caused it in but 
one case, appearing on the eighth day and lasting 
three days. Aronson's gave rise to no urticaria. The 
serum of the Massachusetts State Board of Health 
produced in about four and a half per cent, an erup- 
tion, appearing on the (average) second day, and dis- 
appearing in a day and a half. This serum at present 
very rarely gives rise to anything cutaneous, although 
at first urticaria was of pretty common occurrence. 
In three instances the erythema was papular, and very 9 
closely resembled measles. In two instances an erup- 
tion like scarlet fever was present. Occasionally a child 
whose skin remained clear after the first or second or 
third immunization, broke out with an erythema, or 
an urticaria after a subsequent injection. The same 
brand of serum may produce an urticaria, an erythema, 
or no skin eruption whatever in the same subject, as 
proved in more than one instance where repeated in- 
jections were given. Pain (at times intense) was no- 
ticed about the point of injection in sixteen ; edema 
in seven; axillary or inguinal glands enlarged in 
three; general malaise (in one instance a mild deli- 
rium) in three. Pain in the articulations in less than 
one per cent. Nausea, with or without vomiting, in 
two per cent. Diarrhea (ephemeral) in less than 
three per cent. Increased frequency of micturition 
was noted in rare instances. The urine of 82 chil- 
dren was very carefully examined with reference to 
the effects of antitoxin on the kidneys, and the result 
of 540 examinations may be briefly stated as follows : 
In 20 per cent, no change whatever was detected. Of 
the remaining 80 per cent., those which had been free 
from albumin previous to immunization, showed a 
slight trace-in most instances the slightest possible 
amount, which could be detected only when placed in 
front of a dark back-ground. This within twenty- 
four or forty-eight hours after injection. In cases 
where albumin had been present before the use of anti- 
toxin, there was a very slight increase of the amount. 
In no case was there any diminution in the amount 
passed, or any evidence of failure to eliminate prop- 
erly. Repeated microscopic examinations revealed 
nothing more than an insignificant amount of renal 
irritation in any case; and when the albuminuria was 
produced by antitoxin, it disappeared in a period 
varying from two or three days to a fortnight. 10 
With regard to the protection afforded by antitoxin, 
our experience has tended to show that the serum, 
when fresh, can be relied upon to immunize against 
anything resembling clinical diphtheria thirteen days, 
and very probably for a longer space of time. More- 
over, in no instance was the bacillus detected in the 
nose or throat of any child who started with a clear 
record in a shorter space of time than that just men- 
tioned. This last point (if eventually established) is 
of practical importance as showing that an immunized 
child is not only safe from diphtheria, but is also safe 
as concerns others for a definite length of time. I 
am by no means sure that daily examinations of cult- 
ures from every case might not have shown the fal- 
lacy of the theory ; but the fact that quite numerous 
examinations were made, with the results described, 
certainly deserves mention. In the cases which broke 
down in eight and ten days after being immunized, 
the serum used had become decomposed. The color 
differed from ^hat usually presented, but so slightly at 
the time of injection that it was used without hesita- 
tion. Forty-eight hours later it was of the color of 
milk. 
Regarding the use of antitoxin for curative pur- 
poses, our experience, while decidedly favorable, has 
been too slight to warrant the expression of an opin- 
ion. Statistics at the Children's Hospital, if made up 
from the standpoint that the mere presence of the 
bacillus in the nose or throat constitutes diphtheria, 
would justify the extremely favorable and entirely 
fallacious statement, that our mortality has been less 
than three per cent. For of 34 patients who have 
been inmates of the infectious wards, only one died ; 
and all of them received antitoxin -the great major- 
ity, however, never more than one small injection, for 
the purpose of immunization upon entrance, before 11 
the reports of their cultures had been obtained. As- 
suredly one might as well claim, that the existence of 
the pneumococcus in the saliva implies the presence 
of pneumonia, as to call all cases which have the 
Klebs-Lbffler bacillus, diphtheria. Equally absurd is 
it to treat such cases with antitoxin, unless some clini- 
cal evidence of the disease is present. I have con- 
vinced myself that full doses of the serum has no in- 
fluence on the mere presence of the bacillus after it 
has once obtained a foothold. The more ardent sup- 
porters of the treatment, will greatly endanger its 
reputation if they present claims based on statistics 
such as I have described. On the other hand, I do 
not doubt that equally enthusiastic opponents of anti- 
toxin will bring forward abundant proof that it does 
no good whatever. I can well remember something 
of the kind being done in the case of salicylic acid, 
and kindred preparations, by conscientious men, who 
showed by apparently flawless statistics, that cases of 
acute rheumatism did better under the old treatment 
by alkalies; but the remedies whose merits they de- 
nied. have stood the test of time wonderfully well, and 
if taken away from us to-day would be badly missed. 
Results of the serum treatment, if they are to in- 
spire confidence, must be based upon such cases as are 
clinically diphtheria, and the diagnosis of which is con- 
firmed by bacteriological examination. Care must be 
taken to exclude all cases in which a membrane, 
which to all appearances is identical with that of diph- 
theria is present, but which is due to the work of 
other germs. Instances of this sort are far commoner 
than was formerly suspected - I have observed four 
(two at the hospital and two in private practice) dur- 
ing the past six months. 
In the present state of our knowledge, the Klebs- 
Lbffler bacillus may be said to resemble an idle but 12 
extremely competent workman, who under certain 
unknown conditions may suddenly accomplish a won- 
derful task. He gives no warning of his intentions, 
and does not trouble himself to put on working clothes 
- at least none of a sort which can be recognized 
under the microscope. 
Even such cultures as have every appearance of 
virulence may prove to be benign when tested, and 
when they look doubtful may promptly kill the in- 
jected guinea-pig. Every active diphtheritic germ is 
undoubtedly a Klebs-Loftier, but every Klebs Loftier 
is by no means an active diphtheritic germ. On the 
contrary, it does not, as a rule, harm those who afford 
it shelter. Of 34 patients who have passed through 
our infectious wards at the Children's Hospital during 
the past six months, but seven have had anything 
resembling what used to be called diphtheria before 
the birth of the bacillus was announced in the journals, 
and two of these cases were caused by other germs. 
But I cannot do^ibt that the bacteriologists who have 
given us so much of inestimable value during the past 
few years, will before long extricate us from the di- 
lemma caused by our uncertainty of the sanitary status 
of a person who has only bacteriological diphtheria. 
Until this knowledge is vouchsafed us, we must con- 
tinue to regard such a one as a dangerously indefinite 
quantity; and in an institution like the Children's 
Hospital, this implies the absolute rejection of a large 
number of cases, and the disaffection of many others, 
who cannot he admitted until reports of their cultures 
have been obtained; for after such alterations shall 
have been effected during the coming summer as will 
render the building safe, and immunization is no 
longer a routine, no case can be permitted to enter 
which is open to suspicion of harboring the bacillus. 
Another thing: Are we justified in admitting a 13 
child on the strength of a single negative report ? As 
to the reliability of these reports, there are defects in 
the present method of obtaining specimens for bacteri- 
ological examination (and very probably in any possi- 
ble method) which render occasional errors unavoid- 
able. 1 do not wish to be understood as questioning 
the skill and accuracy of the gentleman at the bacteri- 
ological laboratory who make the cultures. If there 
are no bacilli in the specimens handed in to them, we 
cannot reasonably expect positive reports; and I 
merely state an obvious fact when I say, that the 
wires used for obtaining specimens, may be justly 
compared with a hook which is lowered into a dark 
pool in the hope of jigging fish. If the fish are plenty, 
there is a strong probability of success - if scarce, the 
chances are fewer. And whether they are plenty or 
scarce, the element of luck must be taken into account. 
Of course, if membrane is present and the wire pushed 
under the outer edge, there is but little probability of 
failure. 
To arrive at an estimate of the frequency of errors 
due to the uncertainty of bringing away bacilli on the 
wire when they are present, I have taken the bacteri- 
ological reports concerning patients in the infectious 
wards, from whom specimens were examined at short 
intervals, and called such negative reports erroneous as 
are immediately preceded and followed by positive cult- 
ures. Of 253 reports 26 were incorrect - a little more 
than 10 per cent. Under these circumstances I think 
two negative reports of specimens taken twenty-four 
hours apart should be obtained - nor can we then feel 
absolutely safe. 
Some of the patients in the infectious wards were 
very slow in getting rid of their bacilli. One case was 
lodged and fed at the expense of the hospital for two 
mouths, for the sole reason that we failed to obtain 14 
two negative reports in succession. He was in robust 
health, and a particularly noisy and troublesome boy. 
Finally he was discharged, much to the relief of all 
concerned. 
Various means were tried in cases of that kind to 
hasten the departure of the bacillus. Good results 
were finally obtained by atomizing strained lemon 
juice into the noses and throats six times per diem. 
Cases which had resisted equally frequent applications 
of peroxide of hydrogen yielded promptly to this treat- 
ment. It is not a pleasant procedure. Children do 
not like it - but neither does the bacillus. At first it 
occasions considerable irritation about the nostrils and 
upper lip; but tolerance is soon established, and the 
end justifies the means. Since finishing this paper 
(May 13th) a sufficient number of injections of anti- 
toxin have been given at the Children's Hospital to 
bring the total close to five hundred, and with no 
fresh evidence to alter the views which I have ex- 
pressed. I think ^hat the fact that we have not had a 
single abscess resulting from so many injections, 
speaks well for the careful attention to cleanliness on 
the part of the internes of the hospital, Messrs. Hall, 
Wylie and Washburn, whose good and painstaking 
work deserves mention. 
In conclusion, I wish to express my thanks to Drs. 
Ernst and McCollom for the unvarying courtesy with 
which they have borne the severe strain upon their 
patience which the many hundred cultures made at my 
request must have caused them.  THE BOSTON 
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