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REPOAL
Cr ake |
LIRECVOR Gr vKe BOSPI TAL
fC Thk CORPURALION CP THE ,
i
ROCKHFELLER INSTITU$E FOR MEDICAL 2eSkaRCH |
OCTOUER, t018,
; oi ie ig 4 ° eh

 
ANNUAL REPORT OF THE DIRECTOR OF THE HOSPITAL

OF T oc INSTITUTE FOR MEDICAL RESEAR

October 1918.

To the Members of the Corporation of
The Rockefeller Institute for Medical Research; ‘
Gentlemen:

In my report of one year ago I stated that a large
number of the members of the hospital staff had joined the medical corps of
the army and many of them had been ordered elsewhere. This exodus has con-
tinued, and more of the staff members have gone into the service, until now,
Dr. Van Slyke and the Director are the only members not in uniform. The
hospital has also received a quasi-military character through its designation
as an auxiliary hoapital, and it has now seemed wiss for the Director, as
Well as for Dr. ‘Yan Slyke, to apply for commissions, .. This has been done, <<
and within a very short time the entire ataff will consist of army officers. -:..
the Director hopes: that, tor the present at least, he will be permitted by
aa Surgeon. General to reaiin at the hospital and: to continue ite direction.

In January Dr. Cohn ¢ entered the service and in March -

wae ordered to France whore he has been acting as a consultant in cardio-
wo

MR
vascular diseases. In May Dr. Chickering, the Resident Physician, was
ordered to Camp Jackson to carry on instruction of medical officers in the
diagnosis and treatment of pneumonia. Groups of officers have been ordered
thers from time to time, and Dr. Chickering's work, which ie still in progress,
has been of much value, His departure left us without any resident physician
who had had any considerable experience in the work of our hospital, and to
moet the emergency Dr. Stadie, who entered the hospital in January to assiat
in the studies on syphilis, was made acting resident physician. In spite of
the extreme depletion of the staff, it has been possible to continue our actiy~
ities and care for a considerable number of patients. This has been rendered
possible by the army sending to us a small number of officers to be trained
in the diagnosis and treatment of pnewsonia and detailing to the hospital sev-
oral men to assist in the investigation being made of the new drug for the
treatment of syphilis.

In May a Board for the Investigation of Respiratory
Diseases in the Army was appointed by the Secretary of War, and Dr. Cole was
made a member of this Board. This has necessitated considerable absence froa
the hospital due to frequent trips to Washington, and to an extended trip to
camps in the west.in May and June, and lately a trip to southern camps, which
occupied about three weeks... ‘This, with the trip to Texas lasting two months,

of which mention will.be made below, has made it impossible for the Director

 

to give the same continuous personal attention to the hospital as has been the
case in preceding years... BB ek ee bas tege thet ovens
Instruction for Army Officers in the Institute and Hospital, =

| | During the entire year courses in bacteriology for -
army medical officers have been given in the Institute. The instruction regard-

ing the bacteria concerned in pneumonia has been given by members of the hospital
“BOs

stafi. During one week of each month, this teaching work has occupied a
large part of the time of Dr. Dochez and of Dr. Avery. They have also been
assisted in this work by Dr. Ernest Stillman. Before Dr. Chickering's
departure for Camp Jackuon, he hud charge of the instruction concerning the
typhoid bacillus.

On April first, a laboratory course of instruction in
medical chemistry for chemists in the Sanitary Corps was organized py [r. Van
Slyke, ans has been given in the hospital chemical laboratory. Each month
about twenty men have been ordered here and have received inetruction in the
methods of medical chemistry. Thies hus made it necessary to turn over a con-
sideractie portion of the laboratory space to this work. The work has been
under the immediate direction of Dr. Van Slyke with the aseistance of Capt.
Robinson, who wus ordered here for this purpose.

Last autuan, acting upon the authority of the Board
of Scientific Directors, the Director cf the Hospital invited the Surgeon
General of the Army to send to the hospital “a limited number of medical offi-
cere to assist in the treatmont of patients with pneumonia, in order that the
officers could become thoroughly familiar with the methods of treatment em-
ployed here", The Surgeon General has responded to this invitation by sending
officers to the hospital from time to time for, various lengths of residence.
Up to the present, 27 officers have been detailed here. Some have remained |
for only a couple of weeks, most of them for periods of from one to three, ...
months. These officers have lived in the hospital and have taken the places.
of the hospital internes who have entered the service. This arrangement has
permitted us to care for a considerable number of patients with pneumonia,
which care would otherwise have been impossible. On the other hand, it is

believed that this service has been of very great advantage to the army. It
has been a source of gratification on visiting the army hospitals to find that
the officers trained here, even though this training was only very short and
fragmentary, are being relied upon to direct and organize the care and treat-
ment of the patients suffering from pneumonia.

The problem of determining accurately the etiologic
agent concerned in cases of pneunonia in the army hospitals has proved a diffi-
cult matter in spite of the fact that large numbers of men have been trained
in this work in the bacteriological courses being given in the Institute labor-
atories. The chief reason for thie difficulty has been that the trained men
have been ehifted about from place to place, and from one kind of work to an-
cther, and very large numbers of these men have been sent overseas. The only
feasible plan to make this work satisfactory seems to be to train especially
for this work women who can be kept permanently in the camp hospital laboratories.
With the authority of the Board of Scientific Directors, we have agreed to train
women especially for this service, and arrangements have been made to send here
at once ten women for such training, For this purpose we shall use the labor-
atory previously occupied by the laboratory for the study of cardiac pathology
and physiology.

inica dies.
During the past year, the facilities of the hospital

wards have been eaployed ‘alnost entirely in the care of patients ‘suffering ‘from

 

pnounonia and of those suffering from ayphilis. . A large number of the patients |
treated have been soldiers sent in fron ‘nearby camps. Certain difficulties |
have arisen in the control of these soldiers, though these difficulties have

not appeared to be serious. “However, it has been felt by the army authorities
that these difficulties could best be overcome by giving the hospital a purely
nominal army status. This has been done by the army by designating the hospi-

tal U. S. Army Auxiliary Hospital No. 1 and by giving Capt. Edgar Stillman, a

EA
Saas”

member of our staff, the designation Commanding Officer. Capt. Stillman

then reports weekly to the Chief Surgeon of the Port of Embarkation the condi-
tion of the soldiers being treated and informs him of the number of beds
available for patients. A lieutenant to act as adjutant has also been detailed
to the hospital to look after the records of the men. This entails no added
obligations on the part of the hospital and will probably enable us to be of
etill greater service in the way of caring for sick soldiors.

Clinical Studies Concerning Ppeuponia.

In the report to the Scientific Directors for the
meeting of January 19th, I drew attention to the fact that among the cases of
pnoumonia in soldiers treated in the hospital, 4 were apparently due to haemo-
lytic streptococci, all of them were associated with empyema and two of them
died. An autopsy was obtained in one of these cases. "The lungs in this
case showed an irregularly distributed patchy pneumonis process, the areas bear-
ing some relation to the bronchi, but the entire picture, however, not being
a@ characteristio broncho-pneumonia. In certain places emall areas were seen
where the entire lung tissue failed to stain. In other words, there was begin-
ning necrosis or abecess formation."

During the autumn and early winter, pneumonia had
been very prevalent in the camps, especially pneumonia in association with
measles which was prevailing to a very great extent. On December Ath Capt.
Doches of our staff had been ordered to Camp Bowie, Fort Yorth, Texas, to useist
in investigating the pneumonia epidemic there. He was joined there by Dr. |
Jobling, and together they carried on certain studies concerning the etiology
and pathology of the cases of pnemmonia. They found a large number of cases
of lobar pneumonia associated with the presence of pneumococci, but in addition

they discovered a very large number of cases of broncho-pneumonia or atypical
BS

lobar pneumonia, many of them associated with or following measles. Autopsies
Were performed in 27 such Cases, and in 32 of them empyema was present. Bac-
teriological examination of 16 of the empyema fluida showed the presence of a
haemolytic streptococcus in 13 of them. The pathology of the pulmonary lesions
was not exhaustively studied.

These observations taken in connection with our own
indicated that the pneumonia Prevailing in the camps was not all of the typical
lobar pneumonia, but that, as I stated in my report of January 19th, "two kinds
of pneumonia existed; first, typical lobar pneumonia due to pneumococci of the
various types, and second, atypical or broncho-pneumonia due to streptococci
and possibly also to pneumococci®, In this report I outlined the problems
which demanded solution. I consequently brought the matter to the attention
of Col, Russell and Col. Longcope of the Surgeon General's Office and requested
that in order to solve these problems I be permitted to organise a group of in-
vestigutors to study the matter intensively in one camp. Permission was grant-
ed for this and Dr. MacCallus of Baltimore was persuaded to join the party,
since it soemed most important that careful pathologic studies be made on the
cases suffering from the atypical disease,

A commission was organised consisting of Dr. Cole, Dr.
Avery and Capt. Doches of thie hospital, Dr. MaoCallua and Lieut. von Glahn éf
the Johns Hopkins University, Lieut. Blake, formerly of thie hospital, (Capt.
‘Kinsella, and Lieuts. Rivers, John and Stevens. .

Tt was decided to carry on the study at the Base Hospi
tal, Fort San Houston, San Antonio, Texas. In the prosecution of this work
the Director was absent from his regular hospital duties from January the 28th
to March the 25th.

The preliminary survey of the cases in the base hospi-

tal made it evident that all the cases were not of the same variety and that
our present knowledge did not permit a ready differentiation of the cases of
the different kinds. An extensive statistical study was therefore out of the
question and therefore a very careful clinical, bacteriological and patholog-
ical study of a limited number of cases was undertaken. The following ig a
copy of the conclusions from my report to the Surgeon General.

i i a ions.

"The studies indicate that the cases of pneumonia at
the Base Hospital, Fort Sam Houston, are chiefly of two varieties: first, acute
lobar pneumonia, which does not differ essentially from that which occurs else-
where; and second, broncho-pneumonia, which in most cases, at present at least,
followa moasles.

“The pulmonary lesions in most cases of this type of
broncho-~pneumonia are characteristic and specific and have been studied and
described by Dr. MacCallum. The etiologic agent in all the cases studied by
us has been Streptosccous haemolyticus. There is no evidence presented by
this work that indicates that pneumococeus causes the lesions and symptoms
of this condition. Pneumonia following measles may te due to pneunccocel,
but the pulmonary lesion is then of the lobar variety. This complication of
measies, however, is comparatively rare. Cases may occur in which both types
of infection and both types of lesions are present. The sequence of events in
such cases is difficult to determine and is probably not always the same. —

, - "Streptococcus infections folloving lobar pneumonia
occur with considerable frequency in this hospital. Broncho-pneumonia simi-
lar to that following measles may also probably occur ag a sequel of acute
lobar pneumonia, though the evidence for this is not conclusive. Whether in
the cases of streptococcus empyema, complicating lobar pneumonia, pulmonary
lesions due to the streptococci are always present or not, has not been doter-

mined.
"The mortality in the cases of broncho-pneumonia is
pneumonia
very high; that of uncomplicated lobar is low. Practically all the fatal
cases of broncho-pneumonia are complicated by empyema. The incidence of
empyema among the uncomplicated casea of lobar pneumonia does not seem to be
extremely high.

"The number of measles cases infected with haemolytic
streptococei on admission to the hospital is not large. The majority of the
patients with measles acquire this organism during their stay in the hospital.
The chance of developing post-measles streptococcus infections is therefore
increased by residence in this hospital.

"A very large number of the patients in this hospital
suffering from asute lobar pneumonia have haemolytic streptococci in their
throats. We have no direct evidence that thay acquire these bacteria in the
hospital, but the presumptive evidence indicates that many of them do so.

"fhe work indicates that the high incidence of pneu-
monia in this hospital, and the resulting high mortality, has been due, to some
extent at least, to infection occurring within the hospital itself, The ton-
ditions are not unlike those surrounding puerperal fever and surgical wound
infections, While in measles,. raw surfaces do not exist on which infection can
occur, this disease renders the respiratory mucous membrane especially vulnera-
ble to infection with atreptococci, Possibly in-other diseases, as scarlet
fever and even lobar pneumonia, similar conditions exist. - When infection is
once started in a ward in which the patients are closely associated, the strep-
tococcd become widely distributed; they probably gain in virulence with repeated
transfer through the human eudject, and serious and widespread infection results.

. . "Probably the conditions in this hospital are not
unique. It is possible that the widespread incidence of fatal pneumonia in

the other army hospitals may have a similar explanation.*
 

 

; ORB

Our studies in Texas indicated the important part
which empyema played in the mortality from. the streptococcus pneumonia and we
etrongly urged upon the officers at the Surgeon General's office the importance
of further study of this complication, especially with a view of devising in-
proved methods of treatment.

The results of our study in Texas were rapidly con-
firmed by obasrvations in other camps. The nature of this serious malady is
now fairly well understood. There remain, however, many problems awaiting
solution Vefore satisfactory procedures for prevention and treatment can be
carried out. Many of these problems were considered in a conference of bac-
teriologists and clinicians held at the Department of Animal Pathology of The
Rockefeller Institute at Princeton on June first. The study of certain of the
questions dewanding early solution has been undertaken by Major Doches, Captain
Avery and Lieut. Stillman at this hospital, and the results so far obtained are
described below. |

Very recently a new form of pneumonia has appeared
in the army camps and to a less extent among the civilian population. Last
spring reports appeared in the newspapers of the appearance in European coun-
tries of an epidemic of acute respiratory disease resembling influensa. ‘This
disease has prevailed to a considerable extent in the armies abroad. ‘The exact. -
extent and ‘severity of the disease there cannot be determined from the reports”
so far published. In certain localities at least it ccourred as @ serious dis-
ease. There seems as yet to be no unanimity of opinion by foreign observers
as to the etiology, though certain observers have indicated their opinion that
it is due to the Influenza Bacillus of Pfeiffer, and they believe the disease to
be identical with that occurring in epidemic form in 1890-91. The disease has

now appeared with great suddenness and severity in certain of our army camps.
 

 

10

As a member of the Board for the Investigation of Respiratory Diseases in
the Army, the Director was last week called to Camp Devens, Massachusetts,
for consultation. In this camp within two weeks thera have occurred over
12,000 cases, in a considerable number of which pneumonia was present and
with a large number of deaths, reaching on some days over 80 per day. Judg~
ing from a few autopsies seen by the writer, it is evident that we now have
to deal with another distinct form of pneumonia. Pneumococci and strepto-
cecci are present in these cases, but it seems certain that they are not the
primary etiologic agents concerned in thie disease. At the time of my visit
influensa bacilli had not been isolated in any considerable number of cases,
but Capt. Avery of our staff, whom I called upon to assist me, succeeded in
demonstrating the presence of these organisms in a considerable proportion of
the cases examined.

Patients suffering from this disease are now being
admitted to the Hospital of The Rockefeller Institute, and from most of them
it has been possible to isolate the influensa bacillus. It is believed to be
important that a considerable part of the resources of thie hospital for so
long as may be necessary be devoted to a study of this disease. Dr. Avery is
already busily engaged in attempts to improve the methods for demonstration of
influensa bacilli in the sputum of such cases. It is also important that im-
munological studies be at once undertaken, and this will be done by Dr. Doches
as soon as he himself recovers from an attack of the disease from which he is

now suffering.
Clinical Studies of Pneumonia. Met BOY

During the past year, 311 cases of pneumonia have
been treated in this hospital. This is by far the largest number of pneu-
monia cases treated in this hospital in any one year since its opening. of
the patients treated 146 were soldiers and 165 were civilians. Of the cases
undoubtedly due to pneumococci, 34 per cent were Type I, 32 per cent Type II,
6 per cent Type III, and 28 per cent Type IV. Forty-four cases were dus to
Streptococcue haemolyticus. Of the 84 cases due to Type I, 8 died - a mor-~
tality of 9.5 per cent. Of the Type II cases, 9 died - a mortality of 23 per
cent; of the Type III cases, 4 died - 28 per cent; of the Type IV cases, 5
died + 7.8 per cent. As in our previous experience, the mortality due to
pneumococci of Type I was low. Tho total mortality also was low. This was
undoubtedly due in part at least to the low mortality of Type I cases, most
of which were treated with serum, as will be mentioned below, Of the 44 cases
duo to Streptococcus haemdlyticus, 30 were complicated with empyema. Fifteen
of the Streptococcus haemolyticus cases died - a mortality of 34 per cent.
Of the cases complicated by empyema, 28 were operated upon and 10 died = a mor-
tality of 35 per cent. ‘Two of the empyema cases were not operated upon and
both died.

Serum Treatment.

As stated above, the mortality in cases due to Type
I, 9.5 per cent, was very low as compared with our experience before we began
the treatment of cases with serum. Two of the fatal cases wore patients ad-
mitted very late to the hospital - too late for serum treatment. Tf we omit
these two cases in which serum treatment could not be carried out, the mortal-
ity was 7.3 per cent, which is a most satisfactory result, It soeme that
there can be little doubt that the excellent results obtained by the treatment

of this type of case has been largely due to the proper adzinistration of
untipneumococc ic serun.

The results of serum treatment in the army, as far
as reported, have been quite uniformly satisfactory. It must be stated, how-
ever, that in most camps it has been difficult or impossible to carry out the
serum treatment in the manner in which we have advised. In certain camps no
attempt nas been made to treat only the Type I cases, and all cases, due to
whatever type of organiem, have had serum administered to then. In a few
camps, however, notably at Camp Upton and Casp Jackson, very accurate deter-
minations of the type of infecting organism were made, and the serum was
properly administered. In both these campe the mortality in the cases due to
Type I infection was very low. It is hoped that during the coming winter sat-
isfactory exploysent of the serum may be made in a larger number of the camps.

Treatment of Cases with Espyema Due to Streptococcus haemolyticus,.

The results of operative treatment of these cases
Will be discussed in the repert from the War Demonstration Hospital. The
diagnosis of empyema was made early in all cases, and the surgeon was at once
called in consultation. In most of the cases operation was performed within
a short time after the discovery of the purulent exuiate, dut in seme of the
cases, repeated aspiration was performed before operation. The number of such
cases, however, is not sufficient for us to drew any conclusions as to the rel-
ative value of the two methods. The mortality in the cases of onp yous. due“ to
streptococcus was nigh, but not so high as that observed in many of the camps.
During the period when the largest number of these cases occurred, the Director

was away, and no special study directed toward demonstrating the advantage of

delay in operation was made.
Studies by Dr. Doches and Dr. Avery Concerning Streptococcus

Haemolyticus.

The problem aesigned to us was the biology of this
organism, having particularly in view the character of its immune reactions,
Much work has previously been devoted to this problem, but there are still a
nusber of questions to be answered. A most important question is whether there
exists unity or diversity among the etrains of Streptococcus haemolyticus known
to be pathogenic for human beings. An attempt to answer this question has been
made by making use of the methods previously employed in the study of the biol-
ogy of pneumococous,.

A large number of strains of S. haemolyticus were
obtained from pathological lesions in human beings, the majority of strains
being from patients suffering from broncho-pneunonia, and a lesser nuzber froa
infectious processes in other parts of the body. The organisms were studied
with regard to the following points: ‘The general biological reactions which
would justify their being classed as S. haemolyticus; their virulence for the
ordinary laboratory animals; the Production of active immunity in animals to
these organisms; the production of protective immune sera; the determination
of the identity or diveraity of different strains by the protective reaction
in animals; the relationahip of the agglutination reaction to the protective
reaction. a - |

I, Cultura and termentative reactions.

The cultural and fermentative reactions of all the
strains studied were such as to justify their being included within the group
S. haemolyticus or s, Pyogenes, whichever nomenclature is preferred, All the
organigms were round, gram positive chain cocci with the characteristic cultur=

al charactere of S. haemolyticus. All were bile insoluble, and all hemolyzed
vt «
of,
a

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red blood celle both when grown as superficial colonies on blood agar plates
and when a twenty-four hour broth culture was added to a tive per cent suspen-
sion of red cells. The sugar farmentations of all the straine were also tested
and in general they corresponded to those already described for S. haemolyticus.
Most strains fermented lactose and 20 per cent of the etrains fermented man-
nit. The capacity to ferment these latter sugara, however, did not seam to
be related to any other fundamental biological differences and could not serve
as a basie of final classification.
II. Virulence for laboratory animala.

The virulence of moet of the etrains for white mice,
rate, raboite and guinea pige was found to be low, using pneumécoccus as a
atandard of comparison. fhe virulence could not be raised to a high point
for either rabbite or guinea pige. The organisms were somewhat more virulent
for rabpits than for guinea pigs. The virulence could be raised to a higher
point for white rate. By repeated passages through a series of white rate,
it waa possible to raise the virulence of a number of the strains to a very
high point for white mice, so that in a considerable number of instances a dase
of 0.00000001 cc. of an 16 hour broth culture was eufficient to kill the ani~
wals in twenty-four hours. This high degree of virulence is necessary in order
to titer satisfactorily the protective value of immune sora. in experiments to
test cross immunity between different strains. | :

a In the experiments to test active imsunity, three
types of animal were used, white mice, white rats and rabbits. Tho experiments —
with mice and rate were unsatisfactory, no active immunity being observed after
repeated inoculation of killed organiems. In rabbits, however, sufficient |
immunity was obtained after three inoculations of killed organiems to enable
the animale to withstand ten times a certain lethal dose of living virulent

streptococci.
OR
IV. The development of protective immune sera.

In the effort to produce an immune serum which would
afford passive protection to unimals against S. haemolythcus, rabbits, sheep,
dogs and one horse were used for purposes of immunization. All of these ani-
mals, with the exception of the horse, gave good protective sera. The anirals
were immunized by injecting firet heat-killed and then living cultures intra-
venously. The intravanous administration of living culturea had to be abvan-
doned because of the localisation of the living organisms in joints and other
parts o! the body. The subcutaneous route was then substituted for the intra-
venous. The immune sera were considered sufficiently potent for use when 0.5
cc. given intraperitoneally in whita mice afforded protection against 0.001 cc.
of a broth culture that killed the animals in doses of from 0.000001 cc. to
0.00000001 cc. in twenty-four hours. Por the succesaful performance of the
test, the serum must be given intraperitoneally at least eight hours before

the administration of the infecting dose of streptococcus.

V. Diversity of strains of Streptococcus haemolyticus.

Use of the above sera has demonstrated that strains
of 8. haemolyticus are diverse in their immunolozic reactions and do not consti-
tute a unit group. Furthermore close immunologic relationship can be demonstra-
ted between certain strains and the evidence obtained up to the present points
to the existence of types of haemolytic streptococci just as there are types of
pneumococci and meningococci, At least four such types have been identified
so far. In general there seems to be a separation between what may be Classed
as the respiratory strains and the septicaemic strains, including in the latter
group strains from septicaemia, cellulitis, erysipelas, puerperal sepsis, etc.
Where the point of contact is between these two greups has not yet been deter-

mined.
VI. Agglutination reactions.

Great difficulty was experienced at first in the ob-
taining of satiafactory agglutination reactions. With the very highly active
immune serum which we now possess more satisfactory agglutination reactions are
veing obtained, especially when the reaction is carried out at 55° C., and when
the dilutions are made in broth rather than 1n gait solution. Ae far as the
work has progressed, the agglutination reactiom correspond with the protective

reactions.

Prophylactic Vaccination.

A fow experiments have been carried out with a view
of studying methods of prophylactic vaccination. It was found that mixtures
of gelatin and agar can be prepared which melt at 40° c. These have been used
as a vehicle for the suspension of bacterial waccinos. Such vaccines when in-
jected subcutancously in anizale give a good immunity and also produce a mild
local reaction. This method will have to be tried out in human beings in order

to judge its general usefulness.
KY

-

Differentiation of Streptococci from Human and Bovine Sources.

With the assistance of Dr. Cullen, Dr. Avery has
investigated the limiting hydrogen ion concentration in culturea of Strepto-
coccus haemolyticus isolated from human and bovine sources. Many investigators,
especially Clark and Lubs, have shown clearly and conclusively that the final
hydrogen icn concentration of a culture is a definite biological conetant, but
that the titratable acidity is variable, depending on the buffer action of the
salts and protein, as woll as on the acid produwed.« This fact, not yet uni-
versally accepted by bacteriologiste, has been strikingly demonstrated by Ayers,
who finds that certain cultures may actually show “negative acid" upon titration,
although the hydrogen ion concentration has increased.

Approximately 125 strains of S. haemolyticus from human
sources have been studied and compared with about 50 strains of this organism
of bovine origin isolated from mastitis in cows, from milk and from cheose.
The latter were authentic strains, some of which were obtained from the Depart-
ment of Animal Pathology and others isolated directly by us. The hydrogen ion
concentrations were all made by the colormetric method. A definite and distinct |
dif ference has been found between the bovine and human types of this organism in
the final hydrogen ion concentration of cultures grown in dextrose broth. Using
methyl red as an indicator, cultures of bovine origin isolated from milk, masti-
tis and cheese have consistently shown a pH of 4.5, while those of human source

have a pH of 5.1. Cudtures with the more acid reaction exhibit a definite claret- *

  

red color, while those with s reaction of 5.0 to 5.2 show only a faint salmon tint, —
Using this colorimetric method, 90 to 95 per cent of all known straine have re- |
acted true to type - the others forming an intermediary group in which the Ymethy) |
red reaction” fails in absolute classification.

By the use of medicinal methylene blue, a further difier-

entiation has been found between the hunan and bovine strains on the one hand and
 

cultures of haemolytic streptococci isolated from cheese, on the other. The
former, the more pathogenic group of human and bovine types, fail to grow on
agar plates containing a dilution of dye 1:20,000, while the latter, the more
vegatative cheese varieties, grow luxuriantly. Haemolytic streptococci, with
the exception of these last named organisms, are extremely sensitive to methylene

blue, even in dilutions as high as 1:500,000.
The possible chemotherapeutic significance of this ob-

servation has been considered, but further study is required before any conclu-

sione may be drawn.
 

 

mo’

Persistence in the Human Throat of Haemolytic Streptococci

derived from Milk and Cheese.

Certain investigators have raised the question as
to whether the streptococci responaible for acute respiratory disease in
man may not be acquired by eating cheese and drinking milk, The studies
of Dre. Dochez and Avery, and others have demonetrated conclusively that
the streptococci found in pneumonia in man are not identical with the
haemolytic streptococci commonly found in milk and cheese,

The epidemiological conclusions concerning this
form of pneumonia, however, have been based largely on culture made from the
pharynges of healthy mman beings as well a; from the throat of patients
euffering from the disease itself. |

The question has arisen whether these conclusions
may not be vitiated by the persistence in the throat, for a limited time at
least, of haemolytic streptococci which were present in cheese or milk
which had been ingested.

To teat this question Dr. Ernest Stillman has
made cultures from the throate of individuals a short time following the
ingestion of milk end chease known to contain haemolytic streptococci of
the bovine type. ‘Cultures fron the same throats, made before taking
the milk or cheese, ‘had been show to be free from haemolytic streptococci,
The experiments made with milk, which have. been frequently repeated, have
shown that within an hour following the ingestion of the milk, even though
the latter contained large mimbersa of streptococci, no haemolytic streptococcus |
colonies can be demonstrated on the surface of the plates inoculated by swabs
in the ordinary way The rason for this is probably two fold. First,
by natural processes the pharynx is probably very quickly rendered clean of

any milk particles, and second, the haemolytic streptococci in mili have
 

 

& relatively slignt power to produce haemolysis when only isolated colonies
occur on the surface of blood agar, It 1a not likely, therefore, that
errors may Arise from the presence of milk streptococci in the human throat,
As regerds the cheese streptococci, however, there
is & greater possibility that they may give rise to error in epidemiological
studies. The greatest length of time that these streptccoci may be found
following the ingestion of cheese has not yet been deternined, but certainly
for several hours. In the first place these Orgunisms are more actively
haemolytic, when grown on the surface of blood agar, than are milk etrains;
and secondly, the throat probably rids itself of the particles of cheese with less
readiness than it does of the milk. The possibility of error due to this
Cause should, therefore, be kept in mind in etudying Carriers, out it is not

likely that any considerable confcsion has arisen from this source in the past,

Antipneumococcus Vaccination,

In the annual report one year ago, attention was
Called to the possibility of employing prophylactic vaccination in the pre-
vention of pneumonia in the Army, and it was atated that studies concerning
this method were being made by Dr. Chickering. The resulte of these
studies, as well as mmercus studies made by Dr. Cole in the production of
immunity in animals, as well as the studies carried out by Dr. Lister in
South Africa indicated atrongly that prophylactic vaccination in mn against
pneumococci of Types I, II, and III would be very likely to yield favorable
results, This matter was brought to the attention of Colenel Russell of
the Surgeon General's Office,and Captain Austin was ordered to the Hospital
to carry on investigations conceming the technique of mamfacture of vaccine.
Miss Pauli was employed by the Institute to assist in this work. by the

use of a special form of centrifuge, it was found possitie to prepare large
cee ete pnt det acl

a a

Sy

 

 

amounts of vaccine without difficulty, and tests were made on various members

of the Staff to determine the most suitable dosage, etc, With the cooperation

of Major Cecil of Camp Upton, a large muber of soldiers at that camp (abot
12,000) were then given prophylactic injections, The men remuined in the camp
only for two to three months following the injections and were then transferred
Overseas. During this period, however, not a Case of pneumor.ia due to the
types of pneunocoxciused for the inoculation Occurred among the inoculated men,
while a considercble number of such cases occurred among the men not inoculated,
Attempts were made to obtain records of the occurrence of pnevinonia in these
men following their transfer to France, and a grant of money was generously
made by the Directors for this purpose, but for military reasons it has been
impossible to carry out this intention. The results, however, have been
felt to be sufficiently promising to Justify the employment of this method on
@ larger scale.

The work has been taken over by the Army, and the
vaccine ie being prepared on a large scale at the Army Medical School, By
making an emulaion of the bacteria in oi] instead of in salt solution, it is
believed that one inoculation will suffice, instead of using three injections
as was formerly done. Large numbers of soldiers are now being inoculated

by Dre.Cecil and Vaughan at Camp Jackson, and by Dr. Austin at Camp Dix,

Rapid Method of Etiologic Diagnosis in Cases of
Pneumonia due to Pneumococei.

During the year Dr. Avery has developed a method
whereby the types of pneumococci present in sputum can be determined within
five hours in many cases without employing mice for this purpose, By in-
oculating the sputum in one per cent Slucose broth containing five per cent

of blood, a rapid growth of pneumococci Occurrs, while other organisms present
da.

do not multiply to any great extent. After the blood cells and bacteria
are removed by centrifugalization, the type of pneumococcus which has grown
aay be deteruined by the demonstration of the specific precipitins in the super-
nutant fluid, This method, while not @pplicable in all cases, has proved

of great walue in the Campa, especially when mice were not available,

Use of Masks in Preventing Infection in
Respiratory Diseases,

During the past winter gauze maske have been employed
in a number of camps for the Purpose of preventing the transference of the
bacteria causing pneumonia from the persons suffering from the disease to
healthy persons. The use of masks is based on the well-known experiments
of Pflagge concerming droplet infection. No cureful experinente, however,
have yet been made to determine the efficiency of the masks employed in this
country. Consequently, it was thought advisable to have Capt. Doust and
Lieut. Lyon, Amy Officers sent here for instruction, investigate this sub-
ject. They have repeated the experiments concerning droplet infection,
employing masks prepared in different ways, and have devised a mask which has
been shown by experiment to be efficient, _ They have also show that
many of the maske now being employed are of little or no value. Tha results
of this etudy will be mblished inmediately and will undoubtedly be of mch
prectical value, |

Chemical Studies.

During the year Dr. Goto, a volunteer aceistant,
has, under Dr, Van Slyke's direction, carried on a study concerning the leca-
tion of the reservesof mineral alkali which are drawn upon in acidosis. He
has also made an interesting study of renal diabetes, and has also devised

a method for detenmining carbonate in mineral analysts.
Dr. Dernby of Sweden, a voluntary assistant, haa
studied with Dr. Avery the effect of the reaction of culture media on the
growth of pneumococci, Under Dr. Van Slyke's direction he haz also studied

the autolytic enzymes of the tissues.

Diabetes.

Dr, Alien hae completed his studies in the Hospital
concerning dalabetes, and the clinical report of his work is now in procees
of publication by the Institute as a Monograph. Dr. Allen haa entered the
medical service of the Arcy and has been assigned to the hospital at

Lakewood to undertake the care of soldiurs suffering fron diabetes.
 

 

Clinical Studies Concerning the Use of A 169 in the Treatment
of Syphilis.
In the fall of 1917, planes were made to test clini-

 

°
5 Ne

cally in the hospital the arsenical preparation, A 169, which, out of a oon-
siderable number synthetized by Dr. Jacobe and tested on animale by Dre. Brown
and Pearce, had been selected as the most promising for the cure of human syph-
ilis. After several conferences between members of the staff of the hospital
and the laboratories, it was agreed that the hospital undertake the problem of
working out the clinical application of the drug. The reaponsibility and
expense of this work was to be borne by the hospital, with the exception of the
preparation and standardization of the drug.

Origine) Plan of Investigation.

The original plan of investigation was to take patients
with active, primary and secondary lesions, as well as positive Wassermanns, in
order that the effect of the drug on both the lesion and the blocd reaction
might be ascertained. The patients were to be chosen from those who had had
no previous treatment. As the drug, if successful, promised to have great ail-
itary importance, arrangements were made with the officials at the Port of Bnbar-
kation, whereby soldiers suffering from syphilis wore transferred to this hospital
as patients, where Dr. Stillman, and later Dr. Stadie, accepted commissions in
the Medical Department of the Army. The work was begun in January 1918 by Drs,
Stillman, Van Slyke and Cohn. It was planned that Dr. Stillman should study the
therapeutic effect on the Wassermann reaction and the effect of the drug on active
manifestation; that Dr. Van Slyke should study the mode in which the drug was ex-
creted and retained: and that Dr. Cohn should control the electrographic behavior
of the heart during and after administration.

On the first of March, Dr. 7. C. Stadie from the Pres-
byterian Hospital wae added to the steff, and has divided the clinical work with

Dr. Stillran and cooperated with Dr. Van Slyke on tho problen. of arsenic excretion
“poe

and distribution in the tissues.

During the present month, Colonel Russell has detailed
to us two additional men, Dr. Fortuine, formerly of the Presbyterian Hospital,
and Dr, Klauder, who had been for a considerable tine treating syphilitic
patients at Camp Upton. Occasionally Dr. Fordyce has examined the patients
and has assisted with advice. Drs. Brown and Pearce have been reguiarly consul-
ted in connection with the plans made for administration of the drug. Sugges-
tions which they have made, based on their animal experiments, have been utilized.

The following points have been investigated. They
have not been taken up chronologically in the order in which they are given
here, as several points were, during most of the time, simultaneously under in-
voatigation.

l. whgt t a t i t
It was found that the injection of dosage of 7 mg. of drug por kilo body weight
once a week resulted in the disappearance of the external lesions within an
average period of 9 days, and a negative Wassermann on an average number of 47
days. Some patients cleared up much more rapidly than others, while some re-
quired extensive treatment. In no case, except those in which treatment was
stopped for reasons other than failure to tolerate the drug, did we fail to
finally obtain a negative Wassermann reaction, As the soldiers who were patients
could not be kept from their military duties for an indefinite period, the nega-.
tive Wassermann reaction, when obtained consistently and rapidly, was taken as
indis ating the end of the treatment. . | |

- We have not, therefore, se yet, and in the imp diate

future may not have, date as to the frequency of recurrence, although it is hoped

‘that the follow-up histories may be obtained on at least part of our discharged

‘patients. They have all been instructed to return to us on their return to New
~~ ff

York. It is probable that a consideradle numder of navy men may be thus kept
under observation,

c. For the given rate of administration, the question was raised as
to whether a cure could be effected more quickly when the drug was dissolved in
23/4 les t when it was dissolved in 1 molecule. The animal experi-
nents of Dra. Brown and Pearce had indicated that only 1/2 to 1/3 as much drug
was required for a cure when a larger amount of alkali was used. Our’ reaults
have shown no differences whatever in the therapeutic effect, whsther the drug
was dissolved in 21/4 or 1 molecule of alkali.

Of sixteen cases treated with 1 molecule of alkali, the average time
required for negative VWassermann was 42 days. Of nineteen cases treated with
21/4 molecules, the average time wae 47 days.

3. The question was aleo raised as to whether the administration of
the drug with excessive alkali, namely 2 1/4 molecules, diminishes the toxic
effect in man. The foblowing toxic effects were noted for a record when they
occurred in the cases under each mode of treatment: Thrombosis, abdominal
pain, fever, chill, headache, nausea, vomiting, appearance of albumin or casts.
Of these there was no murxed differences in the two series except in thrombosis.

The caustic effect of alkali, when 2 1/4 molecules were used, resulted
in thrombosis after 21 per cent of the injections, while, when only 1 molecule
of alkali was used, thrombosis occurred following only 1.5 per cent of the ine
jections. The other effects may be noted by reference to the table below. |

Table I. |

Relative therapeutic effects of A 189 dissolved in

i and in 2 1/4 molecules of NaOH,
1 pol, 21/4 le.

 

No. cases treated with open lesions. . 81. 25.
Average no. days until lesions healed. 7.8 10.9
No. cases treated with positive W. R. 16 19

Average no. days until F. R. became negative 42 47
Table II. Th

Relative toxic effects of A 189 dissolved in 1 and 2 1/4

molecules of NaOH.

1 mol. 2 1/4 mols.

Total no. cases treated, ‘2) 34 37

Percentage of cases showing abdominal pain at (2)

some stage of treatnent. 41 16

Total no. of injections. 197 217

Percentage of injections followed by thrombosis. 1.5 21.0
e " ® " © fever. 14, 24.
" " " n * chill. 2.9 17.5
" " " " " headache. 9.2 12.4
" . n " " * nausea, 5.8 11.5
" ® ® ® * vomiting. 4.8 6.0
" ® " ° * albduain or casts. 12.1 25.8

(1) Only 71 of our cases have been treated throughout purely with
either 1 or 2 1/4 molecules of alkali. Of the remainder many have been start-
ed with 21/4 molecules, and during the treatment changed to 1 molecule, because
their veins were sensitive to alkali and thrombosis regularly followed the in-
jections. Such cases are not included in the table. If they were, the per-
centage of thrombosis recorded against the ‘aAls molecule treatment in Table Ir
would be increased. : |

(2) The cause of this high percentage of pains is that 21 of the 34
cases on 1 molecule NaOH ‘received the drug at the rate of 10 mg. per ‘kilo every .
5 days. None of the 2 us molecule cases received it as rapidly. mong cases
receiving the drug at the seme rate the percentage of abdominal pains is about
the same, whether it is given in 1 or 2 1/4 molecules of NaOH. With the dosage
chosen as the optimum, 7 mg. per kilo every 7 days the pains seldom occur with

either 1 or 2 1/4 molecules NaOH.
 

SI ASIEESSSSX_SEZ ree ee
TOs

“>

Among these effects the abdominal pain is especially vi

important. It apparently occurs from administering the drug in doses of 10 mg.
per kilo too closely together. When the dose mentioned previously of 7 mg. of
drug per kilo body weight once per week is given, abdominal cramps are seldom
obtained. When the dosage was increased to 10 mg. per kilo body weight every
five days, cramps resulted in more than one half of the cases. They were
extremely painful, cyclic, and might occur within a few hours or several days
after the last injection. In no cage, however, did examination of the urine
o indicate kidney injury, nor could any effect on the heart action be detected
by the electrocardiogram even during the attack. All patients having cramps
recovored. In no case was there evidence of permanent dajury.
4. imum rapidity in which the d@ can be administered with
safety. This point has been considered in paragraphs 1 and 3.
5. Effect on kidney funotien. Routine examinations of the urine
have been carried on twice a week on every patient under observation, and in
moat cases the kidney function has been also examined once a week by the phenol-
sulphonphthalein excretion method and by biweekly determination of the blood
urea. Occasionally slight albumin and casts have been encountered, but only
in one case was real kidney injury determinable. This patient had received
about 7 grams of the drug, and after the last dose suddenly developed anuria.
He was | treated by Dr. Stadie in the manner utilised for handling patients with
bichloride poisoning and recovered completely. |
. Elfect of the ‘drug on heart action. Flectrocardiograms were taken
of the patients during the ‘injection of the drug, and at whatever other tines
promised to be of interest, especially during and after abdominal pains re-
ferred to above. The drug had no effect on the electrocardiogram, but an
interesting abnormality was noted in a considrable percentage of the syphilit- .

ica who came to us for treatment.
iy TO

Out. of 85 casea observed, 35 showed a split T-wave in
the third lead. This phenomenon indicates soma aortic involvement. So far
as ie known, this phenomenon hag never before baen observad, It was noted
that thie notch disappeared after the Wassermann became negative. The exact
Cause of this change is not at present Clear, but we hope to continue the
study of this phenomenon. It may be of intereat to know here that this notch-
ing of the T-wave was observed ina Convalescing pneumonia patient who, upon
examination, showed a four plus Wassermann. Another case wae sent in by a doc-
tor from Montolair who found this notch and was unable to explain it. Bubse-
quent examination of the blood showed a four plus Wassermann.

7. Rate of elimination of arsenic administered as A189. A Practical
method for the determination of arsenic in the urine and feces was worked out.
It was found that about equal amounts of arsenic are eliminated by the kidney
and the intestines. Kiimination begins immediately after injection and on
succeeding days becomes gradually slower. Within three weeks after the
most rapid treatment, the elimination has practically ceased,

Sitilar excretion experiments were performed on rabbits, and their
tiseues were analyzed at varying periods after the injection of large doses
of A 189. | The animals also in about three weeks showed approximately
complete elimination. It was especially interesting to note that when
elimination in the urine stopped, ‘ne more arsenic could be found in the tis-
suse. “Mats indicates that the drug is not stored in the tiasues, but te |
completely excreted, and that: when at ie not given too rapidly, there is
probably no danger of accumlative effect.

B. The distribution of arsenic in the tissues of rabbits after the

injection of A 169 was studied. © It was found that the drug accumlates

especially in the liver. The lungs, kidneys, intestines, and muscles con-

 

tained less arsenic than the liver. The administration of the drug with
TOR

3 molecules of alkali as compared with 1 molecule had no effect on either
distribution or rate of elimination of tha arsenic, except when very massive
doses were given. The one exception was noted when the tremendous dose,
namely 150 mg. per kilo, was injected, When this dose was given with only
1 molecule of the alkali, large améunts of arsenic were found in the lungs,
apparently because the drug was precipitated in the blood and stopped by the
capillaries of the lungs, When 3 molecules of alkali wera given, this
did not cccur, It occurred with one molecule only when the above massive
test was given, not when doses comparable with those used therapeutically
Were given. Even when the doses were as high as 50 mg. per kilo or 7 times
the therapeutic dose adopted for man, there was no accumlation in the lungs,
In such doses the occasional alkali was without any effect on the distribu.
tion of the drug on the body.
9. The Wasaermann reactions were followed at weekly intervals

by at least two laboratories. At first the blood specimens were sent to
the Board of Health laboratory and Dr. Jagle. Since then, however, the
facilities for performing our own Wassermann reactions were developed, and
the results obtained from these laboratories are compared with those of

Dr. Jagle's, At present we are relying upon our ow Wasseruanns as the
technique was developed to such a point that the results became thoroughly

- consiatent. oe oe

10, Darkefield determinations. Lesions are regularly examined
for spirochetes by the dark-field. One of the problems at present under
investigation concems the length of time which Clapses after the first
injection. before the spirochetes disappear from the external lesion.
11. Charting the results. | Charts were printed in detail tab-—

in
ulating concise form, both laboratory and clinical data, bringing out all

the above points.
PLANS FOR THE IMMEDIATE FUTURE.

At present the following plan seems to be acceptable:
A dosage of about 7 mg. A 189 per kilo body weight weekly is the optimun.
It is seldom followed by abdominal pain or other serious effects, and re-
presents a maximom rate of administration. It is possible to inject this
amount with only 1 molecule of alkali since largar amounte result in in-
creased percentage of thrombosis without apparent effect in either increas-

ing therapeutic power or ducreasing toxicity.

The following problems seem to be the next demanding

 

solution:
1. The optiaum concentration for the administration
of the drag. Tims far the concentration has been varied from 1:1000 to

12150 without apparent effect on therapeutic power or toxic action, If

the drug ia utilised for military purposes on a wide scale, it may be necee-
sary wider some conditions to give it a more concentrated form with a syringe
if it is given at all. Consequently we are contimally increasing concen-
tration in order to diminish the volume. of solution injected, in order to
determine the greatest concentration which may be given with safety without
effecting the therapeutic results.

2. Combination of A189 with mercury. “Since it is.

generally held that the dest results with salvarsan are obtained when the - .
treatment is reinforced with mercury, we are attempting to find whether the
same is true with A 189. Consequently a series of cases have been started
that are receiving A 189 and sismltaneously dichloride and mercury intrasuscu~-
larly, At present with the data which we already have on hand, the results
from these cases should indicate within a few weeks whether the mercury

shortens the period required to obtain a negative Wassermann.
 

 

éor

OH PA

3. Comparison with salvarsan. After the appropriate
mode of administering A 189 has been ascertained, it appears desirable to
compare it in the same wards with salvarsan on a sufficient number of cases
to get satisfactory data on which a comparison of the peculiar merits and
disadvantages of each drug might be tested.

4. The work thus far has been purposely limited for
the most part to primary and secondary cases. It is now being extended
to nervous, tertiary, and congenital syphilis.

5, We have been unable to find in the literature or
in consulting with syphilologists any accurate data as to the status neuro
rezidive. It, therefore, seems advisable in our treatment of our primary
and secondary cases to do lumbar puncture pefore, in the middle, and at the
end of our treatment in each case, in order that this important question
may be settled.

6. It 148 our purpose to continue the electro-
cardiograph study mentioned above in order to clear up the cause of the
anomaly noted and also to find out, if possible, whether this may be a

rather important diagnostic point in early vascular syphilis,
SUMMARY OF CASES TREATED WITH A lag ganuaRY 1 - OCTOBER 1, 1918.

l. No. of cases treated 128
2. a ® “ discharged Wasserman negative 45
3 ._ #4 ® . positive 2
4. » e  * under observation 57
5. ._ * 8 Aled _t
128

In the 25 cases discharged with positive Wassermann
reactions, one refused sufficient treatment, twenty were discharged as
unsuitable cases for observation, and four were discharged for disciplinary
reasons, The one death was in a case who died within four hours of admie~
sion, before treatment. The cause of death as revealed by autopsy was

que to cardio-vascular failure, resulting probably from diphtheria,