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F. J. (Frederic John) Poynton.

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overlooked by those who have investigated the tissues in rheu-
matic fever.

Thiroloix, 18 following Achalme's investigation of this bacillus,
in a series of papers fully confirmed his results. In addition,
in five cases of rheumatism he obtained this bacillus and
inoculations into rabbits gave the entire picture of rheumatic
fever. Again, he obtained the organism from the blood and
pleural effusion in one case of rheumatic fever, and this pro-
duced in guinea-pigs sanious exudations and in rabbits a
heart but not a joint inflammation. In two later cases he
obtained the latter also. Triboulet 19 in a case of rheumatic
fever found a bacillus resembling that described by Achalme.
But later Triboulet and Coyon 20 found a diplococcus in five
cases. In two of these the diplococci were associated with
Achalme's bacillus, and they argue that severe and complicated
cases are due to Achalme's bacillus together with the associated
diplococci, whereas the simple cases of rheumatism are due
to the diplococci alone. Riva 21 in 1897 isolated a specific micro-
organism from eight cases of rheumatic fever. The organism
varied much in shape in different media and occurred in both
coccal and bacillary forms. He made use of a complicated
medium slightly acid in reaction, an essential constituent of
which was the synovia from the joints of horses. In 1898
Apert and Triboulet 22 obtained some remarkable results by
the inoculation of a rabbit with a diplococcus isolated from the
blood of a patient suffering from rheumatic fever. Twenty
days afterwards they found thickening of the mitral valve
with hypertrophy and dilatation of the chambers of the heart
and excess of clear fluid in the pericardium. There was also
pleurisy but no peritonitis. None of the joints were affected.
This diplococcus was identical in character with that found
in 11 other cases of rheumatic fever. In spite of the absence
of any joint lesions Triboulet considered this organism to be
specific. Injected under the skin Apert found the diplococcus
produced a local induration. Bettencourt 23 in 1898 supported
the researches of Achalme and Thiroloix. Gustav Singer 24
in a monograph gave the results of an extensive investiga-
tion of many cases of rheumatic fever and was led to the
conclusion that acute rheumatism is not a specific disease but
owes its origin to streptococcal and staphylococcal infection.

In 1889 Kronenberg, 25 in a paper upon angina faucium

7



9 3 THE .ETIOLOGY OF RHEUMATIC FEVER

in acute rheumatic fever, expressed doubts that rheumatism is
a disease sui generis, but he thought rather that it was a peculiar
reaction of the joints and other tissues to a series of bacterial
influences — as, for example, the gonococcal, the streptococcal,
and the allied infections. In 1899 Westphal, Wassermann,
and Malkoff published a paper, " Ueber den Infectiosen
Charakter und den Zusammenhang von Acutem Gelenkrheu-
matismus und Chorea." 26 Westphal narrated the history of
the case from which the material was obtained. It was a
severe case of chorea that followed acute rheumatism, occurring
in January 1899. Violent delirium with hyperpyrexia and
collapse resulted in death on February 24. The necropsy
a few hours later showed minute vegetations upon the mitral
valve and parenchymatous nephritis ; there was no suppura-
tion. Cultures were made from the heart's blood, pericardial
fluid, mitral valve, spleen, and brain. Wassermann, after
alluding to the resarches of Loffler, Michaelis, Eberth, Litten,
and von Leyden, described the bacteriological results. A
diplococcus resembling morphologically that found by von
Leyden in rheumatic valvulitis was isolated and in 80 rabbits
produced fever and multiple arthritis. This organism appeared
as a diplococcus in the tissues but grew in culture as a strepto-
coccus. The number of micro-organisms in the tissues of the
patient was very small. It required a higher degree of alkalinity
than that of the ordinary media, upon which it refused to grow.
The incubation period was from three to ten days. All the
tissues of the joint were inflamed and in the fluid of those
which had been affected longest there was a considerable
number of leucocytes. In addition there was exudation in the
tendon sheaths and bursas. The micro-organism was found
in the arthritic exudation and cultures from the animals repro-
duced the disease in other animals. Litten 27 at the same
date isolated from a malignant form of rheumatic endocarditis
(non-suppurative) a very minute streptococcus which was fatal
to mice and guinea-pigs but rapidly lost virulence upon culture.
In a footnote to his paper he is of opinion that Westphal and
Wassermann have probably found the true excitant of acute
rheumatism but suggests that there may possibly be more than
one. It appears to us that this diplococcus must resemble,
if not be identical with, that investigated by Triboulet in 1897.
This brief survey is sufficient to show how complicated



THE /ETIOLOGY OF RHEUMATIC FEVER 99

and uncertain the present position of the bacteriology of
rheumatic fever still remains. In the following short analysis
of the various hypotheses we hope to make clear that view
of the subject which seemed to us the most probable and to
indicate the direction in which our researches tended. There
may be some who still decline to regard rheumatic fever as a
microbic disease, but we have started upon the assumption
that it is an infection, being led to this conclusion by the
results of clinical and pathological experience and teaching.
The broad clinical view of rheumatism which has been taken
by such authorities as Dr. W. B. Cheadle, Dr. Thomas Barlow,
Dr. D. B. Lees, and Dr. A. Garrod in this country appears
to us to support this hypothesis very strongly.

View No. 1. Allowing that the cause of rheumatic fever
is microbic, one view that has met with considerable support
maintains that there is no specific micro-organism, but that
rheumatism is but a form of septicaemia which owes its origin
to staphylococcal and streptococcal infection. The close
analogy between the rheumatic processes and those of pyaemia
and the frequent discovery of staphylococci and streptococci
in cases of rheumatic fever have naturally led to this view.
It is undoubtedly a very important one and involves bacterio-
logical and clinical problems of the greatest difficulty. It raises
the question of what is ' really the definition of the specificity
of an organism and deals with what is still an unknown quantity
— viz., the extent of variability that is possible in a micro-
organism and its results under varying conditions of virulence
and resistance. We have fallen back upon the teaching of
clinical medicine and pathology as our guide in this matter.
Rheumatic fever as we meet with it in England is a common
disease with, on the whole, very definite characteristics. How-
ever virulent the disease it may be practically asserted from
the clinical standpoint that suppuration does not occur.
Many cases die in the course of a year with acute cardiac in-
flammation, yet the heart and other viscera do not show
abscesses. We were inclined to expect that an organism the
cause of rheumatic fever if isolated and inoculated into suitable
animals would produce in them a condition resembling the
rheumatic fever of man in the absence of multiple foci of
suppuration. That this limit may be overstepped both in
man and animals under exceptional, and perhaps as yet



ioo THE ETIOLOGY OF RHEUMATIC FEVER

unknown, circumstances seemed to us very probable, but the
general and 1 average result that we expected was a condition
in which the absence of suppuration would be a prominent
feature.

View No 2. Another view maintains that the cause of
rheumatism is a specific diplococcus. It is to this view that
we inclined, though we would repeat once more that the
definition of what is meant exactly by " specific " involves
many difficult problems concerned with the virulence of the
infection and nature of resistance.

View No. 3. A third view maintains that the cause is a
specific bacillus. This view is a decidedly simpler one, if it
were proved to be true. If the bacillus, as for example, that
described by Achalme, be found to be invariably present in
rheumatic fever it is easily distinguishable from the staphy-
lococci and streptococci that are found so frequently associated
in rheumatism, and its morphological characters alone would
be of the greatest assistance in establishing the truth of its
claim.

View No. 4. A fourth view raises the question of a mixed
infection of bacilli and micrococci, an analogy to winch is
readily supplied by diphtheria. To us this view appeared one
of great difficulty and withal unsatisfactory. There can be
no reasonable doubt in the face of the numerous investiga-
tions that have been made that micrococci of some form or
other are frequently present in rheumatic fever and hence the
origin of such a view as the one under consideration. Nor
can there be reasonable doubt that they are capable of pro-
ducing polyarthritis, valvulitis, pericarditis, pyrexia, sweating,
infarction, and other manifestations closely resembling those
of rheumatic fever. If then, both the bacilli and micro-
cocci are needful to produce rheumatic fever the association
must be a mysterious one. If the micrococci are the cause of
the symptoms it is possible that they are restrained from
causing suppuration by the presence of the bacilli. If the
bacilli are the cause of the symptoms it is possible that they
produce them only when associated with these micrococci,
though this is difficult to realise when it is remembered that
the latter may themselves produce almost similar lesions.

View No. 5. This last view holds that rheumatic fever is
not a disease sui generis but a particular reaction of the tissues



THE AETIOLOGY OF RHEUMATIC FEVER 101

to varied infections. We thought that the remarkable con-
stancy of the clinical symptoms of rheumatic fever, as met with
certainly in England, were much against its being a condition
that would result from many and varied infections.

Not only is there this diversity of opinion regarding the
organism, but opinions differ also as to the explanation of
the way in which the symptoms are caused. Does the micro-
organism remain localised to one spot — for example, the
tonsils — and pour its toxins into the system, giving rise in
this way to carditis, arthritis, nodules, and other local lesions ?
or is it widely distributed and present in the local lesions ? We
inclined to the belief that the organism was to be found in the
local lesions, though perhaps only with great difficulty. The
probability of its occurrence at these sites seemed to us to be
indicated by the analogy of pyaemia.

To summarise our point of view at the start of this investiga-
tion we thought it most probable that the. organism would
always be present in cases of rheumatic fever ; that it would
be capable of isolation ; that it would produce the symptoms
of rheumatic fever in a suitable animal ; and that it would
probably exhibit some definite peculiarities upon culture. We
also thought that it would be present in the local lesions and
that the infection would be a simple and not a mixed one.
The analogy that there appears to be between rheumatic
fever and septic infections pointed to the infection being
micrococcal rather than bacillary. We were, however,
naturally influenced by the positive results of Achalme and his
corroborators, and their results appeared to us so definite that
we gave especial attention to the discovery of this bacillus in
our earlier cases.

The Outline of the Investigation

After. this brief consideration of these various theories we
give in outline the results of our investigation, then in detail
the methods, cases, and bacteriological investigations, and
finally a short summary of the facts which have been established
with some concluding remarks.

In January 1899, we undertook the study of the bacteriology
of rheumatism with the intention of confirming, if possible,
the results obtained by Achalme. For some long time we
were influenced by this intention, but finally abandoned the



102 THE ETIOLOGY OF RHEUMATIC FEVER

attempt, having failed to obtain a bacillus morphologically
resembling anthrax either in culture or in the tissues. On
the other hand, we obtained later in eight successive cases
a diplococcus which grew in liquid media in streptococcal
chains. This organism did not thrive upon ordinary agar or
serum agar, and though we were able to grow it eventually
upon blood agar it appeared to grow best in a liquid medium
of milk and bouillon rendered slightly acid with lactic acid.
Upon three occasions we isolated the organism in pure culture
from the blood of patients during life who were suffering from
acute rheumatic pericarditis. It was also obtained from the
pericardial fluid after death and from the cardiac valves and
lastly from the throat of a rheumatic patient. In our first
two cases we did not investigate the characteristics of the
diplococcus and in one recent case it was associated with
numerous small bacilli. In one case a sarcina was present as a
contamination. In five of the eight cases it was in pure culture.
When we became acquainted with the researches of Wasser-
mann, Westphal, and Malkoff, it seemed clear that this was
the organism they had described, and we feel no doubt that
it is identical, although there have. been certain differences in
the results that we have obtained. As stated above, we
succeeded best in cultivating it in an acid medium and have
not had success with a strongly alkaline medium, as recom-
mended by Wassermann, though we are in doubt as to the
exact degree of alkalinity that Professor Wassermann found
to be most suitable, about which point he made no definite
statement of which we are aware. It is of considerable interest
that we succeeded in growing the diplococcus on two occasions
in the pericardial exudation and noticed in one of these instances
an increase in flakiness of the fluid. On both these occasions
the pericardial fluid was distinctly acid, so that there is this
proof that the organism will grow in an acid medium. The
demonstration of these diplococci in films from the pericardial
fluid after incubation is very definite, and we have also found
them in scanty numbers in films from recent vegetations, from
unincubated pericardial fluid, from blood from the heart, and
from the throat. Their demonstration in the tissues is by no
means easy. We have however, demonstrated them un-
mistakably in the tissue of a rheumatic nodule and in the
valves, pericardium, and tonsil. Mr. H. G. Plimmer under-



THE ^ETIOLOGY OF RHEUMATIC FEVER 103

took a series of inoculations for us from the pure cultures that
had been obtained and made intravenous inoculations into
rabbits with results of which the following is an outline.

The pericardial fluid from Case 4, that of a boy who had
died from an exacerbation of rheumatism, gave the first positive
result. Three days after inoculation the animal limped upon
the left fore leg, the left shoulder- joint was swollen, and the
animal had lost flesh. Later the right hip-joint and right-
shoulder- joint became affected, wasting continued, and the
rabbit died 10 days after inoculation. The post-mortem
examination shenved excess of clear fluid in the right shoulder-
joint and right hip-joint with reddening of the cartilages.
The left shoulder- joint contained an opaque fluid which
microscopically contained numerous endothelial cells and a
few leucocytes. The heart appeared larger than natural, there
was an excess of clear fluid in the pericardium, but apparently
no evidence of pericarditis or endocarditis. The liver w 7 as
dark red. In the lungs there w T ere patches of broncho-pneu-
monia. There was no sign of abscess formation in any of the
viscera. The clear fluid from the joints taken with every
precaution, was inoculated into milk tubes. Films were also
made and a diplococcus was demonstrated and cultivated
from this clear fluid. It was also demonstrated in the mitral
valve. Thus it will be -seen that in some respects our results
in this case corresponded exactly with those of Wasserman.
A polyarthritis had resulted and the joint first affected con-
tained a fluid in which there were fibrin and some excess of
leucocytes, the cartilages of the affected joints were redder
than normal, and in none of the viscera were there any foci
of suppuration. In one respect there was a difference and
this was an important one : we had demonstrated the organism
in the mitral valve. A second rabbit w 7 as inoculated from a
culture of the joint fluid. The cultivations upon six blood
agar tubes were injected intravenously into this rabbit
with the following results. Upon the third day the right
knee-joint swelled and the animal had lost 160 grammes in
w 7 eight, then followed in succession the other knee-joint and
the left shoulder-joint, and finally all the larger joints became
implicated. The identity of the course of the disease with
that in the first case w 7 as remarkable and certain further
results developed. Seventeen days after the inoculation a



104 THE ^ETIOLOGY OF RHEUMATIC FEVER

systolic murmur was detected at the base of the heart somewhat
superficial in character and the heart was acting with great
rapidity. This murmur was detected for two days and then
was lost and at the same time the heart sounds became
faint. We diagnosed pericarditis with subsequent effusion.
The next day the animal died. During the last week of the
illness all the joint swellings had disappeared except that of
the right knee. The necropsy showed an excess of clear fluid
in the pericardium and a fibrinous coagulum in the sac with
some roughening of the visceral layer over the large vessels.
The right knee was full of an opaque fluid which, as in the
first case, contained the diplococci, endothelial cells, and
leucocytes. There was some excess of fluid in the other joints
but this was clear. Upon the mitral valve there were two
small white opacities resembling an early granulation. The
liver was dark red and contained some small white areas which
were quite firm and slightly raised. The spleen and kidneys
were pale but otherwise natural. The tonsils were natural.
Microscopic examination of the mitral valve did not confirm
the suspicion of endocarditis. The opaque patches in the
liver proved to be localised areas of coagulation necrosis.
There was no trace of suppuration in the viscera. The myo-
cardium showed well-marked fatty changes in the fibres com-
parable to the changes demonstrated in the human heart as
occurring frequently in acute rheumatic carditis. The culture
of the organism was repeated as before and the cultivations
upon three tubes injected into a third rabbit, but with a negative
result. The cultivations upon six tubes injected into a fourth
rabbit resulted as follows. Four days after the inoculation the
right knee-joint swelled and subsequently the right carpal
joint and left knee-joint also and there was general wasting.
Upon the tenth day we detected a soft murmur which next
day we localised as mitral ; this disappeared, but on the
fourteenth day there was a murmur upon the right side which
we diagnosed to be tricuspid in origin. The confirmation of
these diagnoses being a matter of great importance upon the
same day that the tricuspid murmur was detected the animal
was killed. The necropsy showed that two joints contained
an opaque fluid comparable to that found in the preceding
cases and one a considerable quantity of clear fluid. There
was excess of clear fluid in the pericardium. The mitral valve




V



FIG. 13

A fragment of the parietal pericardium stretched in a film on a slide and dried,

stained and cleaved, showing a blood-vessel in the parietal pericardium of a rabbil

dead of carditis. (Zeiss, olrj. ,',,, oc. 3 I.

A. Blood-vessel.

B. Wall of the vessel.

C. Pericardial tissue external to the vessel.
Diplococci are seen in each position.



THE .ETIOLOGY OF RHEUMATIC FEVER 105

showed a condition macroscopically comparable to that of an
early rheumatic endocarditis, and the tricuspid valve showed
also, in the very earliest stage, a row of granulations along the
border. The condition of the liver resembled that found in
Case 2 and the kidneys also showed some white slightly raised
areas quite firm on section. The tonsils were unaffected. The
microscopic examination showed points of the greatest interest.
In the parietal layer of the pericardium, stretched out and
stained, we found the diplococci following the course of the
blood-vessels in the perivascular lymphatic spaces. We
also demonstrated them in the mitral valve and — what by the
light of subsequent events was especially noteworthy — we dis-
covered them in the kidneys in great numbers. There were
no suppurative foci in the viscera.

The organisms were once more isolated and injected intra-
venously into a fifth rabbit. This rabbit developed poly-
arthritis, pericarditis, pleurisy, and pneumonia, with slight
valvulitis. The animal was killed at the height of the disease
and the especial point of interest in the necropsy was the
macroscopic appearance of the thoracic viscera. There were
plastic pericarditis and mediastinitis, with plastic pleurisy
over those parts of the lungs that are contiguous to the peri-
cardium. The liver had the mottled appearance that is
seen in a man as a result of severe and acute rheumatic carditis.
During the illness the rabbit had passed urine which was
acid and contained numerous urates, granular casts, and
diplococci. From the contents of the bladder we isolated and
cultivated the diplococcus by the usual methods. There was
also exudation into the tendon sheaths around the affected
joints and the connective tissue near the larger joints had
the gelatinous appearance of the nodule in man. We demon-
strated the diplococci in the valves, pericardium, joint
exudate, liver, kidneys, connective tissues around the joints,
and in large numbers in the lungs and pleurae. It is, we
think, impossible not to recognise in this case the extra-
ordinary similarity to the most severe types of rheumatic
fever in childhood.

Another case in which some remarkable results occurred
was the second of those in which we obtained a pure culture
of the diplococcus from the blood of a living patient suffering
from rheumatic pericarditis. The organism was grown upon



io6 THE ETIOLOGY OF RHEUMATIC FEVER

the acid medium and transferred to blood agar. Intravenous
inoculation of a rabbit produced the following symptoms.
Four days after inoculation the rabbit had begun to waste
and limped upon the right hind leg, and the knee-joint became
swollen. This continued for a week, the animal still wasting,
but then it improved so much that the limp disappeared.
The heart all this time acted very rapidly but there was no
murmur. Five weeks after this there was a relapse and both
the hind legs became very weak and the animal very emaciated.
There did not appear to be any joint swelling at this time. This
condition continued for about three weeks and then gradually
passed off, and no cardiac murmur was detected at any time.
Was this a paralytic phenomenon ? It was a natural sugges-
tion that it might be chorea, but if so, there was not the
slightest twitching, only great weakness of both lower ex-
tremities that gradually passed away.

A third case which produced an experimental result was
that of Case 6. The case was one of severe rheumatic carditis
with early pericarditis. Associated with the diplococci there
were scfme short bacilli and the growth in the pericardial fluid
was accompanied by an offensive odour. An inoculation of
the two organisms into a rabbit proved negative. An inocu-
lation of the diplococci only into another rabbit also proved
negative. We were surprised at this result and three weeks
later a third attempt was made, though we felt very doubtful
that any result would be obtained because of the difficulty of
maintaining the virulence of the organism. This rabbit
remained apparently well, but three weeks afterwards we
found the temperature raised and a definite systolic murmur
at the apex. There was no arthritic change, but the murmur
remained constant for a week and was more definite than
any that we had previously heard. The animal was then
killed and the tricuspid and mitral valves were found to be
inflamed. There was also a moderate quantity of clear fluid



Online LibraryF. J. (Frederic John) PoyntonResearches on rheumatism → online text (page 9 of 42)