SECONDARY MIXED INFECTION 
IN SOME OF THE 
ACUTE INFECTIOUS DISEASES OF CHILDREN. 
A Thesis read before the Chicago Gynaecological Society, Jan. 25, 1889, 
By Bayard Holmes, M. D. 
ATTENDING SURGEON COOK COUNTY HOSPITAL, DIRECTOR OF THE BACTERIOLOGICAL 
LABORATORY OF CHICAGO MEDICAL COLLEGE, PROFESSOR OF 
SURGERY IN THE POST-GRADUATE MEDICAL SCHOOL. 
Reprinted from the North American Practitioner, of 
February, March and June, 1889. SECONDARY MIXED INFECTION IN SOME OF THE ACUTE 
INFECTIOUS DISEASES OF CHILDREN. 
By BAYARD HOLMES, M. D. 
Mr. President, and Fellows of the Gynaecological Society: 
The humoral pathology of our forefathers met its end in the post-mor- 
tem room, and under the microscope. It would not be surprising if an 
equal revolution should now follow the investigations of the bacteriolog- 
ical laboratory. Our present accurate knowledge of chemical elements 
and principles has been attained by careful, conscientious experiment, 
often carried out on an preconceived erroneous theory. In the same 
manner, our knowledge of mycological pathology has been advanced by 
experimental investigation undertaken to sustain false or imperfect the- 
ories. Thus the idea of a specific pneumonia was, for a time, disputed 
on the ground of bacteriological research demonstrating pneumonias 
due to various other forms of infection. It is needless to say that the 
value of these researches is in no way diminished because the significa- 
tion of their results wasat first imperfectly understood or misinterpreted. 
I. 
We may safely say that among the earliest manifestations of the 
struggle for existence, there was developed between individuals relations 2 
HOLMES, SECONDARY MIXED INFECTION. 
which ultimately terminated in true parasitism. In the course of time 
these relations became essential to the existence either of the parasite, 
of the host, or of both. 
Not only among the lowest forms of animal and vegetable life did 
parasitism arise, but, also, between forms high in the scale of develop- 
ment, and those of the lowest and intermediate forms. We may see a 
form of parasitism existing to-day between two of the most undifferenti- 
ated organisms. Thus, the JMajcoderma aceticum depends upon the pres- 
•ence of the Sacharomyces cervisice to prepare a small quantity of alcohol 
for its nourishment. Among the infusoria, the Paramecium aurelia, at 
least, has a parasite. It seems strange that a form of parasitism may 
not only be destructive or harmful to the host, but, from an adaptation 
of the parasite, the host may at last become entirely dependent upon it 
for the perpetuation of its own species. This is admirably illustrated 
by the relation existing between some of the flowering plants and 
insects. The secretions of the plants, and, especially, of their flowers, 
become the necessary food of the insect; and, because these insects can- 
not depend upon the perpetual and uninterrupted flowering of the 
plants, they have learned to prepare store-houses, and, also, as the more 
certain means of perpetuation, to live in large, highly specialized colo- 
nies. They have become modified in their forms, their habits, and their 
social life by their condition of parasitism. The host also reacts to the 
constant presence of the parasite. Even whole orders have been so 
modified that fertilization is absolutely impossible without the presence 
of the insects. Those plants that furnish only occasional food remain 
independent, others that are constantly associated with the parasite are 
somewhat modified, but not dependent upon it; while those forms which 
from long and constant association, or from change of environment 
which can only be endured by the modifications which render the insect 
fertilization necessary, become, at last, entirely dependent upon its 
■existence for their perpetual ion. Among the highest forms of life even, 
parasitism may become necessary to the existence of the host species. 
In all mammalia, the young exist for a considerable time as parasites upon 
the mother. In the Bonellise, the parasitic male occupies, during nearly 
the whole of its existence, the sexual organs of the female. 
Many parasites are, on the other hand, very detrimental to the exis- 
tence even of the host. Certain Unios are invaded by Nematoda that 
multiply in the mollusk's heart until is so impeded that a 
sufficient activity of the branchial cillia is not maintained to furnish an 
adequate supply of food. Death results to the mollusk, and the para- 
sites are carried into the intestinal canal of the scavenger fishes to com- 
plete their existence as sexual worms. The echinnoccus is also a destruc- 
tive parasite, at least in some mammalia. It is remarkable how a virtu- 
ally non-destructive parasite may incidentally become a source of danger 
to its host. In the powerful muscles of the unionida? of certain streams HOLMES, SECONDARY MIXED INFECTION. 
3 
tributary to the Fox river, I found very generally a peculiar parasitic 
Dystoma. Specimens thus affected were abundant where the stream 
passed through a village, but very rare elsewhere. The explanation 
was soon forthcoming. About the muskrat houses away from civiliza- 
tion. were piles of shells which these animals had emptied, besides many 
unopened and living specimens. Almost all the open shells were found 
to belong to individuals in which the muscles had been weakened by the 
invasion of the parasitic Dystoma. We see from these illustrations that 
parasitism may be either destructive to the host or necessary to the exis- 
tence of the host species, or it may occupy an intermediate relation. 
When we speak of a destructive parasitism, we understand that the 
host species must not thereby be entirely exterminated, because this 
would bring the condition suddenly to an end. To take a remote illus- 
tration, the destructive parasitism which exists between the Carnivora 
and Herbivora falls short of the extermination of the latter order from 
various obvious and well-recognized causes. We conclude from a con- 
sideration of the evolution of parasitism that (1) a destructive parasitism 
may not be an obligate parasitism. For, let us for a moment suppose 
the existence of an obligate parasite which invariably and rapidly de- 
stroyed its host; with abundant opportunity for the spread of the para- 
site there would soon result extermination of the host species, and most 
certainly an extermination of the parasite. But should a few individ- 
uals escape the attack of the parasite through the favor of locality, then 
W'ould the host species multiply, but there would remain no chance of 
resurrecting the parasite. 
2. A destructive obligate parasitism may exist when the causes 
determining the initiation of the parasitism are the same as those deter- 
mining the perpetuation of the host species. 
Syphilis is a form of comparatively destructive parasitism which 
depends on the reproductive act, as a rule, for its spread from one indi- 
vidual to another. 
3. A destructive obligate parasitism may exist when its relations 
are such that it appears only after the reproductive period has passed, 
or after the reproductive act has been accomplished. This theorem is 
illustrated in the animals among whom one of the parents becomes the 
host of the offsprings, and dies in their care, or where the destruction 
of the male is essential to the fecundation of the female. 
4. An obligate parasitism signifies an ancient and long continued 
parasitism. 
5. Most obligate parasites are not only non-destructive, but even 
helpful. 
These theorems are so nearly axiomatic that a discussion of them 
at this time seems almost unnecessary. Hence, when we observe a very 
destructive form of parasitism in a species, we almost immediately con- 
clude that it is occasioned by a facultative parasite, at least, a facultative 4 
HOLMES, SECONDARY MIXED INFECTION. 
parasite so far as this species is concerned. All apparent exceptions, 
at least, so far as I know, are susceptible of explanation. Tuberculosis, 
which seems to be a destructive obligate parasite of man (although it 
does not conform to all the requirements of a destructive parasitism), 
is, in fact, only an obligate parasite of the warm-blooded animals as a 
whole.- Among a number of these, tuberculosis is a comparatively 
harmless affection. In the Aves it results in the production of new 
connective tissue showing very little tendency to break down (Etudes 
Experimentales et Cliniques sur la Tuberculose, D. H. Martin. Vol. II, 
page 365, 1887). 
6. The less destructive a parasite is to the host, the fewer the 
means of offense and defense which the host species offers to the attack 
of the parasite; and, vice versa, the more destructive the parasite and 
the longer it has continued, the greater the resistance which the host 
species manifests. The obligate character of measles and scarlet fever 
indicates an ancient and continued relation with man. Nevertheless, 
from the comparatively harmless character of measles, scarcely any in- 
dividual immunity has been developed. All individuals, of whatever 
age, who have not been protected by a previous attack, suffer from the 
slightest exposure. Not so, however, with scarlet fever. Age alone 
renders the individual immune in most cases, while many of the youth 
suffer repeated exposures without falling victims to the disease. This 
acquired immunity stands in direct ratio to the destructiveness of the 
disease. 
Let us now consider some of the relations of the facultative and 
destructive parasites of man. 
7. As a converse of what has already been premised, we should 
conclude that all destructive parasites were facultative parasites, and 
depended upon unusual circumstances to permit or induce them to 
assume a parasitic existence. Generally they lead an independent ex- 
istence, or, at least, are only messmates of their host. In point of fact, 
our most dangerous and destructive enemies are the ever present bac- 
teria of our intestinal and respiratory tract, and one of the most impor- 
tant subjects which the study of parasitism forces upon us, is a con- 
sideration of the causes which determine the localization of infection. 
AU destructive forms of parasitism necessarily depend on accidental 
moments to open the doors which ages of evolution have closed against 
them. These avenues may be thrown open as a whole by causes which 
diminish the general vitality of the host, as inadequate or perverted 
nutrition or innei vation ; or a point of diminished resistance may be 
affected by local causes. Among the latter, we are accustomed to think 
of traumatism as the most potent. Perhaps a more careful considera- 
tion of the effect of local infection upon the tissues will lead us to con- 
clude that the most important factor determining the localization of 
infection is an antecedent and comparatively harmless infection. HOLMES, SECONDARY MIXED INFECTION. 
5 
Tetanus is a most destructive infection in man, but it is clinically and 
experimentally shown to be invariably a hanger-on upon a much less 
destructive pyogenic infection. Indeed, it has been impossible, so far, 
to cultivate the bacillus of tetanus on any soil alone, but only when 
growing with other bacteria. 
In this relation, the kind of infection is a matter worthy of study. 
Some forms of infection thrive only in the blood channels, and they 
might properly be termed haematophytic; while the greater number 
invade the lymph spaces and their smaller intercellular prolongations, 
and therefore might be termed lymphophijtic. Among the former are 
the Spirillum of relapsing fever and the Plasmodium malaria. 
Foremost among the facultative parasites of man, both in the num- 
ber of individvals they destroy, and in relation to the present subject, 
are the pyogenic bacteria. Of the three or four forms of suppuration 
ordinarily met with, that produced by the Staphylococcus aureus of 
Ogsdon is the most common. It is pre-eminently a parasite of the cell, 
producing multiplication of the nuclei, and latter coagulation and pep- 
tonization of the protoplasm. This peptonizing power is manifested 
in the nutrient gelatine by its liquifying that solid medium. 
However, the study of no other pyogenic microbe is so interesting 
from a theoretical and clinical point of view, as that of the Strepto- 
coccus pyogenes. It appears frequently as a simple infection, but most 
often as a secondary or mixed infection. Unable to invade the healthy 
and uninfected human body, it follows in the train of the acute infec- 
tious diseases, and through the doors they throw open, it gains access to 
the body. Though it is unable to compete with other suppurative bac- 
teria in readiness of attack, and being therefore more rarely met with 
clinically, its unusually varied and often masked destructive powers 
commend it to the consideration of every physician and surgeon, and 
its exhibition of various degrees of virulency, and its peculiar reaction 
on the tissues of, different species and different individuals even, rec- 
ommend it to the study of the zoologist. Its remarkably small size 
and its power of linear advance through fission give it a peculiar 
advantage over the other pyogenic microbes after an invasion has once 
begun, which modifies all of our ordinary notions of suppuration. 
The Streptococcus pyogenes is found in abscesses which are often 
slow in formation, and which present some of the symptoms of cold 
(tubercular) abscesses, in that they are very often unaccompanied by 
any rise of temperature. The tissues about the abscesses are not much 
inflamed or infiltrated, and the abscesses can be taken up in the fingers 
and moved about with the overlying skin. Sometimes, if not gener- 
ally, the abscess wall is not distended under any pressure, so that 
doubt may exist as to the presence of fluctuation unless great care and 
a delicate touch are exhibited. The same conditions render the diag- 
nostic use of the hypodermic needle more difficult. The overlying skin 6 
HOLMES, SECONDARY MIXED INFECTION. 
has a normal color until the paniculus adiposus is destroyed and the 
nutrition of the skin impaired. Then it becomes tawny, and, as inva- 
sion approaches, it dies, and the contents of the abscess are discharged 
through the resulting defect. Occasionally after an abscess of this 
kind has been observed for some time, it unaccountably disap- 
pears, and a casual observation discovers no trace of it except a 
little looseness and movability of the surrounding tissues. In such a 
case, a dissection will show that the abscess has opened into an adjoin- 
ing connective tissue space, has perforated some fascia, and sunk into it, 
or been forced into some distant and remote part of the body by atmos- 
pheric pressure, or by the mechanical force of some adjoining motor 
apparatus. 
The contents of the streptococcus abscesses present the greatest va- 
riety of appearance; in one case, resembling closely macroscopically the- 
staphylococcus pus; in another, colored with the pigment of muscle, 
bone or blood; in another, made up of a thin dirty fluid in which floats 
the debris of the destroyed tissues. The walls of the abscess are not 
covered with a granulating tissue, but are ragged and necrotic. They 
are themselves invaded to a considerable depth with the invading mi- 
crobe, and the increase in size of the abscess is due to their progressive 
destruction. The facia of the muscles and the fibrous sheaths of the 
blood-vessels present considerable resistance to the advance of this des- 
truction, and, therefore, it is not unusual to see at the bottom of the ab- 
scess or in its center a bundle of large blood-vessels, or a whole muscle 
desected out as if for demonstration. Microscopical examination of the 
pus shows a small number of leucocites and a large amount of unrecog- 
nizable detritus, the result of tissue necrosis and fatty degeneration. 
With proper staining, the streptococci are seen as small spheres, four to 
ten in a chain. They occupy not only the leucocites, but are found be- 
tween the cells composing the wall ofthe abscess, and also in the intercellu- 
lar lymph spaces. The connective tissue spaces and thejymph spaces are 
invaded to a considerable distance. This may become very general, and 
involve vast areas without the formation of abscesses. The perimycium 
and the endomycium are semetimes found crowded with the strepto- 
coccus. (Ziegler, I, p. 366.) 
When the streptococcus is cultivated on the nutrient gelatin, the 
growth is very significant. There is soon seen a mass of colonies along 
the line of the needle, which spreads out on the surface of the gelatin, 
forming a tulip-shaped growth. The gelatin remains solid all the time, 
that is, it is not peptonized. A corresponding reaction is observed on 
the tissues. While the staphylococci produce a liquifaction of the 
gelatin and a circumscribed suppuration, the streptococci produce a less 
active tissue reaction. The suppuration is of a modified kind; the ex- 
udate is sero-purulent, serous, or fibrinous, or all of these combined. 
In some animals (rabbits) the reaction is an inconsiderable inflammation. HOLMES, SECONDARY MIXED INFECTION. 
7 
while in others it is a mild suppuration (mice). They may be injected 
into the jugular vein of rabbits without producing any serious conse- 
quences. 
II. 
While no satisfactory demonstration of the pathogenic micro-organ- 
isms, which no one doubts are the etiological factor of the "acute infec- 
tious diseases," has been made, we may safely conclude that such a dem- 
onstration only awaits a better method or greater diligence than has al- 
ready been used. Sahli says that it is not wonderful that many in- 
vestigators have failed to discover the prime cause of diseases which 
have been recognized clinically to be infectious. And he remarks that 
they may either be too small to be seen, or may be insusceptible to the 
staining methods which have been tried. 
In this discussion it will be assumed that all of the acute exanthe- 
mata are due to micro-organisms, whether they have been demonstrated 
or not. 
It is very well recognized clinically that scarlet fever, measles, 
whooping cough and mumps are due to obligate parasites of man, 
or, at least, of the warm-blooded animals. We should therefore con- 
clude that in these diseases, as we have already found in typhoid, the 
pure and unmixed infection would be productive of a very small 
mortality. 
MEASLES. 
The investigations of Cornil and Babes establish the fact that in 
measles numerous diplococci are uniformly present in the interstitial 
lymph spaces of the lungs, as well as in the larger lymph channels and 
concentric glands. These bacteria resemble somewhat the gonococci, 
but are surrounded by a clear, unstained capsule like that of the pneu- 
mococci. Later in the disease, the same bacteria are found in the blood 
vessels everywhere. While it cannot be said that this diplococcus is 
the demonstrated etiological factor of measles, we may safely consider 
it so until later and more perfect researches confirm or refute its claim. 
One thing is certain, the pathogenic micro-organism of measles attacks 
the lining membrane of the respiratory tract, and its connecting mucous 
tracts. In these a self-limited inflammation is set up, which, however,, 
diminishes the resistance of the whole respiratory tract and its annexa. 
Secondary infection is therefore apt to follow in these regions 
page 688), especially those forms which occupy the lymph spaces. In 
the upper respiratory tract and the adjoining mucous membranes, 
secondary infection with the ordinary pus microbes frequently sets up 
suppurative otitis media, suppurative conjunctivitis, keretitis, laryn- 
gitis and pharyngitis. In the same regions diphtheritic inflammations 
are occasionally observed. Suppurative broncho-pneumonia and true 
specific pneumonia are observed as secondary infections in the lower air 
passages. "Measles is regarded by all authors as one of the frequent 8 
HOLMES, SECONDARY MIXED INFECTION. 
causes of secondary pneumonia in the child." (See, page 80.) It occa- 
sions more than one-fourth the cases of broncho-pneumonia in children. 
This pneumonia is a suppurative process, and is occasioned by the as- 
sumption of a pathogenic parasitism by the heretofore harmless sapro- 
phytic bacteria in the secretions of the respiratory passage. Babes 
found no other bacteria in the products of such cases of broncho-pneu- 
monia. Pneumonia should always be feared when the thermometer 
shows a rise of temperature after the first remission, or when the 
dyspnoea, cough, or circulation show any departure from what we con- 
sider a normal course of this disease. In some cases of broncho-pneu- 
monia, cough and hectic continue for along time, and upon post-mortem 
examination multiple small abscesses are found in every part of the 
lung, and, perhaps, in the mediastinal glands, with dilitation of the 
bronchioles and atelectasis. But pneumonia and pulmonary oedema 
are not always due to local origin. In certain cases they arise, as in 
scarlet fever, from the flooding of the venous current with suppurative 
bacteria from an abscess originating near the respiratory openings, or in 
distant bones and joints. Such cases are not infrequently reported. 
(Henoch, page 696.) 
Adhesive pleurisy is observed over the affected lung, while serous 
and suppurative pleurisies are relatively rare. The rupture of a suppu- 
rative broncho-pneumonic cavity into the pleural cavity has occasionally 
resulted in a pyo-pneumothorax. (Henoch, page 638.) 
When infection with the Bacillus septicwniiaz liemorragiccc takes 
place, all the symptoms of hemorrhagic infection follow in many or all 
parts of the body. The temperature is generally high, and all the secre- 
tions and excretions are mixed with blood. Sometimes the patient 
withstands this drain, and then falls into a typhoid condition. It has 
appeared as late in the disease as the third week. (Henoch, page 697.) 
All other forms of mixed infection are apt to follow. 
When a suppuration in the lung or a local phlegmon elsewhere 
occurs, the infection may be taken up by the lymphatics, and emptied 
into the blood current, where characteristic symptoms will result. A 
streptococcus abscess is likely to be followed by pyaemia, or, at least, 
by a glomerulo-nephritis, while other forms of infection produce malig- 
nant septicaemia. Ulceration sometimes takes place in the mucous 
membrane of the eye, mouth, and throat. Diarrhoea, or more properly, 
dysentery, is a remarkably frequent complication of measles. It is 
sometimes so excessive that it leads to collapse and death. Upon post 
mortem, an intense inflammation of the colon is found, with ulceration 
of the follicles and superficial lymphatics, and the] enlargement and 
even breaking down of the tributary mesenteric glands. (Henoch, page 
690.) 
But the most dreaded and frequent of all secondary infections 
which result from this disease, is tuberculosis. All authors notice the HOLMES, SECONDARY MIXED INFECTION. 
9 
frequency not only of pulmonary and laryngeal tuberculosis, but the 
remarkable disposition of tubercular disease to appear in the joints and 
and other organs on the arterial side of the lungs after this disease. 
This unusually numerous following of tubercular joint diseases is due 
to the formation of tubercular foci in the lung at the point of acquired 
diminished resistance and the transportation of the bacilli directly from 
the lung to the fated joints where traumatism has provided a suitable 
habitat. The tubercular infection is stored up in the lung tissue until 
degeneration of the primary focus allows a further dissemination. If 
this is the mechanism of this sad complication, we should expect it to 
occur as a rather late sequela. This is uniformally the case. 
As measles predisposes to all the lymphophytic forms of infection, 
we should expect to find it frequently combined in the same individual 
with those obligate parasitic diseases which are of this nature. Indeed, 
this is clinically shown to be the case with whooping cough. Associa- 
tion of measles with pre-existing disease usually makes a graver prog- 
nosis, and it is especially to be feared in those children that have suf- 
fered from exhausting diseases, such as diarrhoea, pneumonia, or tuber- 
culosis. Measles in most of these cases appears as a terminal disease. 
One of the rarer forms of secondary infection which occurs with 
measles is acute pemphigus. (Kleutfel,Steiner, Loeschner,and Henoch, 
page 692.) It appears either alone or with hemorrhagic infection, and, 
usually, rather early in the disease (3d to 8th day). Demme has dem- 
onstrated the presence of a bacterium which he thinks is the especial 
cause of Pemphigus acutus. Noma and erysipelas are sometimes ob- 
served, and gangrene may follow any extensive or acute form of infec- 
tion. (Henoch, page 696.) Nephritis is not an unusual concomitant of 
the various forms of secondary infection, and disease of the kidneys 
should never be considered as anything but a symptom of septicaemia. 
It is probably due in all cases to capillary embolism in the tufts of the 
glomeruli, either by living bacteria or dead products of their growth. 
The various forms of nephritis which accompany or follow measles are 
natural consequences of various forms of infection. In the mild and 
early septicaemia of measles the nephritis is mild, as in typhoid fever, 
pneumonia, and erysipelas. In each of these cases the etiological mo- 
ment of the disease has been demonstrated to be the true cause of ne- 
phritis. When a streptococcus infection follows measles, there may be 
a streptococcus nephritis exactly resembling that so frequently occur- 
ring after scarlet fever. Occasionly hematuria is observed as the only 
sign of septicaemia hemorrhagica. Most cases of suppurative pneumo- 
nitis are found post mortem to be accompanied by secondary bacterial 
nephritis; and there is no doubt that many cases of vicious or imperfect 
nutrition after measles, accompanied by occasional traces of albumen 
in the urine, are due to this cause. 10 
HOLMES, SECONDARY MIXED INFECTION. 
III. 
No form of secondary infection is so mournfully interesting as that 
which occurs after scarlet fever. Although scarlet fever is not so con- 
tagious as measles, the fatalities which follow it exceed those of measles 
by almost 50 per cent. The class affected is one which appeals to our 
sympathies in the highest degree. While the older members of the 
family are immune to this contagion, the helpless children are almost 
universally susceptible, and the remote consequences of the disease are 
obscured by the triviality of the onset. Diphtheria alarms by its rapid 
and terrible destruction, while the terrors of scarlet fever are put off 
for months, or even years. Therefore 'it behooves the State to defend 
its helpless youth by salutary laws, efficiently executed, and by a con- 
scientious, educated medical profession. 
During the last twenty years the death rate from scarlet fever has 
been diminished in the State of Michigan from 4.85 per 10,000 inhabit- 
ants per annum to 2.75. It is easy to estimate approximately the num- 
ber of lives thus saved to the State, but it stands to reason that a much 
larger number of individuals have been saved from nephritis, 
otitis, and resulting deafness, cervical adenitis and subsequent tubercu- 
losis, and many of the rarer accidents of the disease. With a death 
rate of two or three per 10,000 inhabitants, the charitable institutions 
of the State are still tilled with pitiable, helpless, and expensive citizens; 
and many are endured and supported at home by private charity. The 
saving of life alone, by the proper isolation of this disease, is not the 
only thing to be considered. We must also take into account the di- 
minished necessary charitable appropriation from the State treasury, 
and the indirect support, through private charities, of individuals who 
would otherwise become helpless and a charge to the State. There 
can be no doubt that the number of helpless, pitiable, and vicious indi- 
viduals now supported at the public charge is sufficient to demand an 
earnest consideration of this subject from every humanitarian and econ- 
omist. 
Scarlet fever begins as a septicaemia with a local lesion in the pha- 
rynx. We have every reason to suppose that it is due to the infection 
of a lymphophytic micro-organism. It seems to be an obligate parasite 
of man, but also a facultative parasite of some domestic animals. 
Netter has shown that the mouth, in a very large per cent, of individu- 
als, is constantly occupied by the Streptococcus pyogenes, which has 
been shown to be also a lymphophytic microbe (Baumgarten). It 
would be nothing more than natural to expect that the primary lesion in 
the throat would predispose to infection with the ever-present strepto- 
coccus. This, we find to be very frequently the case. No complica- 
tion of scarlet fever is so frequent as that which the clinicians have 
termed "cervical involvement." This cervical involvement, we arc 
told, appears any time after the appearance of the primary throat le- HOLMES, SECONDARY MIXED INFECTION. 
11 
sion. The intercellular mucous tissues of the pharynx are found 
crowded with chain cocci, which always occupy the intercellular 
spaces, and are usually non-destructive directly to the surrounding 
cell elements. My own examinations are in accord with what has 
been reported from all parts of the world. In seven cases of post- 
scarlatinal abscess in the region of the neck, which I have examined 
during the past three years, three have been accompanied by abscesses 
elsewhere. In all of these cases, I found the unopened abscess, and 
by aseptic operation made inoculation in nutrient gelatine. In every 
case, there resulted a pure culture of the Streptococcus pyogenes. Three 
of the seven cases were accompanied by abscesses elsewhere; one in 
the neighborhood of the right seventh rib and the cheek, one in one of 
the phalangeal joints, and one in the axilla. All of these abscesses 
contained the Streptococcus pyogenes alone, except the one in the 
cheek, which contained besides the Streptococcus aureus. Indirect 
cell division rapidly appears in the wall of the blood-vessels, 
and escape of the elements of the blood greatly increases the 
mass of the tissue invaded. Multiplying, as the streptococci do. by 
fission, and doubling their length every few minutes, they are able to 
force themselves rapidly forward in all directions from the point of 
primary invasion. Very early the cervical glands contain the multi- 
plying streptococci, and appear greatly enlarged. Until the surround- 
ing tissues are directly invaded, there is little periadenitis. In this re- 
spect the streptococcus lymph adenitis resembles that of tuberculosis. 
The whole cervical region on both sides of the neck may become infil- 
trated and indurated in a most incredibly short time. The formation 
of pus is, however, slow; and, at most, after weeks or months the 
intercellular spaces are filled with a sero-purulent exudate. The 
sheaths of the large blood-vessels are dissected up for a great length. 
The infiltration may advance to the origin and insertion of the muscles 
of the neck and pharynx, and when suppuration occurs, the pus may 
be discharged spontaneously into the throat. Large areas of skin may 
be separated from the underlying connective tissue, and in this way, its 
nutrition is cut off, and necrosis follows. Great black sloughs are apt 
to occur, which may extend nearly around the neck, following the line 
of a bandage, or the area of counter-irritation. When the slough is re- 
moved, the most perfect anatomical dissections are presented to view. 
Gravitation abscesses may occur, which, upon rupturing into the peri- 
cardium or pleura, result in all the sad consequences of infection of 
these large cavities. When the infiltration of the connective tissue of 
the throat has been sufficient to shut off the nutrition of the part, gan- 
grene has followed, with the enormous enlargement of the pharynx 
(Thomas, page 217). Among the milder symptoms of this infiltration 
are dysphagia, aphagia, and dyspnoea. (Edema of the glottis, destruc- 
tion of the epiglottis, and exfoliation of cartilage are not unknown 12 
HOLMES, SECONDARY MIXED INFECTION. 
(Gee, page 341). Not unfrequently the large blood-vessels of the neck 
are open by necrotic erosion, and sudden and fatal haemorrhage follows. 
When these serious and terrible appearances are combined in one clini- 
cal picture with the emaciation, the otitis, the suppurating joint and 
bone diseases, the terrible diarrhoea, or the nephritis, we have a picture 
from which the bravest physician would fain turn his face. 
If such serious and alarming destruction about the seat of the pri- 
mary lesion is rarely observed, the more insidious and delayed conse- 
quences of streptococcus colonization are sadly frequent. I shall be 
able to call attention in this limited time to but a few of the more im- 
portant. 
The number of mutes and of totally or partially deaf persons as 
the result of scarlet fever is very great. About one-third the inmates 
in the various public institutions are reported in this category. Of 
course, there are many who are incapacitated by defects in hearing 
without loss of speech. This number is still larger. These unfortunate 
individuals often receive credit for defective intellect instead of im- 
paired audition. This is especially the case in the public schools, 
where teachers have large numbers of pupils for a few weeks or a few 
months only. The stupidity and viciousness of many a pupil is the 
result of a failure on the part of parents and teachers to appreciate this 
defect. These children become useless and disagreeable, if not expen- 
sive and criminal citizens. They are directly or indirectly a burden to 
the State. It is worth our while, therefore, to study, even at some 
length, the cause of such a calamity as this. 
Coryza is not as frequent a symptom of scarlet fever as of measles, 
but an inflammation of the naso-pharynx is often observed which pro- 
duces a copious secretion. That this is due to the streptococcus infec- 
tion of the tonsil or pharynx, or extension of the infection along the 
pharyngeal muscles, there is no reason to doubt. The greatest danger 
lies in infection of the tissues along the Eustachian tube and the closure 
of its nasal end. Then follows destructive inflammation of the middle 
ear and its annexa, rupture of the drum, and protracted otorrhoea. 
Actual destruction may interrupt, or cicatricial contraction may impede, 
the transmission of sound to the internal ear, or more extensive infec- 
tion of the bone may actually destroy the internal auditory apparatus. 
The infection of the petrous portion of the temporal bone may interrupt 
audition by destruction of the auditory nerve. The petrosa is traversed 
by a number of other nerves and blood-vessels, which may be destroyed 
with the destruction of the bone. Thus results paralysis of that portion 
of the face supplied by the facial. The glandular apparatus may cease 
to operate, and mastication and taste become impaired. But these de- 
formities are scarely to be considered in comparison to the danger to 
life which follows infected thrombosis of the intercranial sinuses, in 
close proximity to the petrosa. Into any of these larger blood-vessels, HOLMES, SECONDARY MIXED INFECTION. 
13 
thrombi may protrude from the smallest nutrient vessels of the bone. 
About the protruding thrombus, the blood plaques collect until the 
the sinus is occluded. This white thrombus is infected, and, in time, 
becomes a generator of ptomaines, the absorption of which is mani- 
fested by constitutional symptoms. Later on it is broken down and 
scattered into all parts of the body, or gives rise to local suppuration, 
meningitis, or cerebritis. Frequently the, infection of bone advances to 
the periosteum and gives rise to no serious symptoms until by contact 
the meninges are infected from contiguous extension. It is even possible 
that distant portions of the brain may be infected through wandering 
phagocytes and the membranes remain intact. 
There is no doubt that the majority of cases suppurative otitis 
media arises by extension from the naso-pharynx to the eustachian 
tubes (Wolf, Centralblatt fuer Baderlologie und Idarasitenkunde, 3, 
page 545). The observation of Zaufal {Baumgarten's Jahresbericht, 3, 
1887, page 417) of the rare coccus of Friedlander and the capsule of 
Frankel in the secretions of the ear, and also in the coincident secre- 
tions of the nose, in extra clinical evidence (See also Rohrer, Centrlbl. 
f. Bad. u. Pajrasitenk., 3, p. 644). Habermann {Baumgarten's Jakres- 
berickt, 1, p. 83), in commenting on the etiology of tubercular otitis 
media, mentions the probability of the transportation of tubercular 
sputa up the Eustachian tube by coughing. Clinically this method of 
origin has long been recognized. Nevertheless, there can be no doubt 
that disease of the petrosa may arise by metastatic infection, and 
such a possibility should always be considered. 
Pneumonia is a rather rare complication of scarlet fever, and has 
not received as much attention as its theoretical importance in relation 
to nephritis and other lesions on the systematic side of the circulation 
would command. Early in the disease there is a catarrhal pneumonia 
as there is a catarrhal nephritis (Friedlander). This early pneumonia is 
due to the septiciemia of the pure scarletinal infection, and is usually 
coincident with the exanthema. The secondary pneumonia is the only 
form to be considered. It occurs rather late in the disease, usually in 
the second or third week. It is due to the infection of the venous side 
of the circulation with bacteria which have entered the walls of the 
pharynx and escaped through the cervical lymphatics and been poured 
out through the thoracic duct. The kind of pneumonia resulting de- 
pends upon the character of the infection. If it is a form which will 
produce local destruction in the lungs, small abscesses may be formed 
which may discharge through the bronchi or into the pleura. More often 
the infection is with the lymphophytic streptococcus. Then a broncho- 
pneumonia follows, which, though alarming, is not necessarily fatal. 
It may continue a very long time, even months, and is apt to be fol- 
lowed by tuberculosis. That this is the correct explanation of this com- 
plication the researches of Thaon and Pipping leave no room for doubt. 14 
HOLMES, SECONDARY MIXED INFECTION. 
In extremely rare cases a true specific pneumococcus pneumonia 
may occur in a patient recently affected with scarlet fever. This is, 
however, a remote chance, and I am unable to cite a case in which its 
demonstration has been made. Then, too, a patient suffering from 
diphtheria as a secondary infection is apt to have a diphtheritic pneu- 
monia from extension of the disease downward by aspiration. How- 
ever serious these accidents may be, they are too rare to require further 
mention. 
It is evident that a streptococcus pneumonia, however slight the 
local symptoms may be, is a very serious matter when we consider the 
remote consequences. The bacteria, of whatever kind, escape the 
capillaries of the lung and enter the arterial side of the circulation. 
Most of them are quickly included in phagocytes, and their multiplica- 
tion is arressed. It is well known that a traumatism is frequently the 
determining cause of the localization of infection. The function of the 
heart valves furnishes this factor. Upon their edges the streptococci first 
gain a foothold and thrombosis sooner or later begins. These infected 
thrombi are carried off in the arterial circulation and scattered in every 
part of the body. The valves themselves may become rapidly incom- 
petent, and compensatory hypertrophy of the heart may result. More- 
over, through the coronary arteries, the tissues of the heart may be 
directly affected, and coagulation necrosis and fatty degeneration, with 
resulting aneurism or sclerosis, follow, with serious interference to the 
heart's function. But the larger portion of the blood passes to the 
aorta, and infection may be carried to every part of the body. The 
spleen becomes enlarged, and shows its characteristic septicsemic appear- 
ance. The liver, kidneys, serous cavities and the brain do not always 
escape. Some of these forms of infection will be noticed in detail. 
In all the acute infectious diseases, nephritis appears as a constant 
and early symptom. In typhoid it is noticed in the first week, and the 
typhoid bacillus is then found in the urine by means of cultures. In 
small-pox, measles, typhus fever, and sometimes in whooping cough, 
an early nephritis has been observed. In these cases, however, no 
etiological factor has been discovered. The early nephritis in scarlet 
fever appears as a slight albuminuria in the early part of the first week. 
Purdy, however, mentions a case which came to section in the middle 
of the second day of the disease, in which all the evidences of glomerulo- 
nephritis were present. In these cases the lesions of the kidneys are 
usually slight, and they interfere very little with the course of the 
disease. 
Quite a different thing, however, is the post-scarlatinal nephritis. 
It appears about the end of the third, and only rarely later than the 
sixth week. Its appearance stands in no relation to the severity of the 
scarlet fever infection. The hypefexia of the disease disappears from the 
seventh to the eleventh day, and a week or more of convalescence inter- HOLMES, SECONDARY MIXED INFECTION. 
15 
venes before the gradual or sudden onset of nephritis. Some have noticed 
a slight irregularity of the temperature chart in those cases which later 
develop nephritis. Others assert that nephritis is apt to follow in case 
the cervical glands which have once subsided enlarge again. I shall 
endeavor to show that this disease is frequently due to capillary em- 
bolism in the tufts of the glomeruli resulting from the presence in the 
circulation of the Streptococcus pyogenes. 
We have already seen that the sub-mucous tissue of the pharynx 
and naso-pharynx, the cervical lymphatic, the lungs, the heart, the 
joints and bones, and especially the tissues about the middle ear, are 
invaded by the streptococcus with unusual frequency as a complication 
of scarlet fever. Let me add to these researches the direct examination 
of the blood. Escherich gives a complete account of the in- 
vestigations which have been published up to date of his essay on the 
presence of bacteria in the blood of patients suffering from scarlet fever. 
It appears that all authors have found the streptococcus in unusual 
numbers. Riess, Loeffler, Babes, Fraenkel, Cooke agree in the mor- 
phology of the microbe which they found by culture methods in the 
blood in the early weeks. There can be little doubt that it is one or an- 
other of the varieties of the Streptococcus pyogenes. 
Streptococcus invasion gives rise in other instances to glomerulo- 
nephritis. Baumgarten (p. 339) gives an account of such a case, from 
which I copy the accompanying figure. It occurred in a case of pyaemia 
beginning in an abscess of the face. The drawing is made from a sec- 
tion stained with methyl-blue. Both the afferent and efferent capillaries 
are distended with cocci. The distinct beaded form of the coccus can 
be made out in some of the central loops where there is less crowding. 
The nuclei of the vessel wall are unstained, showing that coagulation 
necrosis has taken place. 
Bamberger, Aufrecht, Litton and Perret find nephritis due to bac- 
terial origin, and have proposed such names as mycotische Nieren- 
nephrite parenchymateuse aigue, and nephrite bacterienne 
primitive. An inspection of the history of these cases as given by 
Perret shows, however, that those of Aufrecht were certainly second- 
ary, one to dysentery, and the other to suppurating tuberculosis. 
Mannaberg (Zur 2Etiologie des Morbus Brighti acutus. CentraTblatt fuer 
Klinische Medicin., 1888, No. 30) examined bacteriologically eleven 
cases of acute nephritis. In eight of these the streptococcus was 
found. Three gave negative results. The quantity of streptococci 
stood in direct proportion to the severity of the disease. In four of the 
cases in which the streptococcus was found, there were complications 
which furnished an entrance for the bacteria, and secondary bacterial 
nephritis followed. In one case "croupous pneumonia," in one eczema, 
in one syphilis maculo-pupulosa, and in one diphtheria accompanied the 
symptoms of nephritis. The biological character of the streptococcus 16 
HOLMES, SECONDARY MIXED INFECTION. 
differed slightly from that of the Streptococcuspyogenes or erysipelatls, 
and Mannaberg considers it a distinct species. His researches not 
only show the streptococcus to be a frequent cause of nephritis, 
but illustrate the variability of the species. Mircoli (Primaere 
mykolische Nierenentzuendungen der Kinder. CentraTblatt fuer Bac- 
teriologie und Parasitenkunde, HI, p. 336) describes a form of epidemic 
primary bacterial nephritis which attacked fourteen children in a vil- 
lage of three thousand inhabitants. Of these three died and micro- 
scopical examination of kidney showed acute parenchymatous nephritis 
originating about embolic foci of diplococci and chain cocci. 
Babes describes various forms of bacteria which he found in the 
blood-vessels of the kidneys in the nephritis following sepsis, rheuma- 
tism, yellow fever, and scarlatina. In pneumonia a form of nephritis 
is occasionally observed in which Klebs and others have found the 
pneumococcus of Friedlander. Nephritis frequently follows anthrax 
infection, and in these cases no one doubts that the anthrax bacillus is 
the prime etiological factor. 
The fact that few investigators are able to demonstrate the bacteria 
in sections of the kidney, the urine from which has been shown by cul- 
ture methods to swarm with them, is accounted for by Schweizer ( Virch. 
Arch., CX, and Centralblatt fuer Bacteriologie und 
III, p. 244). He says that they are removed by the osmotic currents 
which are set up in the processes of hardening, staining and mounting. 
In a single case of post-scarlatinal nephritis in a boy I removed 
the urine under every indicated precaution and immediately inoculated 
nutrient gelatine. The resulting cultures were exhibited to this Society 
at a recent meeting. Since that time inoculation has been made in 
the anterior chamber of the eyes of rabbits, and suppuration has twice 
resulted. In another case of post-scarletinal nephritis in a girl from 
whom the urine could not be taken with that care which is necessary to 
an accurate observation, the inoculated tubes were liquified and poured 
out upon plates, and although numerous other colonies were seen, the 
great majority proved themselves to be the Streptococcus pyogenes. 
These meager researches obtain any value only because they are in 
accord with the investigations of the most reliable bacteriologists. 
The frequency with which the streptococci are found in cases of 
pyo-nephrosis is a matter not entirely foreign to our subject. I have 
myself demonstrated the Streptococcus pyog&nes by culture in one case 
operated upon by myself and another operated upon by Dr. Fenger. 
It may not be as conclusively demonstrated as could be required 
by those who have not paid the strictest attention to the progress of 
pathological mycology during the past three years, but I believe the 
following theorems will be sustained by subsequent research. 
1. Nephritis and the concommitant albuminuria in the acute in- 
fectious diseases, erysipelas, typhoid fever, pneumonia, carbuncle and HOLMES, SECONDARY MIXED INFECTION. 
17 
puerperal septicaemia has already been shown to be due to embolic in- 
fection in the arterial tufts of the glomeruli and the resulting defect, 
and there is reason to believe that the same pathology prevails in the 
early nephritis of measles, scarlet fever, diptheria and rheumatism. 
2. In all cases of secondary infection after the acute infectious 
diseases when nephritis arises it is due to the escape of the products 
of secondary infection.into the systemic side of the circulation and the 
consequent embolism in the kidneys, and the resulting local disturbance. 
3. The presence of bacteria corresponding with the primary dis- 
ease or with the secondary infection in the kidney and in the urine is 
in no other manner explained. 
4. In post-scarlatinal nephritis the aetiological factor is the 
Streptococcus pyogenes or a microbe which cannot at present be dis- 
tinguished from it. 
I can only refer incidentally to secondary infection with other than 
the pyogenic bacteria. 
All authors mention the occasional appearance of haem'orrhagic in- 
fection (Smith, p. 509; Thomas, p. 210, 225, 227). In these cases there 
is haemorrhage from all the excretory and secretory organs of the body. 
The skin, mucous membranes and conjunctiva are separated from the 
underlying tissue by larger or smaller extravasations of blood. Coin- 
cident haemhorrhage in the kidneys gives rise to a haematuria which is 
entirely distinct from that which occurs in the ordinary streptococcus 
nephritis. In the intermuscular fascia such extensive extravasation 
appears as to give rise to symptoms of acute anaemia. Riess has made 
a most perfect demonstration of the infection in the blood. Abercrom- 
bie says, "Changes in the blood-vessel take place in scarlet fever, 
measles and whooping cough, but especially in diphtheria, resulting in 
haemorrhage." And he looks upon cerebral hemorrhage in children as 
frequently due to this cause. Such haemorrhage within the cranium 
may result in sudden death (Henoch, p. 256) or permanent paralysis 
with the formation of scar or cyst, and subsequent general cerebral 
sclerosis manifested by epilepsy and insanity. The young are most 
often affected with this form of infection, but a fata] case of septicaemia 
haemorrhagica after scarlet fever is reported by J. L. Smith (p. 509) in 
a man 32 years old. 
Secondary infectin with noma, diphtheria, pemphigus and ery- 
sipelas, present no unusual anomalies. Perhaps the relation of diph- 
theria to scarlet fever has already furnished a sufficient ground for 
discussion. 
The most interesting and frequent secondary infection of all, yet 
remains to be noticed. Should the little patient escape all the dangers 
of suppurative otitis, streptococcus pneumonia and nephritis, and the 
pyogenic infection of bones and joints, the general and local resistance 
of the tissues may be so greatly impaired that be falls an easy victim to 18 
HOLMES, SECONDARY MIXED INFECTION. 
the attack of the tubercle bacillus. The enervating influence of the 
general disease is greatly aided in this matter by the lymphophytic in- 
fection of the pharyngeal cavity by the streptococcus. The tonsils and 
folds of the pahrynx furnish a reservoir for tubercular food, and that 
temperature is maintained which is most favorable to tubercular 
growth. Is it a wonder, then, that tubercular cervical lymphadenitis is 
such a frequent sequela? of scarlet fever ? In measles pulmonary tuber- 
culosis follows, but in scarlet fever we are accustomed to look for a 
precursor of scrofula. 
In following back the history of tubercular infection outside the 
lungs, I have been surprised to find that ahistory of scarlet fever could 
frequently be elicited which had escaped the recognition of the attending 
physician and the family at the time. There is every reason to believe 
that tubercular infection of the young rarely appears as a primary dis- 
ease, but always or almost always follows the train of measles, scarlet 
fever, typhoid fever, diphtheria and especially of cholera infantum. 
IV. 
MUMPS. 
Mumps clinically answers all the requirements of a parasitic dis- 
ease. The aged and infants are immune to its attacks. It is generally 
looked upon as a trifling and ridiculous affection, but it is followed by 
complications scarcely less formidable than those already noticed. 
Every physician of experience has noticed the occasional enlargement 
of the cervical lymphatics after mumps, and has doubtless recognized its 
tubercular nature. Pyogenic infection also appears not only in the 
parotid and other salivary glands, but in the adjoining tissues, and des- 
truction of the auditory apparatus occasionally follows through suppu- 
rative otitis media (Henoch and Eichorst). 
Infection of joints is not unknown, though fortunately very rare. 
My own experience with the secondary infections in mumps is con- 
fined to two cases. One case of bilateral epidemic parotitis was fol- 
lowed by tubercular infection of the cervical and submaxillary glands, 
with subsequent breaking down and discharge through the skin. The scars 
resulting from the protracted discharge were so deforming that surgical 
relief was sought. The other was a case of right-sided parotitis, which 
was followed by tubercular infection of the gland itself or a portion of 
it. The patient was living at the time in Scotland, and was under the 
care of Sir McLeod. His advice and prognosis shows that he 
recognized the nature of the disease at the time. Later it broke down 
and ran the ordinary course. I saw the patient soon after arriving in 
this country from Scotland, and several years after the onset of the 
disease. He was a robust young man. Near the old scar, and appar- 
ently in the body of the parotid, there was a firm, hard tumor half an 
inch in diameter. I diagnosed tubercular disease, and advised imme- HOLMES, SECONDARY MIXED INFECTION. 
19 
diate removal of the tumor and the old scar, which had a very repulsive 
appearance. The. patient's family would not consent. Six months 
later the tumor was two inches in diameter and much softened down. 
It was then opened, and has continued to "discharge" ever since. In 
both of these cases there is not the slightest doubt there was a secon- 
dary infection at the point of diminished resistance. One may ask 
where the bacilli entered the body. We can suppose that the patient 
was entirely free from tuberculosis until the parotitis gave entrance to 
the bacilli through the gland or some adjoining tissue which was no 
longer protected by the secretions of the gland. Foetor ex ore is often 
produced on account of the inability to keep the mouth clean (Eichorst, 
p. 189). My second case would seem to be an example. Or we can 
suppose the infection of the cervical glands, with latent tuberculosis, 
which sprung up when the local inflammation and the general de- 
pression of mumps gave a favorable opportunity. 
The ordinary train of secondary infections is observed by all sys- 
tematic authors as sequela? of epidemic parotitis, pneumonia, endocar- 
ditis, ostitis, arthritis, nephritis, and local infections. Nuritis espe- 
cially, especially retinitis, seems to be remarkably frequent. 
I regret that time does not allow me to consider the serious secon- 
dary infections which have been observed in whooping cough and diph- 
theria. Just one word in regard to the summer diarrhoea of infants, 
and I am done. Like puerperal fever, this is a disease which does not 
depend upon a single etiological factor. Beginning as an intoxication 
from the absorption of the products of putrefaction in the intestinal 
canal, it goes on as an infection of the mucous membrane of the bowel 
when the physiological resistance has been diminished by general intox- 
ication and perverted nutrition. Later than this, a general infection of 
the blood and lymph may follow, with all the sad consequences of sep- 
ticaemia. When the little sufferers escape the primary disease, they fall 
easy victims to the attack of tuberculosis, which their milk so abundantly 
contains. 
With this brief and imperfect review of the subject I leave the 
matter with the following suggestions :- 
1. That, as there are no known means of averting the dangers of 
secondary infection, every effort which the State and the medical pro- 
fession can use should be exerted to isolate and prevent the primary 
disease. 
2. That when a patient is suffering from any one of the primary 
diseases, every effort should be made to sustain the vitality and 
strength of the patient at the highest point, and exclude and eliminate 
all avenues by which the secondary infection is known to arise. 
3. That, as the evidence now stands, all the complications of these 
diseases are due to secondary infection, and the examination of patho- 
logical products by the aid of bacteriological methods offers the 
greatest, if not the only hope of that thorough knowledge which is 
necessary to a proper therapy. HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
21 
ADDITIONAL NOTES ON SECONDARY MIXED INFECTION. 
BY BAYARD HOLMES, M. D. 
Perhaps nothing is more difficult to the beginner than to stop when 
his theorem is demonstrated. The importance of secondary infection 
as a factor in nearly all the complications of disease is continually 
forced upon me and I cannot resist bringing the subject again before 
my readers as if enough had not already been said. 
In confirmation of my conclusions in a late number of this magazine 
on secondary infection in some of the acute infectious diseases of chil- 
dren, I beg to be allowed to call attention to a recent publication of 
Babes* which unfortunately fell into my hands too late to be incorporated 
in my original thesis. 
These investigations were carried out some time ago and attempted to 
show the bacteriological condition of the dead bodies of children. It 
was repeatedly demonstrated that the cadavers of children that had 
suffered no previous disease were free from bacteria for a long time in 
winter and from four to ten hours in summer. The condition was very 
different in case they had suffered especially from one of the acute 
infectious diseases. In these cases Babes found the spleen, kidneys, 
liver, lungs, and blood infected with numerous colonies of streptococci 
putrefactive bacteria, capsule-cocci, more rarely staphylococci and 
various bacilli. Without doubt the most of these stood in a relation of 
sequence to the general and primary disease. Of special interest is the 
study of the manner of localization and spread of the secondary infec- 
tion and the peculiar sequence of the infection after different primary 
diseases. For example, in eight cadavers, every one contained one or 
more bacteria in the internal organs. In two cases of diphtheria, the 
bacillus of diphtheria was found ; in one case of septic omphalitis, the 
bacillus of green pus ; in six cases of different kinds, the Streptococcus 
pyogenes; in one, the Staphylococcus aureus; and in five cases, various 
putrefactive bacilli. In many cases it was possible to recognize the 
point at which the different secondary invasions of the body had taken 
place. For example, in a case of sepsis after scarlet fever in which 
streptococci were found in every part of the body and in places mixed 
with a few saprophytic bacilli, a pure streptococcus pneumonia was 
found in the lower part of the left lung, while a number of foci were 
found in the upper part of the right lung swarming with bacilli alone. 
Thus in one part of the lungs was a pure culture of the streptococcus 
♦ Bacteriologische Untersuchungen ueber septische Processe des Kindesalters, von Dr. V. Babes, Director des 
bacteriologischen Institutes in Bukarest, mit 21 farbigen Abbildungen im Text. Leipzig, Veit & Comp. 1889. 22 
HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
and another part furnished the bacilli. From these separate foci the 
infections spread to every organ on the systemic side of the circulation. 
In another case of sepsis after scarlet fever, a submaxillary gland 
was found degenerated and filled with streptococci and putrefactive 
bacteria. In a third case, the same conditions were found in an inter- 
bronchial gland. In both these cases microscopical examination and 
bacteriological investigation showed that the gland and the surrounding 
lymph channels were crowded with streptococci and putrefactive bac- 
teria, and the same forms were found in almost every organ of the 
body. 
It is a most significant fact that out of thirty-four deaths from scarlet 
fever not one of the cadavers was found free from septic infection. The 
largest internal organs were found full of septic bacteria and often fur- 
nished more than one kind. I would call attention especially to the 
cases of nephritis after scarlet fever (loc. c. pp. 4-17.) Let me give a 
brief abstract of a few. 
1. Eight-year-old boy. Haemorrhagic scarlet fever with severe pharyngitis. The 
submaxillary connective tissue infiltrated, resistant, reddened. Temperature of sepsis 
Urine scanty, with abundant albumin and hyaline casts. Post mortem: Spreading out 
from the submaxillary tissues, were numerous sinuous abcesses which were filled with a 
thin pus. The tributary mediastinal glands were enlarged to the size of hazel nuts and 
some of them were cheesy. The spleen was enlarged, congested and softened. The 
kidneys were moderately enlarged and pale, and the capsule stripped off with difficulty. 
The cortical substance was pale, brownish, friable, and oedematous; the pyramidal 
portion, reddish. Out of the papillae, pus-like semi-fluids were easily pressed. Safranin 
or scarlet staining demonstrated rose red masses in the intima of the larger blocd vessels 
of the kidney. The tissues about these vessels were moderately infiltrated with 
mononuclear and polynuclear round cells. Marked changes were found in the 
glomeruli especially. Both the perithelial and endothelial cells were multiplied and 
enlarged. The Malpighian tufts were crowded in places with polynuclear leucocytes. 
Some of the glomeruli were very small and atrophic with destruction and sclerosis of the 
capsule and especially of the tufts, while others were very much smaller than normal 
though no changes in their structure could be recognized. Bowman's capsule was thick- 
ened in most cases and frequently contained red blood corpuscles. The epithelial cells 
of the capsule were enlarged and multiplied. Round cells were frequently observed 
around the hilus of the glomerulus and infiltrating the surrounding intercellular spaces. 
The epithelium of the convoluted-tubules was granular and swelled, staining by Gram's 
method and afterwards with safranin demonstrated no bacteria. Cultivations made 
from the kidneys, spleen and other internal organs in artificial nutrient media as well as 
inoculations in animals demonstrated the presence of the Streptococcus pyogenes in all of 
these organs, beside two bacilli that proved pathogenic to mice 
2. An eight-year-old girl suffered from albuminuria and anasarca the second week 
after scarlet fever. Three days before her death she was attacked with croup. At the 
post mortem, chronic bronchial catarrh and bronchiectasis, with croupous bronchitis, 
was demonstrated in different parts of both lungs. The kidneys were greatly enlarged, 
the capsule easily stripped off. The cortal substance was somewhat thickened, yellowish 
brown and granular. Cultures were made from the croupous products of the lungs, 
from the enlarged bronchial gland, from inflammatory products of the lungs, as well as 
from the oedematous subcutaneous connective tissue and from the kidneys. In all of 
these, except in the croupous products of the lungs, a pure culture of the Streptococcus 
pyogenes was found. In this locality alone Loeffler's bacillus was also present. 
3. In a five-year-old girl, anasarca appeared while desquamation was still going on, HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
23 
ten days before death. The urine was passed in moderate quantities. It was turbid 
and highly colored. Specific gravity, 1.030. Much albumin, hyaline casts and blood. 
The post-mortem showed chronic tuberculosis of the bronchial glands, sclerosis of the 
apex of the right lung, and fibrinous and serous pleuritis on the right side. The kidneys 
were much enlarged; their surface yellowish white; the capsule easily stripped off, 
leaving the cortex glistening. The cortical substance was very thick, friable and 
oedematous. By microscopical examination, many groups of the larger blood-vessels 
especially of the pyramids, showed amyloid degeneration of their walls; and, in the 
same neighborhood, the smaller blood-vessels were filled with thick, hyaline, fibrinous 
masses. In other small blood-vessels in the same neighborhood, were found thick masses 
of streptococci. Similar masses filled some of the blood-vessels leading to the glo- 
meruli. The endothelium of the vessels was often multiplied and detached from the 
walls. The glomeruli were changed in different ways. They were either simply atrophic and 
sclerotic, or they were surrounded and compressed by a sclerotic capsule. The tufts 
were for the most part amyloid degenerated. Their lumen was obliterated and filled 
with hyaline masses. In other places the vessels were most changed at the hilus of the 
glomerulus. In some glomeruli there was no amyloid degeneration, but the capsule as 
well as the tuft was transformed into young, spindle-celled connective tissue. From 
the shedding of the epithelium of Bowman's capsule, a spindle-celled proliferation was 
observed. Similar changes were found throughout the kidneys. 
From all the pathological products cultivations were made in blood serum and agar. 
From the kidney there developed, in the depth and on the surface of the agar, small 
glistening points composed of streptococci, while from the pneumonitic foci and from 
the pleuritic products developed, beside the streptococci, scarcely distinguishable colo- 
nies which were composed of capsule-cocci. These latter bacteria killed guinea pigs in 
twenty-four hours, while the streptococci produced only insignificant local inflammation 
and oedema. A moire inoculated with the streptococci remained healthy. 
4. In a nine-year-old girl that had been one and a half months recovering from the 
scarlet fever, anasarca suddenly appeared seventeen days before she came to the hospi- 
tal. On her admission desquamation and left-sided pneumonia were observed. The 
urine contained at that time a little albumin and a few hyaline cylindrical casts. At 
the post mortem, the upper lobe of the left lung was found in the condition of gray hepa- 
tization. The changes in the kidneys were very slight. They were scarcely at all 
enlarged. The cortical substance was pale, rigid and breakable. The pyramids were 
reddened. The left heart was enlarged and its walls thickened. The cell multiplication in 
the larger blood-vessels of the kidney was slight, though there appeared in the neighbor- 
hood of numerous glomeruli wide zones of mononuclear round cells. The glomeruli 
themselves were unusually rich in cells, and they filled the capsule completely. The 
epithelial cells of the capsule itself were multiplied and granulation tissue was found 
between it and the tufts. Numerous conical infarcts were found pointing from the sur- 
face of the kidney. These were composed of cells, degenerated and lifeless, and 
inclosed by a granulation border. From the kidney and spleen a pure culture of the 
streptococcus was found, while from the pleuritic exudate was cultivated a lance-shaped 
capsule bacterium. From the lungs there was also raised a third kind of bacteria. It 
grew on the surface and in the depth of the agar as a golden yellow point, and it was 
proved non-pathogenic. 
7. A seven-year-old boy was attacked with a heetnorrhagic tonsillitis, which soon took 
on a diphtheritic character eleven days before his death. In the submaxillary region a 
tumor as large as a hen's egg developed which suppurated three days before his death. 
The surrounding tissues were filled with a phlegmonous exudate. At the post mortem 
the abscess and phlegmon in the submaxillary region was found filled with ichorous pus. 
The blood-vessels in this region, especially the veins were filled with infected thrombi 
haemorrhagic infarcts were found in the lungs and spleen. The latter organ was greatly 
enlarged and softened. Suppurative peritonitis was present, and the kidneys were 
doubled in volume. The capsule was stripped off with difficulty, and left a smooth sur- 
face with here and there depressions, evidently resulting from exposed foci. The 24 
HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
Fig 1. 
Fig. 1. From the amyloid kidney of case 3. Drawn from the colored engraving of Babes. In 
the centre is seen the glomerulus with the amyloid tuft and thickened capsule. In the upper left- 
hand corner is a portion of an enlarged vein. In the upper right-hand corner are two urinary 
tubules, with the thickened walls. In the lower left-hand corner and extending upward are seen 
masses of streptococci filling a little blood-vessel, the walls of which are fast becoming granula- 
tion tissue. 
Fig. 2. 
Fig. 2. From the colored drawing of Babes. Case 7. From a case of post scarlatinal nephritis. 
In the centre and on the left-hand side of the drawing are seen two connecting blood-vessels filled 
with streptococci. It will be noticed that the epithelium of the urinary tubules in the region of 
the occluded vessels is lifeless, the nuclei taking no stain, while a little farther away the nuclei 
are intensely stained. In the lower part of the figure multiplication of the connective tissue is 
noticed. HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
25 
cortical substance was yellowish-white, markedly injected in places and very much 
thickened. It was succulent and friable. The pyramids were livid, and appeared 
whipped out at the base. The larger blood vessels of the kidney were surrounded with a 
thick mantle of granulation tissue, for the most part composed of polynuclear cells. In 
the interior of the large veins were found masses of streptococci attached to the wall. 
In the small blood-vessels, especially in the medullary substance, they filled the lumen 
completely (See Fig. 2). Where the blood vessels were filled with red corpuscles, the 
streptococci could be seen reaching forward in long chains. In the region of these foci 
the epithelium of the urinary canal was coagulated and the nuclei had disappeared. In 
the interior of Bowman's capsule, as well as in many of the urinary canals, were found 
blue hyaline masses. The epithelium was everywhere swelled and fatty degenerated. 
Between the urinary canals there was frequently observed a rich proliferation of the 
connective tissue. 
From the infiltrated submaxillary tissue a white mouse and a guinea pig were inocu- 
lated. Both died with all the symptoms of sepsis, the mouse after one and the guinea 
pig after ten days. Another mouse inoculated from the infected mouse also died on 
the next day. From the internal organs of the latter animal a pure culture of the 
streptococcus was cultivated. A direct culture from the infarcts in the spleen, from the 
submaxillary phlegmon, from the pleuritic exudate and from the kidney gave a pure 
culture of the streptococcus Besides the streptococcus there was also found in the 
suppurated pleuritic exudate a micrococcus in the form tetrads without capsules. 
These were stained by the method of Gram. They were about seven to eight-tenths 
micromillimeters in diameter and grew in thin flat flakes on the surface of the agar and 
gelatine. Mice inoculated with them died in from two to four days with septic 
symptoms. 
Animals inoculated with the streptococci taken from this case by means of a platinum 
needle presented reddening and oedema in the region of the inoculation. Mice died two 
to six days after inoculation, with septic symptoms, while guinea pigs died in from two 
to six days, with an inflammatory oedema spreading out from the inoculated ear. At 
the post-mortem of these animals the spleen was always found greatly enlarged and 
there was a serous or fibrinous exudate in the serous cavities. The streptococcus re- 
tained its pathogenic action for six generations or for two months and a half while later 
cultures produced only local inflammation and rarely resulted in the death of the ani- 
mals inoculated. A single other culture was continuously planted for two years and 
was found as virulent as ever at the end of that time. 
I should like also to call attention to an article by Raskin in a recent 
number of the CentraTblatt fuer Bakterlologie and Parasitenkunde. * 
She prefaces her remarks by calling attention to the investigations of 
.Heubner, Litten, Croocke, Henoch, Burkhardt-Merian, Virchow, 
Friedlander, Bokai Babes and others. She points out the uniform tes- 
timony of all these investigators as to the presence of the streptococcus 
in the pathological products found in connection with scarlet fever. 
She calls attention also to the investigations of Klein and Babes and 
considers their conclusions at length. Both these authors found the 
streptococci in the blood of scarlet fever patients and considered them the 
cause of the disease. The researches of Klein and his school were famil- 
iar to all my readers. Raskin says that from a theoretical point of 
view the streptococcus infection must either be secondary to scarlet 
fever and in no casual relation to it or it is the setiological factor of the 
disease. Her own researches would seem to demonstrate the former 
proposition. 
*Klinsche experimentelle Untersuchungen ueber Secundar-infection bei Scharlach, Von Dr. 
Marie Baskin in St. Petersburg. Centralblatt fuer Bakteriologie und Parasitev kunde. V. Band. 
No. 13 and No. 14 March 28th, 1889. 26 
HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
She has examined in all ninety-two cases of scarlet fever. Thirty-one 
of these presented the following complications: Seven cases, suppur- 
ative lymph adenitis; four cases, diphtheria of the pharynx ; one case, 
laryngeal diphtheria with broncho-pneumonia ; two cases, suppurative 
joint inflammation; one case, serous joint inflammation ; one case, 
fibrinous pleurisy; four cases, pyaemia; three cases, septicaemia; seven 
cases, otitis media-one of which was complicated with facial erysipelas. 
In twenty-three cases the blood and pus was examined microscopically 
and by cultures. In those cases that ended fatally sections of the 
internal organs were examined. In twenty-eight cases the scales, and 
in six the skin, and in sixty-four the blood alone was examined. All of 
these examinations were conducted with the strictest attention to the 
possibilities of air and contact infection. 
Raskin comes to the following conclusions from her clinical and 
experimental researches:- 
1. The malignant complications of scarlet fever, viz, suppurative lymphangitis, puru- 
lent otitis, suppurative synovitis, broncho-pneumonia, pleuritis, pyeemia and septicaemia 
and perhaps also diphtheria and serous synovitis, are produced by secondary infection 
with a streptococcus ; and, moreover, other bacteria also may take part in the produc- 
tion of some of these processes; for example, the pyogenic staphylococci in otitis, the 
Micrococcus pyogenes tenuis in pyeemia, and a septic bacillus in septicaemia. 
2. The streptococci enter the body through the primarially inflamed fauces; they 
spread by way of the lymph-channels and are thence poured into the blood streams. 
3. When the streptococci are once in the blood, three possibilit'es remain to be con- 
sidered: a. They may disappear without any other effect than a more or less pro- 
nounced modification of the temperature, b. They may multiply rapidly in all parts of 
the body and produce death by general septic infection, c. Or, what is more frequent, 
they may produce death by pyaemia. 
4. The streptococcus which is found associated with scarlet fever, appears to be a 
variety of the well-known Streptococcus pyogenes or erysipelatis. 
5. It stands in no casual relation to scarlet fever. 
These conclusions are perfectly in accord with my own ideas pub- 
lished in the February and March numbers of The North American 
Practitioner, and in connection with the investigations of Babes they 
furnish all the evidence necessary to the demonstration of every one of 
the theorems laid down in that essay. 
The recently published researches of Prudden and Northrup on the 
aetiology of diphtheria* gain a new significance when considered in con- 
nection with the subject of secondary mixed infection. Although the 
article is fresh in the minds of all my readers, I hope I may be par- 
doned in giving a very brief outline of the work and then be allowed 
to suggest a possible reconciliation with other well established facts. 
In all but two out of twenty-four cases of diphtheria examined, a 
streptococcus was found in large numbers in the pseudo-membrane. In 
most of the cases where examination was made of the kidneys, spleen 
*0n the Etiology of Diphtheria, an Experimental Study, by T. Mitchell Prudden, M. D., Direc- 
tor of the Laboratory of the Alumni Association of the College of Physicians and Surgeons, New 
York. The American Journal of the Medical Sciences, April and May, 1889. HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
27 
and liver, a pure culture of the same streptococcus was raised. In the 
examination of the throats of thirty-one well and sick children not 
affected with diphtheria, only twice was the streptococcus found and 
then in the scrapings from the throats of children suffering from scarlet 
fever. From the scrapings from the throats of twenty-four healthy chil- 
dren, not a colony of streptococci. In only two cases of diphtheria, 
Nos. XVI and XVII, were no streptococci found in the pseudo-mem- 
brane. The author would explain this either by imperfect observation 
or on the supposition that these were cases of k ' croup. " While the 
streptococci were usually present in enormous numbers in the pseudo- 
membrane and the surrounding tissues, they were found only sparingly 
in the viscera. "This condition of affairs, taken together with early 
severe symptoms of systemic infection and the lesions of parenchy- 
matous degeneration of the viscera, especially the kidneys, which are 
apt to occur in diphtheria, would seem to indicate that the systemic 
changes are due to the absorption of some soluble poison (ptomaine), 
produced where the streptococci are most actively growing, namely, at 
the scat of the local lesion, or possibly, as will be seen later in the 
lungs." (1. c. May, p. 459). Prudden concludes that the streptococcus 
is the essential (etiological factor in diphtheria and names it Strep- 
tococcus diphtheria. 
To begin with, the entity of diphtheria is not established. The very 
fact that it is so destructive of life would point to its facultative origin. 
It is an axiom that a destructive obligate parasitism cannot exist for 
any length of time where the means of localization are not greatly 
limited. If we assume that diphtheria is a distinct entity and an acute 
infectious disease of man, and therefore an obligate parasite of man, 
we must cut off from its essential features all those destructive compli- 
cations which make it such a terror to every medical man and parent. 
Then true uncomplicated diphtheria is a simple and non-destructive 
disease, which is malignant only as there is added to it the secondary 
infections which are so dreadfully frequent in other cases under the 
surroundings of modern civilization. Should such a demonstration be 
made by future researches, many facts would be brought into concord, 
viz., various manifestations of the disease in different places and at 
different times in the same place; the discovery of different forms of 
microbes by different investigators, the lack of coincidence in the 
appearance of the streptococci in the blood, and the symptoms of systemic 
infection; the appearance of the same or a similar streptococcus in the 
secondary infections after scarlet fever, measles and mumps. 
Nothing has been said as to the reliability of the work of Dr. 
Prudden. It bears intrinsic evidence of its thoroughness and con- 
sciencious care. It is very difficult for us to appreciate the amount of 
labor these researches have required. It is a matter of true courage to 
deal daily with poisons which are not to be compared with the most 28 
HOLMES, NOTES ON SECONDARY MIXED INFECTION. 
deadly chemicals. Our gratitude is the least we can offer such devo- 
tion. The appearance of the streptococci, under the circumstances 
mentioned, is not to be doubted for a moment. The demonstration is 
adequate. Only one thing would it be possible to oppose, namely, the 
conclusion. 
It seems to me possible that the true, aatiological factor of diphtheria 
(if such an acute infectious disease is extant) is a parasite which will 
not grow on any artificial nutrient material. The bacteria so far found 
in the false membrane, and in different organs of the body, are sapro- 
phytic microbes which have the power of becoming pathogenic only 
when the primary invasion has prepared a way in a point of diminished 
resistance. This, I believe, is the role of the streptococcus which 
Prudden has found so uniformally. If this is not the case we are 
brought face to face with the fact that streptococci, which cannot be 
distinguished from each other by any known morphological, culture or 
staining methods, or by inoculation on animals, produce in one case 
suppuration pyogenes), in another erysipelas without 
suppuration (/S', erysipelcbtis), and in another, diphtheria (& diph- 
theria}). 
This brief discusssion points to a time when all our resources will be 
directed toward securing as efficient antiseptic conditions in medical 
cases as we are able to promise to-day in surgery and obstetrics. 
LITERATURE. 
Henoch, Dr. Eduard : Vorlesungen uber Kinderkrankheiten. Berlin, 1889. 
Thomas: In the Cyclopaedia of the Practice of Medicine, von Ziemssen, American 
translation. New York, 1884. 
Smith: Pepper's System of Medicine. 
Eichhorst: Handbook of Practical Medicine. New York, 1886. 
Baumgarten: Lehrbuch der pathologischen Mykologie. Braunschweig, 1888. 
Perret: Nephrite bacterienne primitive. Lyon Medical, tome Lix, 1888, p. 319.