Environment and Resistance 
IN 
Tuberculosis 
A 'presentation of the nature of environment and resistance 
and their relation to the pathology, diagnosis, symptoms, 
and treatment of tuberculosis 
BY 
ALLEN K. KRAUSE 
BALTIMORE 
WILLIAMS & WILKINS COMPANY 
1923 Copyright 1923 
WILLIAMS & WILKINS COMPANY 
Made in United States of America 
All rights reserved, including that of translation 
into foreign languages, including 
the Scandinavian 
COMPOSED AND PRINTED AT THE 
WAVERLY PRESS 
By the Williams & Wilkins Company 
Baltimore, Maryland, U. S. A. Contents 
Page 
I. Environment 7 
II. Resistance 39 ENVIRONMENT Environment1 
THE discovery of the tubercle bacillus made 
environment a new force in tuberculosis. 
Our surroundings took on importance ac- 
cording to their power to infect. An environment 
of dirt and darkness and overcrowding became an un- 
failing reservoir of germs and therefore of consump- 
tion; or, as an old saw put it, “Clean up your lung 
blocks and you’ll clean up tuberculosis.” 
But with more understanding of the ways of 
tuberculosis came another view of the influence of 
environment. Not all denizens of our most notori- 
ous “lung blocks” fell prey to consumption. In fact, 
the greater number of them never showed a symptom 
of it, and lived to die of other things—of accident, 
of Bright’s disease, of pneumonia, and what not. 
Yet, as we learned new tricks, we found that 
nearly all these refractory subjects were tubercu- 
lous: they had tubercle bacilli in them and seemed 
to keep them. What then, we asked, makes a 
consumptive? Surely not mere infection with the 
1 Revision of an address delivered at the General Meeting of 
the North Atlantic Tuberculosis Conference, Richmond, Virginia, 
October 7, 1920, and published under the title, “Environmental 
Factors in Tuberculosis,” in the American Review of Tuberculosis, 
November, 1920, and the Journal of the Outdoor Life, November, 
1920. The address was originally prepared as part of a sym- 
posium on the topic, “The Basic Cause of Breakdown with 
Tuberculosis: Is it Malnutrition? Is it Heredity? Is it Environ- 
ment?” 
7 8 
ENVIRONMENT 
right germs, for here are hundreds and thousands in 
just this fix, yet not down with illness. Again we 
called upon environment: it was environment which 
reacted upon some in a way that laid the body more 
open to the evil effects of their tubercle bacilli 
until the latter brought them low. As a catchword 
of tuberculosis etiology environment has earned a 
distinction second only to “nonresistance.” 
But what shall we understand by environment? 
It certainly does not mean the same thing to all 
men. Perhaps its scope cannot be strictly defined; 
no doubt, too, there is no general agreement as to 
its scope. To various men it will convey an im- 
pression of larger or smaller domains. 
Not long ago I got to discussing the causes of 
tuberculosis with several men who are in the fore- 
front of our work. After a good hour’s interchange 
of ideas it became plain that each of us cherished his 
own concept of what comprised environment and 
that no two notions coincided at all points. I was 
then told what was really altogether new to me. 
This was that to a large number of our most active 
and most competent antituberculosis workers en- 
vironment from beginning to end meant nothing 
more than those physical objects which encompass 
human beings—more concretely, the cities, the 
streets, the houses and backyards, the rooms in which 
we live and move, the baths, the windows, the stoves, 
the furniture, the clothing, the space, air and sun- 
light which people may or may not have. I learned 
that there was a certain aggregate of all this gear ENVIRONMENT 
9 
which made up a standard of what is called good 
hygiene and that a falling short of the standard spelt 
poor hygiene. I heard further that not a few public 
health workers believed that if good hygiene, as I 
have outlined it, were brought to pass and were kept 
up, tuberculosis as a disease would be checked. 
And, in answer to my inquiry as to who believed 
this, one or two eminent names were cited. 
Now everyone would admit that a thorough 
cleaning up of our physical environment would in 
time bring about a disappearance of tuberculosis, 
simply by removing all chances of contact with 
tubercle bacilli, even though no other influence were 
exerted upon us. But I take it that this evening 
light is desired, not so much on how environment 
may establish or do away with opportunities for 
infection, as on how it may convert a well though 
infected man into a sick one or promote those condi- 
tions which permit infection to assume a more or 
less progressive course. Our task is to discover 
whether environment is in any way responsible for 
the circumstance that many tuberculous persons 
fall ill though most remain in health. And, in 
examining environmental factors, we must of neces- 
sity pay attention to such purely external surround- 
ings as we have just named. 
Yet surely, for our present purpose, this is much 
too narrow a view to take of environment. There 
may, for instance, be an environment of disease—of 
measles, of septic infections, of the common cold, 
of influenza, to mention only a few. If asked 10 
ENVIRONMENT 
whether this type of environment is not of necessity 
bound up with that of conditions of living and 
housing, we would answer in the negative: for the 
recent pandemics of influenza, with their frightful 
toll throughout the world and among all types of 
civilizations and societies, make it impossible to 
view this particular scourge as decisively influenced 
by any habits and modes of living that we are familiar 
with. Measles is of the same piece. 
Again, altogether apart from an environment 
which is to be comprehended under good hygiene, 
there is an environment which would comprise 
numberless opportunities for physical injury to the 
person. This would include many perfectly acci- 
dental happenings, the normal hazards of human 
association, which neither foresight nor law nor 
instruction can do away with wholly. 
There is, besides, an environment of occupation. 
The man at the desk or counter, the shoemaker, 
the tailor, the glassblower, the cabdriver, the farmer, 
the athlete, the peddler, the miner,—all have the 
physical marks of their work upon them. The life, 
the customs, the habits, the demands and necessities 
of the several classes of society leave their traces on 
their members no less. If we compare the peasant 
girl with one gently bred, at age sixteen, we not 
uncommonly find no differences in health, grace and 
beauty; or, if there be a difference, the comparison 
as often as not favors the former. Yet how often 
have we seen two or three decades of rough, country 
life, ever vaunted as the road to health and content- ENVIRONMENT 
11 
ment, make of the one a broken woman, old before 
her time, while the same period of ease and urbane 
existence bring to full flower all that was budding 
in the maiden. 
When, sick with angina pectoris and aware of the 
influence of psychic disturbance upon his physical 
condition, John Hunter said that his life was in the 
hands of any rascal in London who chose to take it, 
he simply indicated the possible more disastrous 
effects of an environment about which our books 
on general medicine are strangely or perversely 
silent, yet which drives thousands of us mortals to 
our practitioners. This is the environment of 
personal association—of antagonistic personal asso- 
ciation, in particular. The older philosophers and 
brooders over our well being were enormously im- 
pressed by this factor in human nosology: dust off 
again your old Burton and read how it appeared to 
him. Yet, for a considerable period, until recently, 
when psychiatrists again brought this type of environ- 
ment into prominence and coined a new nomen- 
clature to speak intelligibly to one another of 
“repressions” and “conflicts,” and the morbid 
results of these, formal medical instruction, given 
to more material and mechanical views of disease, 
was apparently oblivious to its existence and 
influence. 
It should hardly be necessary to point out the 
enormous amount of functional disturbances which 
the reactions of jarring personalities bring into being: 
nor are their effects on already established organic 12 
ENVIRONMENT 
deficiency or disability any less marked. Every 
physician soon becomes familiar with them and is 
mindful to attempt to control them when treating 
his patients. There is a social and family environ- 
ment of amiability and good fellowship and content- 
ment and happiness: it may exist in surroundings 
which physically may be far from our accepted 
hygienic ideal; and its effect on the general well 
being of those happily situated in it is all good. 
This much is, I think, beyond dispute. But there 
is also a radically different environment: one of 
incompatibility, and oppression and brutality, and 
even bestiality. It is by no means the heritage or 
appanage of the hovel exclusively. It may dwell 
where air and space and light and food leave nothing 
to be desired; yet even here it will make for ill 
health. 
It is a statement, worthy at least of debate, that 
the fullest development of the race requires those 
conditions—that social and political environment— 
which will allow the greatest freedom and play of 
individuality. It is nevertheless a commonplace, 
a criticism in fact, that one great weakness of all 
plans for ideal commonwealths, from Plato’s system 
down to the actual feeble shadow of democracy to- 
day, is a certain insistence that all men conform to 
common standards. Out of this struggle between 
the instinct and passion for self-expression, on the 
one hand, and those rules and standards of conduct 
which, on the other, society deems necessary for 
its own fixity and security, innumerable conflicts ENVIRONMENT 
13 
arise. The issue of these may be acquiescence: 
all educational systems teach the child docility with 
the decalogue and society is never lavish with its 
fleshpots to the fractious colt. But only too often 
their ultimate results are what we call misfits, or 
the apathy of despair, or, occasionally, even self- 
destruction. 
In and by reason of all this welter, not a little 
physical ill health emerges. Concerning still 
another side of this phase of environment, that so 
ardently played up by Freud and his followers, I 
think that little need be said here, though I recognize 
much that seems valid in their contentions. 
I would not overemphasize the part played in 
disease by disturbances of the psyche. I wish 
merely to point out that it is a very real influence, 
arising out of what is almost man’s normal environ- 
ment, whether this be made up of relationships 
that exist between him and his kindred or those 
between him and more casual associates or the 
ideals and practices of society at large. I do think 
that to deny its influence on health is to disregard 
some of the most obvious phenomena that con- 
front us. 
I need not give a more detailed recital of what 
enters into my own comprehension of environment. 
The long and short of it is that environment com- 
prises everything and all things that enter into the 
experience of a human being; and that, as regards 
tuberculosis, any experience that may modify in 14 
ENVIRONMENT 
any way the origin and development of infection is 
an environmental influence. 
Perhaps this view is too all-inclusive. It would, 
for instance, make malnutrition an environmental 
factor, unless in any particular case malnutrition 
were the result of inborn tissue or organic vice, 
and not of deprivation of necessary food elements 
or improper ingestion or absorption. Yet, under 
the latter circumstances, malnutrition is assuredly 
as much an affair of environment as is the nature of 
the house one lives in. 
At any rate, too great inclusiveness will undoubt- 
edly lead to less misunderstanding than too narrow 
a point of view. As I see it, only two really funda- 
mental factors can possibly have an influence on 
infection or disease. These are heredity and en- 
vironment. Inheritance determines the nature and 
activities, whether these lie fallow or are at any or 
all times fully expressed, of the tissues as these are 
born into the world. Environment includes every 
mundane experience which, directly or indirectly, 
may exert an effect on the constitution and function 
of tissues. 
There are only two ways in which clinical tuber- 
culosis can develop. These are—once infection 
takes place—through the advance or renewal of 
activity of foci which have existed, perhaps unknown 
to their possessor, for variable lengths of time 
(theoretically, the period may be almost as long as 
a lifetime itself); and through the uninterrupted ENVIRONMENT 
15 
progression of foci from the time of infection to the 
cropping out of symptoms. 
Cases of the first type are common: many are 
comparatively easy of demonstration. We meet 
with patients whose breakdown is of the nature of 
a clinical relapse. It may be a first relapse or a 
third or fourth recurrence of symptoms, coming on 
after perhaps years of good health and working 
capacity. Examination of them may disclose that 
the particular breakdown is due to renewed activity 
of foci which were known to exist and give rise 
periodically to symptoms before. 
Or, as happens often, patients at the very first 
manifestation of symptoms of tuberculosis are 
found to have morbid changes which, because of 
their character and extent, are beyond question the 
culmination of years of quiet infection. Here again 
we are satisfied that clinical disease is the result of 
infection received much earlier in life. Generalized 
miliary tuberculosis and acute tuberculous pneu- 
monia in previously healthy adults invariably 
spring from an extension of infection from preexist- 
ing concealed and quiescent foci: as do primary 
clinical tuberculosis of bones and joints, kidney, 
pleura, peritoneum and brain membranes. The 
frequency of clinical relapse plus the frequency of 
primary symptoms of tuberculosis of the lungs with 
old and extensive infection plus the frequency of 
clinical tuberculosis first appearing in organs without 
direct communication with portals of entry is proof 
enough that very, very often clinical breakdown is 16 
ENVIRONMENT 
not the expression of recent infection from without 
but is the effect of renewed activity or extension 
of long dormant tubercle. 
Whenever anyone asks me why, in general, these 
cases break down, I am accustomed to answer that 
there are many immediate, potential contributory 
causes which are often demonstrable and to which 
I shall refer in a moment. But over and above all 
cases in which the sequence of events is plain, 
careful and practised observation of patients and 
cadavers will bring to light not a few in whom we 
must conclude that the catastrophe happened be- 
cause of purely fortuitous and accidental circum- 
stances. The term accidental may be unscientific; 
yet I know of no better way to put the case, which 
is this—that, as regards such elements as the focali- 
zation of infections and the influence which extra- 
neous factors may exert upon them, there are acci- 
dental circumstances of place and time which may 
be, which I have no doubt are, decisive in moulding 
the subsequent turn of events—for better or for 
worse so far as the patient is concerned. 
I take up these accidental factors of etiology 
and pathology and their results at greater length 
in the essay on Resistance and shall not dilate 
upon them here. But I may be permitted to 
repeat that altogether apart from other factors, such 
as dosage of bacilli, resistance of host, etc., the 
actual point of localization of even the primary 
infection may be of great moment. A focus in 
immediate proximity to a large vein or the thoracic ENVIRONMENT 
17 
duct must; with everything else equal, certainly 
be regarded as pregnant with greater evil than one 
at the very lung apex or a lymph node in the mes- 
entery. We cannot conceive that any element of 
inheritance, resistance, virulence, or ordinary envi- 
ronment, as the latter is understood, was responsible 
for focalization in the one place rather than in the 
other, or contributed to the event in any way. 
There were of course some environmental factors of 
tissue relations and activities, operating at the time, 
which did determine the exact point of focalization: 
but these are hardly ever demonstrable and are far 
beyond the scope of my analysis. We can only say 
that in some instances the place of focalization was 
accidental and let it go at that. 
But note how decisive it can be. The focus in 
apposition to the thoracic duct may ulcerate, to 
spread generalized miliary tuberculosis and death. 
The ulceration of a similar focus in a lymph node of 
the neck would eventuate in a comparatively 
benign condition. 
If we keep alert and receptive, we can get our best 
lessons in the etiology of clinical tuberculosis from 
the sufferers themselves. Their stories, told daily 
in consultation rooms, and our observations, gleaned 
at the bedside, proclaim again and again the immedi- 
ate causes of breakdown, and to me far outweigh 
any evidence, positive of otherwise, to be gained in 
any other manner. I have lately read several 
contributions in which the authors report that they 
have examined the histories of soldiers who developed 18 
ENVIRONMENT 
tuberculosis while in the army, have cast up columns 
of figures and have found that none of the tuber- 
culous soldiers had received wounds that bore any 
relation to their tuberculosis. Or they have gone 
into certain more or less complete records of the 
wounded and have discovered that no tuberculosis 
struck down these men later. In either event, they 
conclude, therefore, that trauma, injury, does not 
bring about clinical tuberculosis. 
Now it may have been perfectly all right for these 
authors to tell us that none of their cases developed 
tuberculosis because of trauma, but to say that 
trauma has no influence on tuberculosis is a totally 
different matter. It may not in most cases: or the 
association may be difficult or impossible to detect. 
But it does have an influence in some cases: and we 
should remember that, when it comes to the complete 
affirmation or negation of a general principle, a 
single positive phenomenon or finding will completely 
outweigh all negative reports, no matter how over- 
whelming appears the numerical evidence against. 
If Claude Bernard had announced his discovery of 
glycosuria by piqure of the fourth ventricle immedi- 
ately after his first experiment and had rested it 
there, any number of followers in his footsteps 
would have no doubt convicted him of error if this 
depended on statistical evidence. For, before he 
made a second sucessful piqure,—until he discovered 
the exact spot where piqure always aroused glyco- 
suria,—the discoverer himself had almost a score of 
failures. It would probably not be difficult for ENVIRONMENT 
19 
some surgeons of large experience to prove numeri- 
cally from their own records that cancer never 
arises from gastric ulcer: in observing hundreds of 
cases of the latter they had never encountered 
cancer. Yet an obscure country physician may 
find that his only case of ulcer of the stomach was 
changing into cancer. I have heard some sweeping 
generalizations about the nonoccurrence of pul- 
monary tuberculosis with mitral stenosis; yet I have 
observed this coexistence of diseases. Not long 
ago, a physician brought to me a patient who fell 
ill with acute pleurisy with effusion not twenty-four 
hours after an injection of tuberculin. The injection 
was one of a series given the patient in order to 
determine the nature of an affection of the eyes: the 
pleurisy with effusion was her first pulmonary 
“episode.” The physician in question had pre- 
viously administered tuberculin hundreds of times 
for the same purpose and always without untoward 
result. Before the excitation of this pleurisy, I 
have no doubt that out of the fulness of his experience 
he would have been willing to have written a paper 
to the effect that tuberculin, as he gave it, would 
never provoke clinical tuberculosis. 
I once saw a man who recovered health in a sana- 
torium and returned, a well-arrested case, to follow 
his occupation as a chauffeur. He remained well; 
until, one day while bending over to crank his 
automobile, the crank flew off and struck him a 
violent blow on the left side of the chest where 
he had had active tuberculosis. He at once be- 20 
ENVIRONMENT 
came very ill and was found to have sustained a 
pneumothorax. 
In this case there cannot exist the slightest doubt 
about the influence of trauma. It immediately 
ruptured an already diseased pieura. I have 
observed hemorrhage to follow a blow on the chest 
and, after the hemorrhage, acute pulmonary 
tuberculosis which was beyond question the first 
breakdown that the patient had ever experienced. 
And this patient, at first examination, was found to 
have an entire lung involved with old, sclerotic 
tuberculosis and a cavity at the apex. It is not to 
the point to ask why she did not break down before. 
What is significant is that an injury precipitated her 
clinical tuberculosis. In a phthisical billiard player 
I have seen a remarkable warty tuberculosis of the 
skin, growing between the thumb and index finger 
of the left hand, in the crotch where the man was 
accustomed to rest and move his cue. 
In my opinion, there is not the slightest doubt as 
to why tuberculosis manifested itself in the manner, 
both as regards time and place, described in these 
three cases. We can unhesitatingly affirm that had 
trauma not been applied, symptoms would not have 
occurred when and where they did. They are all 
striking examples of environmental influences on 
tuberculosis. Trauma does bring tuberculosis to 
light—so much is certain. As to what proportion 
of breakdowns is attributable to trauma is another 
matter, which need not concern us here. ENVIRONMENT 
21 
At this place it may be well to consider for a 
moment the influence of pregnancy, labor and the 
puerperium. There is not a single physician, be he 
obstetrician, phthisiologist or general practitioner, 
who would believe for an instant that the gravid 
state and its sequellae have no effect on tuberculosis. 
By far the greater number of women, of course, go 
through this experience without exhibiting the least 
evidence of tuberculosis. But we do not draw our 
deductions from negative data; and the fact remains 
that the proportion of tuberculous women whose 
breakdown was ushered in by pregnancy or child- 
bearing is still lamentably high. 
I know of no better examples of the direct influence 
of what we may call noninherited factors on tuber- 
culosis than pregnancy will now and again afford. 
Consider the following case; A young woman, 
gently reared and always vigorous and athletic, 
bears a child, and has a protracted convalescence in 
bed, with pleurisy with effusion, which develops soon 
after delivery. She recovers completely and out- 
wardly remains in good health until the birth of a 
second child, when she breaks down with acute 
tuberculous pneumonia. 
Or this second case: A perfectly healthy woman 
becomes pregnant, bears a child, and is then confined 
to bed for an unusually long time because of indefinite 
symptoms of illness, although she has some cough. 
She recovers after a while and two years later has a 
second child; and, this time, during the puerperium 
she again has cough and fever, and now spits blood. 22 
ENVIRONMENT 
Once more she recovers, and several years later 
bears a third child, a short time after which she has 
profuse hemorrhages from the lungs and falls into 
acute pulmonary tuberculosis. 
Every physician could multiply such cases at 
will. In many of them there can be no question 
about what caused the breakdown. We can be 
perfectly certain that an environmental factor, 
speaking broadly, turned the balance against a 
continuance of quiescence of infection. We are 
no less sure that feeding or inherited qualities, or 
other factors of environment, such as housing, etc., 
either had nothing to do with the event or, if they 
did, they played completely subsidiary parts. The 
one outstanding fact is that the patient broke down 
at this time because she became pregnant and bore 
a child and that, if she had not had this experience, 
there is not the slightest reason to believe that she 
would have developed clinical tuberculosis at the 
time. 
Acute infectious diseases, particularly those which 
may cause disturbance of the lymphatic or respira- 
tory system, are very frequently determinants of 
the outbreak of clinical tuberculosis. Measles, 
the common cold, influenza, septic infections 
(especially of the throat), are some of our most 
notorious “whippers-up ” of tuberculosis. We are 
familiar with the harmful effect which a cold may 
exercise on a patient who is being treated for tuber- 
culosis and who, before coming down with the cold, 
may have been making satisfactory progress toward ENVIRONMENT 
23 
arrest of his lung trouble. We are similarly im- 
pressed by the large number of patients who break 
down with tuberculosis for the first time after 
contracting a cold or an acute bronchitis. In both 
instances the same interplay of forces is undoubtedly 
at work: foci which had attained fairly competent 
investment, and thereby relative quiescence, par- 
ticipate in the congestion brought about by the 
inflammation of an added acute infection and are 
thus stimulated to fresh activity. Measles may 
bring about the same result, especially in the lungs 
and lymph nodes; and, as is well known, may in 
addition profoundly depress the allergy of the body 
to tubercle bacilli. So may influenza. 
Physical and mental overstrain and excesses of all 
kinds promote tuberculosis. Their action is well 
understood. Their results are so frequently encoun- 
tered in patients that little room is left to question 
their part either as contributory or decisive environ- 
mental factors. We meet with the spectacular 
case,—the vigorous athlete stricken with pulmonary 
hemorrhage immediately after finishing a race. 
We listen to the stories of gradual let-down in 
health and insidious encroachment on working 
capacity, through months and years of overwork or 
worry or wrong living. And there is every type of 
onset in between these two. 
During the past decade or two our point of view 
concerning the influence of crowded and unsanitary 
living conditions has shifted considerably. I have 
said that at first it was believed that opportunities 24 
ENVIRONMENT 
for infection played the decisive role in tuberculosis 
morbidity. It was then thought that relatively 
much disease developed in the tenements because 
the condensation of population and its attendant 
evils established quantitatively an unusual measure 
of contact with tubercle bacilli. But, as it became 
more and more apparent that adult breakdown was 
a frequent consequence of early and long-standing 
infection, newer explanations were demanded. 
These explanations are not far to seek, and are 
in general much more rational and no doubt nearer 
the truth than was the older quantitative infection 
idea. The evils that create and accompany sub- 
standard living arrangements—poverty usually, with 
its overcrowding, filth, darkness and deadness of 
air—are plain and need but slight elucidation. 
People who live in an environment of this kind, with 
few of the comforts and more refined interests and 
pleasures of life, overburdened only too often with 
children, are exposed to all the stresses and depriva- 
tions that result from this mode of life—improper or 
insufficient food and clothing and heating, irregu- 
larity of menage, overwork, deprivation of the 
recreative enjoyments with excess of those that are 
dissipating and vicious, unusual opportunities for 
contact with many acute infections, lack of proper 
aftercare in pregnancy and disease, etc. In short, 
such an environment is our most fertile soil for the 
development of conditions which go far toward 
undermining and breaking general health, and thus 
lay the train for the lighting up of quiescent tubercu- ENVIRONMENT 
25 
lous infection and bringing it to clinical appreciation. 
As standards of living go down, ignorance, squalor, 
exposure to cold and heat, hunger, lack-lustre 
discouragement and indulgence of bestial appetite 
increase apace. And one general result can be 
nothing else than a deterioration of health. 
In every part of the world comparative statistics 
of tuberculosis have always shown two outstanding 
relations. The curves of illness and of death from 
tuberculosis have always run parallel with those of 
general disease and mortality, and opposite to the 
economic status of a population or any section of it. 
The only time when the second relation was not 
apparent was during the world war when, with whole 
nations deprived of many essentials of normal living, 
modes of life did not accurately reflect economic 
status. 
But, normally, it invariably follows that high 
general morbidity and death rates will be accom- 
panied by high tuberculosis rates of both types, 
and that where poverty prevails there tuberculosis 
will be high and vice versa. These facts furnish the 
most compelling brief for the positive argument on 
the influence of environment on tuberculosis. 
We have thus far been concerned with marshaling 
an array of factors, all of which are to be looked upon 
as environmental, which must be taken into account 
whenever tuberculosis breakdown on the basis of 
preexisting infection comes into question. If we 
be required to bring forward direct evidence of the 26 
ENVIRONMENT 
influence of environment and, further, asked to 
explain its modus operandi, we would, first and above 
all, go to therapy to demonstrate our thesis. 
There can be no dispute over the general proposi- 
tion that the intelligent application of what we call 
hygienic-dietetic treatment will improve the con- 
dition of most tuberculosis patients. The better 
informed opinion also recognizes that the most 
effective element of this regimen is the limitation of 
the patient’s activities—a relief from responsibility 
and stress which is so prescribed as to meet the 
individual patient’s needs and capacities. The 
therapy of chronic maladies will provide few more 
striking examples of functional betterment than that 
occasioned by the judicious use of rest in circum- 
scribed (nongeneralized) tuberculosis. Under its 
influence the consumptive to whom, while active, 
every step was painful with fatigue and every small 
task appeared almost insuperable labor, finds his 
whole outlook changed. Put him to bed or fix him 
to his chair, and he becomes comfortable, his fever 
and too rapid pulse tend to decline, distaste for 
food abates and he puts on weight—all this, very 
often, with astonishing rapidity. A glance through 
sanatorium reports will show that this is the institu- 
tional history of fully three-fourths of all patients. 
And there can be few men, of those familiar with the 
handling of the tuberculous in our sanatoria, who 
have not often thought that if the average time of 
discipline could be lengthened from less than six 
months, as it now is, to say three years, our ultimate ENVIRONMENT 
27 
arrest and mortality figures would be completely 
reversed. 
We are, of course, speaking now of the ordinary 
sanatorium patient—not the phthisicus in extremis. 
And, in this connection, close observation of the 
physical powers of individual patients is highly 
significant. 
While at complete rest, many may be altogether 
without symptoms. Or, if at rest most of the day, 
they may even be able to indulge in some activites— 
walking, for instance—for fifteen minutes, an hour or 
two hours a day, without functional disturbance. 
Every phthisio-therapeutist comes to learn the 
physical limitations of his patients, of each individual 
one of them. He finds that a man who, at a given 
time, may be able to do fifteen minutes’ exercise, 
will suffer if he exceeds this; or that another patient 
who may go through a whole day of light work 
comfortably will have his symptoms return if put 
at heavier tasks; or that some who have been prac- 
tically well for months can be “broken, ” as it were, 
if made to do unusual labor. 
This simple and common clinical experience, 
available to all who wish to make the experiment, 
proves, better than all other evidence, that environ- 
ment does have an influence on tuberculosis—an 
influence, powerful though delicate, and ever active. 
The constitutional symptoms of tuberculosis are 
put in motion by the action of substances that are 
absorbed from foci of disease. The rate and amount 
of this absorption are contingent upon the character 28 
ENVIRONMENT 
of the foci on the one hand and the physiological 
activities of the tissues which enclose them on the 
other. The character of the foci at any time is 
largely the net result of antecedent experiences on 
the part of their possessor: we may, for instance, 
alter them at will by certain manoeuvres in animals 
of experiment. The physiological activities of cir- 
cumtubercular tissues vary, like those of any other 
tissues, with the experience of the individual—the 
experience, which is, of course, the play of environ- 
ment upon the person. Physiological stresses and 
disturbances are set up by environmental conditions 
of many kinds, whether these be physical or 
emotional overstrain, or disease in general. Disease 
is undeniably related to occupation, to position in 
life, to personal association, to living conditions, 
and what not. It produces many physiological 
effects—changes of respiration, circulation, digestion, 
metabolism, etc.—which are not to be distinguished 
fundamentally from those due to abnormal physical 
and psychic activity. 
At any rate, if environment has no effect on 
treatment, we may just as well give up our present 
methods and turn our patients loose to follow their 
own inclinations and take their chances wTith the 
tissue stock that was born with them. Even then, 
some would regulate their activities so as to create for 
themselves an environment such as we prescribe. 
For men suffer when they have tuberculosis. To 
many such, activity becomes painful—painful to the 
point of impossibility to indulge in it. And thus ENVIRONMENT 
29 
slowed up, they would seek rest; when not a few 
would pull through, or experience periods of relief— 
those delusory periods which so normally punctuate 
the natural history of tuberculosis, the seasons of 
the ‘‘false convalescence’7 of Laennec, which quacks 
and nostrum traffickers have learned to exploit so 
well. 
If, however, environment does influence tubercu- 
losis as we encounter the latter in treatment, then 
it must also have its effect in contributing to break- 
down. Any other view is irrational. If the influ- 
ence of environment is so delicate that a few minutes’ 
more or less walking means much to the focus which 
is, as it were, sensitively balanced, its influence on 
quiescent, latent or concealed foci is no less delicate. 
True, in the latter case it may not be so eloquently 
expressed, if the environmental force remains quanti- 
tatively small. A quiet walk of half an hour would 
undoubtedly not have produced the least visible 
effect on the young athlete I knew, who had his 
first manifestation of tuberculosis—a haemorrhage— 
immediately after finishing a half-mile run and who 
is now dead after a prolonged illness with tubercu- 
losis. But relations here are largely those of quantity. 
The mechanism of going into breakdown, or relapse, 
or transient or prolonged increase of activity is not 
very different fundamentally. The sum of the 
effects of environmental forces reaches a totality 
which the balance between foci and surrounding 
tissues can no longer withstand. 30 
ENVIRONMENT 
There remains another angle from which we may 
discuss environment as a factor in breakdown from 
tuberculosis. 
It will be admitted that the presence of tubercle 
bacilli in one’s surroundings is a very real environ- 
mental factor. It will also be agreed that this bacil- 
lary environment is very variable in quantity and 
character of bacilli and in the media that contain 
and transmit bacilli. If, therefore, future observa- 
tion and investigation should disclose that the 
repeated or continued attachment of these germs to 
human beings promotes in many instances the out- 
break of clinical tuberculosis, the nature of one’s 
environment would on occasion play a very decisive 
role in determining the issue of infection. 
During the last decade we have become perfectly 
certain that an initial tuberculous infection endows 
an animal with increased resistance to reinfection 
from without (and, as a matter of fact, also from 
within). At the same time it has become common 
knowledge that the postpuerile ages of man are 
pretty thoroughly infected. 
Out of these two circumstances has evolved the 
opinion, which in some quarters has hardened almost 
into dogma, that reinfection is impossible if a 
person has once been infected and that all manifest 
tuberculosis after childhood develops from infection 
acquired by the time adolescence is established. 
Future work may show that all this is indubitably 
true. But I have never been able to convince 
myself that the evidence at hand warrants the ENVIRONMENT 
31 
assumption of either proposition as a generalization 
of fact. 
The idea of the impossibility of human reinfection 
has been based on work contributed from the labora- 
tory. Yet no experimental work that I am familiar 
with has made as sweeping a statement as that an 
infected animal cannot be reinfected. Indeed, the 
facts of the matter, the all-important details of 
controlled experiment on animals, point all the 
other way. 
It is true that primary infection of animals confers 
a high measure of protection against reinfection. 
But at no time is this ever absolute: sufficiently 
large doses will break it down. We also find that 
even moderate or small reinfections are always met 
by the animals with some kind of tissue response 
(morbid change). Some type of tuberculosis never 
fails to result, even though this be modified. It is 
not the progressive tuberculosis that results from the 
same dose of a primary infection, to be sure; but it 
is tuberculosis none the less; and I have seen it 
persist for a long time. 
In other words, the net immunizing effect of 
primary infection is not so much a flat and complete 
protection against reinfection, as it is a change of 
type in the tuberculosis which follows reinfection. 
In a susceptible animal, a first infection, properly 
applied, is apt to spread rapidly throughout the body 
and take on a progressive character. On the other 
hand, reinfections of the same animal, if dosage be 
small, tend to remain well-localized at the place of 32 
ENVIRONMENT 
infection and pursue a much more sluggish and 
chronic course. The more ordinary clinical tuber- 
culosis of human adults resembles in several impor- 
tant features the reinfection tuberculosis of labora- 
tory animals. As a matter of fact, there is just as 
much evidence to indicate that it may at times 
represent reinfection from without as there is to urge 
acceptance of the doctrine of nonreinfection from 
without. 
Cattle immunization has given us much of our 
best information concerning immunity to tuber- 
culosis. The type of primary infection that results 
in the process of active immunization is also most 
comparable to what presumably occurs in the gener- 
ality of mankind; that is, in cattle it is aimed to 
attain a self-limited, well controlled infection, such 
as usually takes place in human beings under natural 
conditions. 
Yet it is under these very conditions, that is, 
when primary infection in nonprogressive, that we 
find immunity to outside infection to be less high 
and less permanent. All cattle immunizers have 
found, for instance, that, even after a vigorous course 
of protective inoculation, a satisfactory defense 
against virulent reinfection cannot be maintained 
for much longer than two years. In summary, the 
results of investigations on cattle and other animals 
have turned out about as follows: (1) primary 
infection confers protection against reinfection; (2) 
the protection is not complete; (3) as the primary ENVIRONMENT 
33 
infection tends to die out, as it will unless it pro- 
gresses, the protection diminishes or disappears. 
Much more might be said about other more or less 
decisive features of immunity; as, for instance, 
periodic anergy. This, a depression of resistance to 
a point below even that which is native or normal 
to an animal, occurs in the course of every immune 
process and is brought about transiently, by new 
infections similar to or different from the one which 
an animal may be harboring at any time. It has, 
received little experimental study in connection with 
immunity and has thus far been almost entirely lost 
sight of in all applications of allergo-immunology to 
human tuberculosis. But I think I have said enough 
to indicate that the dictum that the average human 
experience is a single early infection with tubercle 
bacilli is, to say the least, highly debatable. 
The whole matter of human infection must be 
subject to vastly more complexities than many 
have assumed. Manifold opportunities for infection 
exist: this much is certain. Between milk and crude 
sputum and dust and consumptives and the articles 
the latter handle, that person must be rare who 
moving in ordinary society, does not come in contact 
with tubercle bacilli, not once or occasionally, but 
frequently and repeatedly. There are, for instance, 
many habitations in our cities, where children, living 
in one or two rooms with careless, phthisical parents, 
must for months ingest and inhale tubercle bacilli 
almost continuously.'!' There must be others who, 
fed tuberculous milk, ingest enormous numbers of 34 
ENVIRONMENT 
bacilli throughout a long period. They do this in 
health and in sickness; when allergy (immunity) 
is high and when, as for example during other acute 
infections, it is low or absent. 
There must also be many whose contact with 
tubercle bacilli is quite transitory; and not a few 
whose initial infection is extremely slight. I cannot 
go into the matter of the complete healing of tuber- 
culous changes here, other than to say that they do 
disappear entirely, as the later developments of 
tuberculous peritonitis of man have frequently 
disclosed, and as cattle inoculations have shown. 
And, until the contrary is definitely proved, we 
must assume—at least, we cannot deny—that many 
initial human infections, if slight, are transitory, 
and that, upon their thorough obliteration, immunity 
dies out, or is so slight that the possessors are as 
open to reinfection as though they had never before 
come in contact with tubercle bacilli. 
Earlier in this address I tried to make plain that 
breakdown on the basis of old persisting infection 
comes very frequently into the practice of every 
physician. But, at the present moment, I cannot 
convince myself that this type includes all or most 
cases of manifest, adult tuberculosis. In view of the 
immunological details which I have just mentioned 
and also because of the varying opportunities for 
infection that obtain outside, I cannot help believing 
that the everyday life of man provides conditions 
that make for a not inconsiderable number of ENVIRONMENT 
35 
tuberculous reinfections from without, in which the 
time and quantity of reinfection may be so ordered 
that, because of these, breakdown results. I do 
believe, therefore, that, in this respect also, environ- 
ment may play a decisive part in the development 
of disease. 
But environment is not the only force that hurries 
a man into tuberculosis or wards it off. Inheritance 
must also play its part. The little that we know 
about specific immunity suggests that at some 
future time it will be found that a cumulative an- 
cestral experience with active tuberculosis transmits 
an increased resistance to the progeny. But how 
much this more resistant tissue stock may be 
balanced or outweighed by environmental relations, 
such as greater opportunities for infection from 
phthisical family associates and the reduced eco- 
nomic conditions that follow in the train of con- 
sumption in a family, is a question for argument and 
investigation. 
There is not a little clinical evidence that such 
diseases (to mention only a few) as gout, epilepsy, 
migraine and cardio-renal-vascular insufficiency arise 
on an inherited background. It has always been 
a byword that longevity is inherited. Nervous 
instability and overirritability certainly are. And 
who knows but that nervous irritability, which at 
bottom must regulate cellular activity in general, 
will not ultimately be found markedly to influence 
the origin and development of infections? 36 
ENVIRONMENT 
But I am not here to discuss inheritance. I 
merely throw out these hints as matters to be 
thought of, and to emphasize that a narrow view of 
the causes of the development of phthisis is unscien- 
tific and not justified by facts or probabilities. RESISTANCE Resistance1 
AS OUR insight penetrates deeper and deeper 
into recesses that were once dark to us we 
consciously or unconsciously demand more 
precise description of terms to denote phenomena 
that obtrude upon our senses but defy our under- 
standing. Upon first appreciating a thing, be it 
light or sound, an abnormal sensation or an unusual 
conformation of the body, we give it a name. But 
we are mentally so endowed that we are not long 
content with the mere name of a thing. We must 
know where and how it begins and ends, and through 
what media it works. We must discover its attri- 
butes and, these made plain, we must enlarge and 
refine our definition and description. As the latter 
grow more exact there comes the perception that 
nothing that we sense is isolated or spontaneous. 
It is born of something and brings forth something. 
And, once our minds begin to deal with its causes 
and effects, then we can say that the thing has 
entered our understanding. Then only can we 
affirm that its name is to us perhaps something 
more than a mouthful of words. 
1 An elaboration of an address, “The Nature of Resistance 
to Tuberculosis,” before the New York Academy of Medicine, 
February 15, 1917, and published in the American Review of 
Tuberculosis, April, 1917. Material from a number of the 
author’s other papers on “Resistance” and related subjects has 
also been included. 
39 40 
RESISTANCE 
Terminology, description and comprehension of 
cause and effect: every domain of knowledge, 
every phase of science passes through these three 
stages on the road from sensation to reason; and 
medicine, focus of all sciences, embracing all, taking 
of and using mathematics and physics and chemistry 
and botany and climatology and sociology and 
psychology, is to-day perhaps in all three stages. 
A genius, a Helmholtz, emerges and lays bare the 
mechanism of the eye. A Richard Bright, a Louis 
or a Gerhard sifts and describes and clarifies a 
confused melange. A man with a knack for obser- 
vation, perhaps a dermatologist, classifies those 
things that are red, or those that are raised, or those 
that itch, or those that are wont to appear on certain 
parts of the body; and he thereby brings into order 
his “science” and takes a step far beyond the time 
when he called everything either a humor or a 
tumor. But terms, mere terms, persist, and too 
often pass for explanations. Nephritis, cardio- 
nephritic, myocarditis, arteriosclerosis, hypertension, 
hypertensive-nephritic, myocardial insufficiency 
with hypertension, hypertension with renal insuffi- 
ciency: what a real evolution of knowledge these 
terms convey! Yet how little more than terms 
they are! Naming much, describing a little, they 
explain nothing, while the sources and paths of 
action of a veritable giant of mortal maladies remain 
buried deep as they were to the men who first 
recognized the disease. RESISTANCE 
41 
I feel very diffident in talking about what has often 
seemed to me to be, as commonly used, a mere term 
or symbol. I have attended clinics, given by some 
of our best men, to hear the affirmation that a liberal 
diet of milk and eggs would increase the tuberculous 
patient’s resistance. I have seen the man of 
authority impressively produce his syringe and just 
as impressively assure the patient that a prolonged 
course of tuberculin therapy would further the 
latter’s resistance. Time and again I read that a 
man overcomes his tuberculosis because his resist- 
ance improves or that he fails because he has no 
resistance. And, hearing these statements, I have 
often wondered just what was going through the 
mind of the man who made them. Did he mean 
anything when he talked about resistance? Or, if 
he did, had he any idea of what he tried to fexpress? 
Or did he merely wish to avoid mental exertion and 
therefore seek to explain an effect by a handy word? 
If there is such a thing as resistance to tubercu- 
losis, then it must mean that the body can protect 
itself in such a way that the tubercle bacillus, a 
parasitic invader, can gain no foothold or make but 
limited headway in it. We must assume further 
that under the influence of a specific irritant, the 
bacillus, the body reacts in a particular manner. 
As long as it reacts sufficiently to prevent or limit 
invasion or spread of the bacillus, just so long would 
we say that resistance is satisfactory. If, however, 
it fails to do so then resistance is lowered or absent. 42 
RESISTANCE 
The entire relation of the tubercle bacillus with 
the animal organism is one of reaction. Vivre c’est 
reagir: to live is to react; and from conception to 
final dissolution man’s vital history is an unceasing 
period of countless myriads of reactions that go on 
simultaneously or unfold themselves in sequence. 
We must look upon every reaction to a potentially 
harmful stimulus or irritation as an effort at adapta- 
tion and protection. The body reacts to the rays 
of the sun in a certain definite manner and thus 
protects itself against them. It reacts to the intro- 
duction of pork or morphine in wholly different 
ways and thus adapts itself to them. It reacts to 
the implantation of the tubercle bacillus in a very 
particular manner, and meets the germ with the 
formation of a special type of cellular accumulation 
which we call tubercle. 
These are trite though fundamental concepts of 
biology. In thinking of any tissue or organic 
attribute like resistance we dare not forget them, 
and it is likely that I shall recur to them again and 
again. To live is to react. And, if the stimulus or 
irritant be one that is noxious to tissue then to live 
is to resist. Whether resistance to a given irritant 
at any time is adequate is another matter, yet it is 
certainly true that if we are to live we must resist. 
Therefore, in addition to the necessary properties 
of assimilation, motion and reproduction, as they 
are generally given for protoplasm, I would add a 
fourth attribute, that of resistance. I am aware 
that this fourth attribute may be partly contingent RESISTANCE 
43 
on the other three, but it is conceivable that in 
highly organized animals resistance goes on inde- 
pendently of them. 
We assume, therefore, that there is a resistance 
to the tubercle bacillus; but in thus stating the prop- 
osition we have got little beyond giving a name to 
the known fact that tissues react to tubercle bacilli. 
We have not explained or illuminated a single 
thing. It is my purpose to inquire into the nature 
of this resistance, to attempt to discover how it 
acts and what are its effects. I trust that you will 
be tolerant while I lead you into regions, which, I 
know only too well, are strewn with obstacles and 
beset with pitfalls. 
Let us first look into what happens when tubercle 
bacilli are taken into the body for the first time. 
In nearly all instances they enter by the mouth or 
nose. After excursions of varying length they 
pause. They may be caught in the vibrissae of the 
nose, or on the moist surfaces of the tortuous nasal 
passages, or in the mucus of the nasopharynx; and 
be almost immediately blown out or spat out with 
the nasopharyngeal secretion. Here, at the very 
beginning, we meet with a protective mechanism at 
the body’s command. 
But some germs, perhaps, get further. They 
penetrate the mucous membrane of the tonsil or 
pass to lymph nodes of the neck. They are now no 
longer on an epithelial surface where they cannot 
produce an effect: they are in tissue. What hap- 44 
RESISTANCE 
pens now? The tissue reacts. Fixed tissue cells 
begin to show unrest and agitation. There is a 
new and unwonted activity in cells of the connective 
tissue type, in endothelium lining the lymph chan- 
nels and spaces. Their nuclei swell, chromatin 
rearranges itself and heaps up in a bizarre manner, 
the cells themselves enlarge, and in a short time 
we find that they are dividing, multiplying and 
piling up into collections which surround and 
englobe the offending parasites. Now, too, cells be- 
gin to slip in from the circulation. Leucocytes 
accumulate in this new, round, globoid speck of 
matter; and a tubercle comes to view. A few more 
days go by; and meanwhile we study the life cycle 
of this tubercle from time to time. What do we 
find? We notice developing under our eyes a 
bloodless growth or tissue formation, which englobes 
and encysts the parasitic invaders and thus shuts 
them off from the rest of the body. The bacilli 
are held within a globular, bloodless wall,—a wall, 
as it happens, of thickness and density which vary 
to a degree. As long as the wall is competent; as 
long as it holds; as long as interchange of body 
fluid between the interior and exterior of the tubercle 
is at a minimum; as long as the fibrous wall of the 
tubercle prevents the carrying out of bacilli from 
within or a flooding of body fluids from without, 
with a consequent softening of the tubercle, just so 
long will the body have the germs in this initial 
tubercle under control. RESISTANCE 
45 
Fortunately, for most of us, this is the extent of 
our more intimate and involuntary association with 
tubercle bacilli. We become infected but remain 
free from clinical disease: we acquire tubercle but 
not tuberculosis. And, once having tubercle, it 
may be that, with never a symptom of specific illness, 
we will go through a long life without thoroughly 
eradicating the tubercle bacilli from our bodies. 
Practically every one of us receives at least one 
infection. No doubt, infection of every degree 
takes place, from infection with one or several 
bacilli to that with huge numbers. Presumably 
many of the slighter infections die out completely: 
presumably too—for the opportunities for infection 
are here—their possessors again often undergo 
infection. There is a growing body of evidence to 
show that much tubercle may heal, and disappear 
without leaving a trace. There is also case after 
case to prove that much tubercle persists, either 
perfectly quiescent throughout life and under condi- 
tions of normal living, or for years and years, when 
active tubercle may develop from it. We can- 
not speak with scientific fulness and accuracy, 
but our present knowledge would make it appear 
that at any time most of us harbor tubercle bacilli, 
either those of a first infection or a reinfection, and 
that in a large number of us the bacilli of a first in- 
fection are never entirely wiped out, yet never bring 
about illness. 
Why then, if all become infected, do so few of us 
fall ill? Where does resistance begin, what does it 46 
RESISTANCE 
consist of and how far does it go? For surely there 
must be some resistance: otherwise, the bacilli 
would multiply and spread through us like wildfire. 
Under the very special premises that I have out- 
lined, is the resistance one to initial infection or 
implantation, or is it merely to subsequent extension 
and invasion? Has any man or animal a native 
resistance to first infection by a type of tubercle 
bacillus to which his kind is susceptible? 
We know that several infectious diseases do not 
decimate civilized communities in the way in which 
they cut down primitive peoples. If introduced 
among the Esquimaux and South Sea Islanders, 
measles and tuberculosis are real plagues, but to-day 
they occur as relatively benign diseases among 
peoples who have a long history of community life 
behind them and among whom they have existed 
for several centuries. For this reason we postulate 
and teach that some groups have developed a racial 
immunity to tuberculosis and measles. This may 
be true to a certain extent; but this racial immunity 
is not an over-resistance to infection as such. If 
exposed, practically every child on earth still de- 
velops measles and practically every human being 
responds with tubercle. In other words, all become 
infected; and we cannot assume that there is any 
native resistance to implantation of the micro- 
organism. 
Again, if a person is not tainted with tubercle we 
cannot by any known method demonstrate that he 
harbors substances that may be antagonistic to the RESISTANCE 
47 
tubercle bacillus: no matter what his stock, we 
cannot put in evidence that he possesses an “im- 
mune substance’ ’ which a member of another race 
may lack. If we treat an animal by certain pro- 
cedures we may find several bodies like agglutinins, 
aggressins, precipitins and opsonins, in its blood; yet, 
unless by infection we give the animal anatomic 
tubercle, it will not be more resistant to a given 
infection than any other normal and noninfected 
animal of the same species that has not been thus 
treated. Because of these facts we must assume 
that man and animals have no native resistance to 
infection by tubercle bacilli in the sense that born 
in them is some substance or substances that 
specifically destroy or neutralize tubercle bacilli 
that gain entrance to the body. 
But, let us now examine more positive phases of 
resistance; and, first, what I choose to call the 
mechanical element in resistance to tuberculosis, 
an element which comes into play after the act of 
infection has been accomplished and its issue remains 
to the future. 
I have often wondered why pathologists have not 
paid more attention to the architecture of the 
tubercle, as a formation designed by its very struc- 
ture to resist further invasion by the bacillus. To 
me the most impressive feature of a tubercle is the 
fact that here we have a wall built around a foreign 
body, that the wall is formed around the foreign 
body to encyst it, shut it off and render it innocuous 
to the infected host, and that as long as the wall 48 
RESISTANCE 
holds the germs cannot get out and spread through- 
out the body of the host. For how does resistance 
manifest itself to us? Through whether infection 
remains confined, does it not? A spreading infec- 
tion arouses in us ideas of nonresistance or a failing 
of resistance: a well limited one suggests that re- 
sistance of host is good. After all, tuberculosis 
takes on gravity as it extends its boundaries and 
spreads; so patent is this to us that, without think- 
ing, we call an infection which remains limited a well- 
resisted one. 
As long, then, as the wall holds the germs cannot 
get out and spread throughout the body of the host: 
this is resistance. And a necessary condition to the 
competence of the investing wall is fibrosis and a 
minimum of circulatory give and take between the 
interior of the tubercle and the tissue that sur- 
rounds it: this is a mechanism of resistance. 
We can go even further. We can affirm that, by 
and large, it is the constitutional symptoms that 
make the clinical disease, tuberculosis, and that to 
produce symptoms of disease the tubercle must 
give up something in itself to the body and that the 
latter must absorb this material. The body can 
absorb something from the tubercle only if there is 
again a sufficient circulatory give and take between it 
and the tubercle, and this circulatory exchange will 
be directly proportionate to the degree of fibrosis or 
sclerosis of the investing wall. 
Thus, resistance to further spread of bacilli and 
freedom from symptoms are to be understood not RESISTANCE 
49 
in terms of the body producing some fighting units 
which go out to battle with the germs or to neutra- 
lize their poisons. They are to be understood as 
being the results of a mechanical barrier which the 
body interposes between itself and the parasites. 
Suppose a man has such a tubercle in his lung 
and lying close to a blood vessel. It has never 
made itself manifest. The man has always been 
in perfect health. In perfect health he runs a hard 
race or plays a fast tennis game. Like a bolt from 
the sky a pulmonary haemorrhage strikes him down, 
and immediately he falls ill. Another man leaves 
home in the morning feeling well. Suppose that 
for years he has had a slow and sluggishly progres- 
sive tuberculous process in a bronchial lymph node, 
yet has never had a symptom from it. Suppose 
further that while he is at his desk the last tenuous 
sheath between this focus of caseation and the 
lumen of his bronchus is broken through, perhaps 
because of coughing or sudden muscular effort. 
And suppose that the contents of this focus are dis- 
charged into his bronchus and scattered broadcast. 
Such a man comes home in the evening sick, with 
beginning tuberculous pneumonia. 
Suppose now that in a third man a small lymph 
node lay close to his thoracic duct and that firmly 
shut within its capsule there smouldered tubercle 
for years. But the time comes when the tubercle 
ulcerates into the thoracic duct, and from full health 
the man is precipitated into generalized miliary 
tuberculosis. 50 
RESISTANCE 
What shall we say about such patients? Shall 
we say that they developed acute tuberculosis 
because their resistance gave way? Yes, we may 
say so. But what did their resistance consist of? 
In these cases resistance surely meant that foci of 
infection and potential clinical disease were isolated 
and confined by barriers of tissue, and that when 
the barrier went resistance went. 
Let us take another instance. Here is a tubercle 
in the lung, with bacilli well shut in and wall 
thoroughly competent under ordinary conditions 
and its possessor a healthy man. He develops a 
common cold or bronchitis and soon afterward 
presents symptoms of pulmonary tuberculosis. In 
terms of resistance how shall we view the onset of 
his tuberculosis? I have often heard just such 
cases explained in terms something like this: that 
the acute respiratory disease lowered the man’s 
resistance and left him in a run-down condition, and 
that the cells of his body therefore lay more open 
to attack by the tubercle bacillus. We need not 
pay detailed attention to the lack of precise reason- 
ing in such an explanation. But I should like to put 
forward one which seems much more plausible and 
square, I believe, more with physiological facts. 
Is it not more likely that during the man’s “cold” 
or bronchitis there was a certain amount of con- 
gestion of the affected tissues, that this congestion 
extended to the neighborhood of the tubercle and 
that it thus established new or better channels of 
communication and circulation between the tubercle RESISTANCE 
51 
and surrounding tissue, penetrating or opening the 
capsule and thus allowing an alteration of the ana- 
tomic character of the tubercle, or an increased 
absorption of focal substances, or a fresh dissemina- 
tion of interned bacilli? If hard exercise will pro- 
duce the circulatory conditions favorable to the 
breaking through of old tubercle and thus cause 
unlooked-for haemorrhage, why will not congestion 
exert a more or less similar action and bring about 
the same result? Here again resistance is a matter 
of simple mechanics: the patient is as resistant as 
the shell of his tubercle. 
Hard physical exercise, sudden and intense muscu- 
lar exertion, emotional stress, coughing, a common 
cold or other acute respiratory infection, childbirth, 
tuberculin in overdose, alcohol, all can produce the 
same circulatory effect in the neighborhood of 
tubercle and, theoretically at least, can bring about 
the same result, a better exchange between tubercle 
and host, with a recrudescence or enhancement of 
symptoms, or a mobilization of bacilli, or both. 
This may be momentary, it may be prolonged, it 
may be occasional, or it may be repeated. If the 
congestion or inflammatory stimulation is not over- 
done, proliferation and repair will set in and good 
may result. If it is too intense, dissemination and 
progression of disease may ensue. But there is no 
doubt that what we have been accustomed to call 
resistance is more or less bound up with the 
mechanics of the circulation around tubercle and 
the structure of tubercle itself. At any time every 52 
RESISTANCE 
tubercle has its maximum of stress which it can 
withstand: physiological activity in the neighbor- 
hood, that is, an environmental factor, supplies 
the stress: and whether activity or extension of 
infection will occur or not is always a matter of 
balance between the competence of the resistance 
against the environmental stress that may be 
applied. 
The body responds to exercise in a definite way: 
the pulse rate and blood pressure rise, and respira- 
tion increases in rate and amplitude. It is not 
difficult to imagine how the lungs are affected under 
these circumstances and what might happen to 
old encysted tubercle, given the proper quantitative 
factors. We recognize this fact in treatment, 
particularly when we warn patients to suppress 
cough as much as possible: in the words of Lawrason 
Brown, “excessive cough is the worst form of over- 
exercise and favors a quick deterioration of the 
bodily resistance.” By rest we aim to put the 
lungs in as complete circulatory inactivity, relatively 
speaking, as possible, and we do raise the patient’s 
resistance thereby. But we do this in a mechanical 
way by striving to avoid any manoeuvre which will 
enhance the activity of the lung and the tissue 
around the tubercle. 
I have no doubt that appearances which often 
pass for features of resistance, or a lack of resistance, 
are the result of purely accidental factors. Con- 
sider those which again and again must modify 
the course that tuberculous infection and disease RESISTANCE 
53 
are going to take. In our struggle to attain defi- 
nite concepts and generalizations of causal rela- 
tions in medicine, I sometimes think that we are all 
too prone to forget or disregard the large part that 
accident plays in the development and termination 
of a pathological process. One man may have 
vegetations on his heart valves, and these may be 
frequently shed off and carried to skeletal muscles: 
in this case no harm may result, and the event 
passes unnoticed. But another man with an iden- 
tical cardiac condition may have the first particle 
which breaks loose swept into his coronary artery: 
and he drops dead. In a similar way accidents 
undoubtedly determine the course of tuberculo- 
sis. What is the leading feature of progressive 
tuberculosis? Wliat makes tuberculosis progres- 
sive? It is the succession of eruptions of new 
tubercles which spring from the seeds of bacilli 
transported to new soil, now near, now remote 
from parent tubercles. What determines where 
first infection shall settle down,—the exact point 
where it will reside? "What marks out the abiding 
place of daughter bacilli that are carried from older 
foci? No doubt, one decisive factor is the activity 
of the host at the particular time when infection or 
metastasis is taking place. His activity will be re- 
flected in the functional activity of his organs and 
tissues, which respond always quickly and delicately 
to the variable demands made upon the several 
parts of the body. And what a man may be doing 
during the moments that infection or extension of 54 
RESISTANCE 
infection is going on is surely fortuitous. There are 
accidents of time and there are accidents of place. 
For a moment I may touch upon the latter first. 
It surely makes a great deal of difference whether 
a first infection (or a later one) in the lungs develops 
near the pleura or at the root or next to a large blood 
vessel or at the apex. The brain is not the only 
organ of the body that has its silent and its eloquent 
areas. The lungs have theirs too: and both the 
immediate and later effects of identical tubercles,— 
identical structurally and in rate of development,— 
will, if the tubercles are placed differently, be not 
so much a matter of resistance as of location. The 
original localization followed no laws of resistance: 
it was no doubt the cumulative result of several 
accidental circumstances—of size of infecting clump, 
and driving power of the circulation of propelling 
lymph or blood, and calibre of channel of transport, 
and amplitude of respiration, and a dozen other 
variable moments. And a similar train of acciden- 
tal, forces will attend the entire life history of the 
infection, as it remains fixed or reaches out from 
place to place. To say that a man, who had a 
caseous lymph node erupt into the thoracic duct, 
went to his death with generalized miliary tubercu- 
losis because he lacked resistance to tuberculosis, or 
that another man, whose cheesy neck node breaks 
through the skin, remains in comparative health 
because of his good resistance to tuberculosis, would 
be of a piece as to affirm that a man who fell dead 
lacked resistance to coronary embolism. RESISTANCE 
55 
The first man, above cited, dies of tuberculosis; 
the second suffers little. Here are two dramatically 
opposite effects of what can easily be identical 
fundamental causes, so far as the nature of the 
infection and the nature of the host are concerned. 
The tubercles in retroperitoneal lymph nodes and in 
neck nodes were exactly alike in age, in rate of 
development, in structure, in content and virulence 
of bacilli, in tissue which harbored them. Wherein 
lay the difference of resistance? In the accident 
of a difference of location. And we may be sure 
that the same factors of accident are continually 
at work in the body; but as a rule beyond our ob- 
servation, and deluding our senses with semblances 
of resistance and susceptibility—that is, if we still 
lisp resistance every time a sufferer is doing well and 
lack of resistance whenever he is failing. 
And now the accidents of time. A great deal 
may depend on just when a patient contracts an 
intercurrent infection, such as acute bronchitis, 
or undergoes unusual strain. The same episode in 
his life may produce very different results. It may 
take place when concealed tubercle is thoroughly 
sclerotic and therefore proof against the changed ana- 
tomic and physiological processes going on in its 
neighborhood. Or it may occur at a time when the 
investing wall of tubercle has just the proper struc- 
ture to establish fresh and easy communications with 
the surrounding tissues under the right conditions. 
Perhaps this is why infants and young children, 
if compared with adults, withstand infections rel- 56 
RESISTANCE 
atively poorly so far as the effect of these on 
quiescent and unsuspected tubercle is concerned. 
Their tubercle is of comparatively recent origin and 
in transitional stages of development, and is much 
more imperfectly fibrosed or healed and is thus more 
open to outside forces. As they grow older, this 
healing process has advanced further and further, 
and encapsulation of bacilli is better established. 
We are familiar with the result: for we say that in 
regard to tuberculosis five to fifteen years is the 
golden age of man’s span. Infection tests disclose 
roughly that about one-half of us city dwellers 
are infected by age five or six, and three-fourths by 
fifteen years. This means that two-thirds of the 
infected strike contact with tubercle bacilli during 
the first six years of life; and that, for most children 
in mid-childhood and later, whatever infection per- 
sists is relatively old. 
After we pass puberty we enter a period of from 
fifteen to twenty years when life’s stresses are at 
their maximum and our reactions to them at the 
same time more intense and vigorous. In many 
cases this increased mental and physical strain 
produces local effects which are more upsetting 
than even healed tubercle will bear. I say “healed” 
with some mental reservation. Perfect healing, as 
we have seen, can and does take place. But healing 
is not infrequently more apparent than real; for I 
would have you recall that living tubercle bacilli 
have been found in the chalky deposits of tubercu- 
lous foci that had healed with calcification. It is RESISTANCE 
57 
for these reasons that I am very fond of telling our 
students that the development of tuberculous disease 
from old benign tubercle depends largely on whether 
the patient gets measles or a cold, or rows a race, or 
becomes pregnant, or goes into bankruptcy at the 
wrong time. 
We have thus far discussed the protective reaction 
by which the tissues seek to hem in and wall off 
the first tubercle bacilli that enter the body and 
exert an effect upon it. We have also considered 
local conditions through which the body resists the 
development of tuberculosis. We have looked upon 
tubercle as a growth or formation, the periphery of 
which acts as a barrier to the egress of bacilli, yet 
is subject to all the physiological disturbance that 
goes on around it. We have seen how the per- 
manence of benign tubercle or the conversion of 
this into tuberculosis with symptoms will depend 
largely on the mechanical interaction and balance 
of these opposing forces. We may anticipate; and 
forecast that upon the latter will play many factors 
of heredity, environment and acquired characteris- 
tics, such as new methods and habits of bodily 
reaction specifically created by the infection. We 
may now extend our analysis to an inquiry into 
those conditions which bring into being the patient 
who presents himself to us with active tuberculosis. 
A person with tuberculosis consults a physician 
because he has symptoms due to his infection, be 
these ever so slight or ill-defined. If he noticed 58 
RESISTANCE 
nothing unusual, uncomfortable or wrong, he would 
not seek medical light and counsel. Symptoms, and 
symptoms alone, betray active tuberculosis. 
Few persons, except very young infants, pass at 
once and uninterruptedly from initial tuberculous 
infection to symptoms. Between the two incidents 
there is an interval of weeks perhaps in a few, or 
months or years in most. All our experience would 
teach us that the ordinary course of the infection, 
even in those who become ill, is marked by longer or 
shorter periods of development and subsidence, and 
of extension and retreat of morbid anatomic change, 
before first symptoms make themselves felt. At his 
very first visit to the physician, the usual tuberculo- 
sis patient has never, I believe, only a single focus 
which represents the exact spot where first infection 
took hold. In the simplest and most elementary 
cases there are undoubtedly several foci. In some 
these may all be comprehended within a very small 
space, yet they represent extensions from some older 
area or areas, and there will always be infection of 
adjacent lymph nodes, whether this is obvious or 
not. 
A process like this takes time to evolve. It comes 
into being haltingly, and by fits and starts, and, until 
symptoms at last come forward, insensibly, and 
unknown to the possessor. As one reads the general 
run of papers on tuberculosis, one gets the impres- 
sion that a good deal of hair-splitting has attended 
our efforts to arrive at a concept and definition of 
activity. Attempts to limit the idea of activity to RESISTANCE 
59 
those cases which exhibit symptoms, either spon- 
taneously or after certain tests of function, provoke 
the rejoinder that there is or can be an activity 
without symptoms—a state that goes under the 
designation of pathological activity. 
This is all very true; but what of it? As a matter 
of fact, every soul alive who responds to infection 
tests must have had some pathological activity. 
Infection tests are indices of the presence of tubercle, 
and the formation of even microscopic tubercle 
represents the stirring at some time or other of some 
pathological activity. The proliferation of a dozen 
cells in response to a single tubercle bacillus is 
pathological activity. No tubercle ever came to 
light except through pathological activity. Pre- 
sumably, no man who has taken in bacilli which 
tarried for a time has ever escaped pathological 
activity of his infection. 
But 80 or 90 per cent of us recipients and carriers 
of infection never experience a symptom of it. 
Pathological activity, therefore, takes on significance 
only as it brings on that state which will be expressed 
symptomatically. Attention to pathological activity 
can no doubt serve its purpose; for instance, in the 
patient with established clinical tuberculosis, when we 
wish to anticipate whether symptoms are likely to 
improve or grow worse. But one will be hard put 
to it to use with any degree of accuracy standards 
of pathological activity to detect or forecast or 
prevent the onset of clinical tuberculosis. Phthisio- 
genesis in practice begins when symptoms begin. 60 
RESISTANCE 
The man with pulmonary tuberculosis becomes a 
patient not after a lobule or a lobe or a whole lung 
becomes a tuberculous structure, but as soon as he 
displays symptoms that are undoubtedly those of 
tuberculosis, even though morbid change is so slight 
or so concealed as to be beyond our observation. 
There is the man with haemoptysis who reveals 
nothing to the stethoscope or the Coolidge tube: he 
has active tuberculosis. There is the man who has 
the work of twenty years of pathological activity 
moulded within his chest, a storehouse of abnormal 
signs and shadows: yet, never ill or disabled, his 
disease has never been active. 
Active tuberculosis, then, is tuberculous infection 
with symptoms. But why symptoms? Under what 
circumstances, symptoms? If we answer these 
questions we likewise throw some light on the 
mystery of why some with infection develop active 
tuberculosis while in most the infection remains 
quiescent. And if, as is often maintained, “resist- 
ance” is the force which keeps infection inactive, 
we may also contribute something to an under- 
standing of resistance. 
For thoroughly good and sound reasons the 
symptoms of tuberculosis have long been classified 
as of two types, which differ in mode of origin 
and in part affected. We recognize some as local 
symptoms and others as constitutional symptoms. 
We find that the former are manifestations of 
impaired function or tissue damage, of structures 
in which tubercle is present, and that this impair- RESISTANCE 
61 
ment or damage results largely from physical forces 
directly applied by the tubercle and set in play by 
it. On the other hand the constitutional symptoms 
affect the body as a whole or parts of it remote from 
the seat of disease, and are plainly the effects of some 
noxious substances which are given out by the 
tubercle and transported to centres which regulate 
the more general body functions. 
Tissues may be damaged by the local effects of 
tubercle in a way that precludes complete restitution 
to normal. Local symptoms may therefore persist 
after tuberculous infection has died out or after 
anatomic repair is concluded. They may, therefore, 
continue after arrest of clinical activity. But the 
possibility of inactivity cannot be entertained as 
long as constitutional symptoms are manifest or 
can be induced. Constitutional symptoms become 
therefore our best indicator and guide of activity, 
and it is these which may illumine the indefinite and 
shadowy line between the actual and potential 
patient. 
Why has the actual patient constitutional symp- 
toms? Because he is absorbing something from his 
foci of disease. Why does he absorb something? 
Because there is a sufficient circulatory (blood and 
lymphatic) give and take between his foci and the 
surrounding tissue. Why this circulatory give and 
take? Because the walls, the envelopes, the invest- 
ments of these foci are not competent to block off 
the interior of the tubercles against particular out- 
side forces that may be brought to bear upon them. 62 
RESISTANCE 
If, in course of time, these walls become more and 
more fibrous and more impervious, the severity of 
the patient’s symptoms will surely diminish. Pas- 
sage of focal substances will be much less through a 
dense and thick envelope than through a thin or 
filmy one, and an enhanced circulation and lymph 
content around tubercle will bring about those 
physical conditions which promote this transit. The 
rate and amount of absorption of focal material, 
therefore intoxication, therefore constitutional symp- 
toms, will always be governed by these two factors. 
This fact is so obvious that I consider it hardly 
necessary to enlarge upon it. Designedly or other- 
wise, we put into practice this principle in every 
recognized method of treating our patients. 
When we induce artificial pneumothorax, we 
exert the most direct effect upon the process in the 
lungs. Just what do we aim to do? To put the 
lung at rest, of course. Yes, but what happens then? 
The excursions of the lung cease, its circulation 
becomes relatively quiet, less lymph bathes the 
tissues, absorption from foci of disease goes on at a 
much lower level or stops altogether, constitutional 
symptoms improve and disappear, and with a 
lessening of hyperaemia around the morbid process 
peripheral fibrosis goes on better. 
Or we put the symptomatic patient at bodily rest. 
With the slowing down of circulation and respira- 
tion, symptoms may abate—often with astonishing 
rapidity. If now we allow our patient to exercise, 
symptoms recur—perhaps immediately. This sub- RESISTANCE 
63 
sidence of or relief from symptoms cannot be due to 
any neutralizing agents which the body elaborates, 
for we cannot imagine that such a prompt response 
to rest or exercise would occur under these circum- 
stances. Rest and exercise exert an immediate 
effect on respiration and circulation and these in 
turn set the pace for focal absorption. It is not 
uncommon for patients who suffered markedly from 
the constitutional symptoms of absorption while they 
had incipient tuberculosis to inform you that they 
feel better after bacilli appear in their sputum. 
Bacilli in the sputum usually means that the pul- 
monary process has ulcerated. Here by ulceration 
Nature has applied the prime surgical procedure of 
more or less thorough evacuation of disease with a 
consequent amelioration of constitutional symptoms. 
In another instance it may happen that we give 
an entirely asymptomatic patient an overdose of 
tuberculin. Malaise, fever, rapid pulse, distaste 
for food, all the well known constitutional symptoms 
of tuberculosis, promptly appear. Tuberculin is not 
a bodily poison: it will not make ill a man without 
tubercle. What happens then in the man with 
tubercle? Undoubtedly something like this: Tuber- 
culin exerts a direct inflammatory effect on the 
tissues of animal bodies that harbor tubercle. This 
action is particularly marked on those tissues which 
are immediately adjacent to and in contact with 
tubercle. They inflame; and there results the well 
known focal tuberculin reaction, a phenomenon that 
is marked by hyeraemia, congestion and inflamma- 64 
RESISTANCE 
tion which, beginning in nearby nontuberculous 
tissue, rapidly comes to involve the tubercle. After 
giving tuberculin to a rabbit with corneal tubercle 
it is instructive and impressive to watch healthy 
eyelids become red, and then fine blood vessels 
come into view and push their way across the 
cornea to the focus of disease, and the entire eye 
soon involved in acute inflammation. Here, then, 
is the same enhanced circulation, which we have- 
been discussing, affecting the envelope of tubercle 
in a way that tends to make it more open, and pro- 
moting the insweep of material from focus to the 
general circulation. 
Marcus Paterson gets the same immediate result 
without recourse to a specific agent like tuberculin. 
He simply puts his patients to work until they get 
what he terms an “auto-inoculation.” And how 
do we recognize this auto-inoculation? By the 
same familiar constitutional symptoms of active 
tuberculosis or of the general tuberculin reaction 
which is really an evanescent episode of active 
tuberculosis. The investment of every tuberculous 
structure has its own limit of resistance to stress—to 
amount, pressure and velocity of lymph and blood 
flow and to rate and amplitude of respiratory excur- 
sion which, of course, influence the former. As soon 
as the labor prescribed by Paterson brings into 
play the proper amount of stress, the particular 
patient will take over to his body focal material 
enough to bring on constitutional symptoms. RESISTANCE 
65 
The point is that the presence or absence of 
symptoms is to a large extent contingent on focal 
mechanics. I think that we can say with perfect 
assurance that increasing fibrosis means a gradual 
release from symptoms, while increasing degenera- 
tion and necrosis—softening, as we term it—without 
coincident and sufficient peripheral fibrosis mean 
added severity of symptoms. The man who has 
extensive anatomic tubercle with comparative free- 
dom from symptoms has his tuberculous process 
well sclerosed and hemmed in. The man who 
has marked constitutional disturbance with but 
slight anatomic change has very slight or imperfect 
focal investment. Whether inactivity passes over 
to manifest disease is frequently determined, not by 
any lack or failure of a hypothetical inherent quality 
of tissue or bodily resistance, but by experiences 
which infected persons are called upon to undergo, 
experiences which set up functional disturbance 
sufficient to bring about that amount of focal 
absorption which is sufficient to produce symptoms. 
Granted that the patient, that most of us, possess 
an indefinable specific resistance, this remains the 
same while we lapse from latency to activity under 
the spur of an unusual environment. Resistance, 
inborn or inbred in tissues, is not wiped out in the 
minute that it takes to run a quarter-mile or the 
fraction of a second that compasses the impact of a 
club with the chest, yet this interval will change a 
healthy person into one sick with tuberculosis. I 
would not maintain that this mechanical element is 66 
RESISTANCE 
all that there is to resistance to symptoms. In fact, 
I plan to discuss other components in the course of 
this essay. But the mechanical side looms large in 
any check which the body offers to the manifestations 
of the disease. 
And, as far as any extension of anatomic change 
is concerned, we can neglect all other factors and 
assert almost dogmatically that, as long as fibrosis 
is the predominant element in any particular case, 
just so long are fresh eruptions of tubercles much 
less likely to occur than if degeneration and caseation 
had gained the upper hand. What gives us our 
conception of progressive tuberculosis? It is ex- 
tension and spreading of the infection. While 
clinical (or latent) infection remains limited and well 
localized we are accustomed to think of its possessor 
as resistant; just as we speak of a failure of resistance 
when we observe infection enlarging its boundaries 
or being repeated in daughter foci from place to 
place. Again, we may admit the actuality of a 
native or acquired habit of bodily constitution 
which we, in various degrees of vagueness, conceive 
of as joining in effective combat with the germs of 
disease, and which we may call resistance; but we 
would at the same time hold fast to a view of a 
resistance which consisted in large measure of local 
mechanical conditions unfavorable to first infection 
or later eruptions. 
Besides the physical resistance which the body, 
through the production of peculiarly designed 
structures, offers to the release of symptoms and the RESISTANCE 
67 
spread of infection, it also possesses an entire system 
of highly competent mechanical checks and barriers 
which must enter into any comprehensive concept 
of resistance. 
Tuberculosis is essentially a lymphatic infection. 
Entering by digestive tract, the germs penetrate the 
mucous membrane of mouth, throat or intestine, 
and come at once within the domain of the lymphatic 
system. In very many instances they pass imme- 
diately into lymphoid tissue like the tonsils or the 
follicles of the intestine. If they are carried further 
into the body, always by lymphatic paths, they are 
soon intercepted by lymph nodes. So far as I know, 
the evolution of the parts and organs of the body 
has not proceeded capriciously. I cannot imagine 
that the lymphoid tissue, nodes, follicles, etc., of 
the body owe their particular distribution and 
quantity, which vary for the several animal species, 
to the requirements of ornament, symmetry or the 
prime animal functions of “getting and begetting.” 
As a matter of fact, they are always situated in 
greatest abundance near those places where there 
are the greatest numbers of foreign bodies (bacteria) 
or they communicate directly with these. The neck 
is an example of this circumstance, and the enor- 
mous increase of lymphoid tissue which becomes 
manifest as we proceed from the highly motile and 
bacteria-poor small intestine to the relatively slug- 
gish and bacteria-rich large intestine is a striking 
instance. Wherever the normal processes of life 
make for most irritation of superficial tissues through 68 
RESISTANCE 
foreign bodies, as well as promote the entrance of 
these particles into the depths of the tissues, there 
you are bound to find lymphoid tissue relatively 
plentiful. We cannot view the lymphoid tissue 
otherwise than as taking an important part in 
blocking the passage of bacteria to more vital 
organs. 
Bacilli which gain any part of the respiratory 
tract in the nontuberculous young are for the most 
part similarly carried to lymphoid tissue,'—to the 
deep nodes of the neck or those at the roots of the 
lungs. Those, again, which come to the lungs by the 
blood from foci elsewhere in the body, tend in early 
life to be carried out of the transporting blood 
vessels into the lymphatic network of the lungs 
and proceed by way of this to the root nodes. 
It happens, therefore, that the ordinary early 
tuberculous infections of life, which almost everyone 
to-day acquires, are first localized in lymph nodes, 
usually the submaxillaries and deep cervicals, the 
tracheobronchials and mesenteries. It happens also 
that, when disease manifests itself in early life, it 
does so most frequently in these nodes or, in a large 
proportion of cases of extralymphatic disease, its 
origin can be traced to these nodes. 
What is significant is that in the great majority 
of infections—fully 90 per cent—the lymph nodes 
are competent in restraining the infection and 
keeping it quiescent. In experimental work I have 
long been impressed by the great resistance which 
they offer to the spread of infection, and particularly RESISTANCE 
69 
to the development of progressive and florid disease 
within themselves. In guinea pigs, unless the nodes 
are receiving large and continuous doses of virulent 
bacilli from more superficial foci which they drain, 
they will keep under control astonishing amounts of 
infection without becoming markedly diseased. The 
average picture is tumefaction, with caseation which 
is well balanced by sclerosis; to an extent, indeed, 
that, if we consider all nodes in the body, sclerosis 
usually gains the upper hand and comparative 
healing is the result. When infection seizes upon 
those smaller collections of lymphatic tissue which 
reside normally within organs and which are not 
true nodes, as in the spleen, the result is usually dif- 
ferent; for it is in these places that we are accustomed 
to find infection developing and progressing. Yet, 
as has just been mentioned, these are not true nodes: 
their structure is quite different as regards tor- 
tuosity of lymphatic vessels and spaces within them 
and they usually exist in peculiarly intimate relation- 
ship with blood vessels. 
Now, lymph nodes and lymphoid collections are 
intercalated at innumerable places along the paths of 
that wonderfully luxuriant and intricate meshwork of 
lymphatics which courses everywhere in the body. 
They undoubtedly intercept many bacteria in their 
transit from the surfaces of the body to the interior 
and thus preserve important organs from massive 
and telling infection and contribute to general 
resistance to tuberculosis. They surely do this in a 
mechanical way by holding up bacilli: a “filtering” 70 
RESISTANCE 
process is the popular conception, but quite likely 
this is not wholly accurate. 
Whether they also act by destroying tubercle 
bacilli through the agency of some constituent 
peculiar to themselves, the lymphocyte for instance, 
is among the undetermined problems of resistance 
to tuberculosis. For thirty years and more there 
has been published an enormous amount of work 
designed to prove that lymphocytes are bacteri- 
cidal for tubercle bacilli. This may be true. But 
whether lymphocytic activity is an important ele- 
ment of resistance to tuberculosis must surely be 
considered as open to argument to-day. We meet 
with undoubtedly increased resistance to the infec- 
tion again and again, under circumstances that fail 
to disclose any association with lymphocytes. The 
fact, known for three decades, that tubercle bacilli 
may persist in small numbers in lymph nodes for a 
long time speaks against a specific ultra-antagonism 
of lymphocytes to them. The tendency of infection 
to develop more in lymphoid collections which are 
not true nodes than in real lymph nodes suggests 
strongly that the structure of the latter is a more 
potent restraining influence than the properties of 
any cells peculiar to it. 
Whatever be the agent at work—and I consider 
a mechanical action as surely playing a part here— 
the fact remains that the lymph nodes in general 
put limits to tuberculosis. The more I observe 
infection and disease in human beings and in animals 
of experiment, the more I am impressed with the RESISTANCE 
71 
function of these small organs as instruments of high 
resistance to the unchecked spread of tuberculosis. 
A sound and competent lymphatic system is a 
strong defense. Unobstructed lymphatic paths, 
permitting free and easy passage to the nodes, will 
allow focalization in the nodes themselves where the 
bacilli are comparatively harmless. Blocked chan- 
nels promote the settling down of germs in tissues, 
the infection of which may be of graver concern. 
Nodes placed between the portal of entry and an 
organ spare the central organ. Open lymphatic 
channels with normal lymph flow in an organ tend 
to carry bacteria away from a part and thus spare a 
peripheral organ. 
Our argument thus far has been concerned with 
establishing the position that nonspecific factors can 
play a decisive part in contributing to a result which 
has all the appearances of being due to a resistance or 
a susceptibility to infection and disease. That is 
to say, inactivity puts on a face of an infection 
being resisted well, and activity the reverse. What 
does really determine activity or latency at times 
are purely accidental factors of location of infection 
and time of occurrence of those stresses capable of 
exciting foci of tubercle to renewed vigor. At the 
same time, in every instance there is always another 
resistance which stands between the body and the 
activities of the parasite. We have designated this 
as a mechanical resistance, one that comes about 
through the interposition of two important barriers 72 
RESISTANCE 
between germ and host. These are the systems of 
lymph nodes, a function of which is to intercept 
and restrain foreign particles, and the peripheral 
p‘art or investing envelope of every tuberculous 
process. This mechanical resistance is more or 
less competent and sufficient, according as a part of 
the lymphatic system concerned is functioning more 
or less normally, as peripheral fibrosis of tubercle 
keeps ahead of or behind central degeneration and 
necrosis. 
All this, of course, has been hardly anything more 
enlightening than a sharper delineation of concepts. 
It has made little progress to the root of the matter. 
Although we may say that good resistance is the 
accompaniment of a sound and competent lymphatic 
system and of tubercle that scleroses rather than 
“softens” and breaks down, before we can venture 
to understand why resistance is high or low we 
must explain why lymphatic systems differ and why 
some tubercles run to scar tissue rather than to 
caseation. 
A partial explanation is to be found in much that 
we have already said. The integrity of the lym- 
phatic system and of tubercle is frequently in- 
fluenced and its character altered by antecedent 
experiences (environment) of the person. This is so 
plain that it need not be gone into further. 
But there is undoubtedly a good deal more than 
this at work. The manner in which tissues react 
determines in no small measure fibrosis and casea- 
tion, degeneration and repair,'—that is, resistance. RESISTANCE 
73 
Underlying this there is always the presumption that 
different bodily constitutions vary in their kinds 
and capacities of reaction, either natively through 
inheritance or through acquired attributes. There 
are also marked differences of congenital lymphatic 
constitution and behavior: these have always been 
so noticeable that we have long recognized the more 
prominent manifestations as deserving of special 
classification and have tried to bring under the 
“lymphatic diathesis” everything from unusual 
tendency to adenoid growths to “lymphatism” and 
“status lymphaticus.” The numerous and multi- 
form congenital aberrations of the lymphatic system 
and their significance in relation to infections receive 
attention in every textbook on medicine. They 
will therefore hardly repay discussion here, except 
that I would point out that, whatever be their 
real nature and whether they represent primary 
and essential abnormalities by inheritance or merely 
reflect more deep-seated changes of the same nature, 
they are striking examples of an apparent association 
of congenital traits and a resistance to infections 
that is below par. It will no doubt be more profit- 
able to confine the rest of our discussion to an 
examination of the probable factors that influence 
or determine the reaction to irritation in general 
and to the tubercle bacillus in particular. 
The ability to form defensive tubercle is a native 
or basic attribute of tissues. It is at bottom the 
power to react to a certain type of irritation by the 
multiplication (proliferation) and proper arrange- 74 
RESISTANCE 
ment of cells. We would assume that the capacity 
to react vigorously to a given irritant in this way 
would make for better protection than a feeble 
reacting power. In the case of infections, over- 
reaction makes for better defense than under- 
reaction. 
Every observing man must be impressed by the 
diversity of reacting power exhibited by different 
people to the same irritant. A very familiar example 
is the varied response to sunlight, through sunburn, 
freckles and tanning. Some men, when wounded, 
will react with a great overgrowth of scar tissue 
(keloid); others, after injury that does not seem 
different in kind or degree, will exhibit only a 
flat and scarcely noticeable scar. Whether one 
tans or is sunburned or produces keloid is surely 
dependent on a native, inherited variation of ability 
to react to irritation. In the case of these particular 
irritants, individual, family and racial variations 
have long been recognized. 
It may very well be that many variations of basic 
reacting capacity come into play in all the contacts 
that are established between us and many irritants. 
We know that the metabolic fault that gives rise 
to gout is inherited. People do not get gout only 
because they eat and drink certain things that will 
give them gout. They suffer from the disease 
because the tendency to gout was born in them: 
others who were not born with this tendency may 
eat and drink gout-precipitating foods with impunity. 
The tendency is quite likely a constitutional aberra- RESISTANCE 
75 
tion or “vice.” Many gouty people belong to a 
distinctly marked physical type: they are short- 
necked and thick-set and have florid complexions 
and reddish hair—all inherited characteristics which 
frequently go hand in hand with the gouty pre- 
disposition. And, in this connection, it may be 
mentioned that the gouty have always been looked 
upon as being peculiarly resistant to tuberculosis. 
Diabetes, another disease of metabolism, as yet 
very imperfectly understood, also appears in certain 
families to such an extent and occurs with such 
frequency in the Jewish race that an inherited basis 
for it is highly probable. Diabetics are unusually 
prone to tuberculosis. 
Maud Slye’s experimental work is extremely 
significant in the matter which we are discussing. 
She works with two large series of mice. The one 
consists of animals that have had cancer bred into 
them; the other, of those which she is continually 
fortifying with a cancer heredity by mating their 
progenitors with members of known cancerous stock. 
She finds that animals of the cancerous strains react 
very differently to irritation than do those of non- 
cancerous stocks. If injured, many of the first type 
develop cancer at the site of the wound, while none 
of noncancerous inheritance ever reacts with cancer 
under the same conditions. Many of the latter, 
however, become ill with the ordinary infections of 
cage life and die. Among the members of cancerous 
strains, infections are very unusual and, if they occur, 
are resisted well. She would therefore generalize 76 
RESISTANCE 
about as follows: Cancer is the result of a congenital 
tendency to overreaction to irritation. Animals 
with this tendency do not easily acquire infections. 
If they do develop them they resist them well. 
Infections strike down the weak. Cancer attacks 
the strong. 
If Maud Slye’s work is sound what shall we say? 
Shall we conclude that the same tissue tendency that 
is responsible for cancer also protects against infec- 
tion? Shall we assume that the irritant, the parasi- 
tic microorganism, gains slight foothold or none at 
all because it is immediately met by an exaggerated 
effort on the part of the body cells to ward it off? 
I am here reminded of a remark which that wonder- 
fully keen observer, Dr. Trudeau, repeatedly made— 
that cancer is a disease of the strong, progressive 
tuberculosis a disease of the weak. He undoubtedly 
based this opinion on his impression that so many 
people who developed cancer had clinical histories 
which were relatively free from infections during 
earlier life. 
Granted that certain capacities of reacting to 
irritation are born with the person, it is also likely 
that the individual’s native manner of reaction 
responds to outside influences and is modifiable by 
these. We shall see that this is certain when 
tubercle bacilli infect susceptible animals. But this 
modification of the way of meeting irritation—of 
resisting infection—no doubt also takes place under 
less specific conditions. I have been highly im- 
pressed by a circumstance which I have observed RESISTANCE 
77 
several times during the course of infection experi- 
ments. If we introduce living virulent tubercle 
bacilli between the layers of the skin of normal 
guinea pigs we may study with particular accu- 
racy the natural evolution of tubercle. The entire 
process comes to light and grows under our eyes. 
Now tubercle develops in these cases because inoc- 
ulated tissues react to tubercle bacilli: there might 
be a flourishing of bacilli, perhaps a septicemia, in 
the absence of cellular reaction, but there would 
be no pathological anatomic process, no character- 
istic tissue change, no tubercle. But in several 
series of inoculations it has occurred that if sick, 
nontuberculous animals were included in the series, 
they did not respond to the introduction of bacilli 
with the formation of tubercle. They lived long 
enough to develop tubercle, through a period in 
which all the healthy members of the series, similarly 
inoculated, did show tubercle; yet sick, weak and 
thin, as they were from other disease, they remained 
free from visible tubercle. 
Observations of this kind surely suggest that an 
intercurrent disease had deprived some animals of 
their native capacity to react to tubercle bacilli, 
to form tubercle. Presumably, also, their resistance 
to tuberculous infection was also changed by the 
intercurrent infection. It is surely not a wild 
assumption that any alteration of resistance would 
dwell in a changed capacity of cellular reaction such 
as I have described. 78 
EESISTANCE 
All in all, I think that we may assume with every 
assurance of justification that men do vary in 
response to irritation. They vary by birth, if 
compared with one another, and the same man may 
vary at different periods under the influence of 
external forces. This variation of response may 
take the form of overreaction, overgrowth or over- 
production of tissue, or of predominant tendency 
to fibrosis, all of which may become revealed to us as 
increased resistance to infection. 
If any foreign body that is not easily assimilable 
gains access to the body the tissues react in a charac- 
teristic way, that is, with the formation of tubercle. 
Similarly, tubercle bacilli which are more or less 
nonassimilable by the tissues incite the formation 
of tubercle. Now there are several things which 
will modify this type of reaction against the irritant. 
One is the number of infecting bacilli. Long ago 
Baumgarten pointed out that if tubercle bacilli 
were very few the earliest tissue response would be 
manifested by the proliferation of only one type of 
cell. If, following a first infection, only a few bacilli 
lodge at a point, then for several days the only 
reaction which we note is a proliferation or new 
growth of those cells which belong to what we de- 
signate as the fixed-tissue type. The resulting 
structure is a minute mass, a nodule or tubercle, 
which has many features of a tumor and few of the 
essentials of an inflammation. Such an early tuber- 
cle may be made up of cells of the fixed-tissue type 
alone: there may not be a leucocyte or any other RESISTANCE 
79 
element of inflammation or exudation in it. Here 
we have really a new growth or tumor, comparable 
to what under ordinary circumstances we would 
call a fibroma. 
If, however, the initial number of tubercle bacilli 
is large, the first reaction is an outpouring of poly- 
morphonuclear leucocytes. But within a few hours 
the fixed-tissue cells begin to show signs of disturb- 
ance, and proliferate. The polymorphonuclear leu- 
cocytes soon disappear, and tubercle formation goes 
on characteristically, with a gradual inwandering 
of leucocytes, mostly of lymphocytic nature, which 
distribute themselves, in diminishing numbers from 
periphery to centre, throughout the mass of fixed- 
tissue cells now termed epithelioid in this location. 
We see, therefore, that under ordinary conditions 
the body reacts to first infection in a variable manner, 
according as the irritation is more or less vigorous 
and intense. But the reaction is very regular and 
definite and, if the infecting bacilli be the first that 
have settled in the body, the result will always be 
the same in that this initial reaction will manifest 
itself as focal tubercle. The relative proportion of 
epithelioid cells and leucocytes in different tubercles 
may vary, but the response to first infection will 
always be focal, with tubercles very definite, isolated 
and discrete formations, with bacilli near the centre, 
and concentric layers of epithelioid cells interspersed 
with leucocytes forming the periphery. And as we 
look at them we think of the wall or barrier about 
which we have said so much. 80 
KESISTANCE 
These reactions go on in a perfectly orderly man- 
ner. Microscopically, they begin to be evident a 
few hours after inoculation, if ordinary doses of 
bacilli are used: macroscopically, they come into 
view from about the eighth to fifteenth day on. At 
the same time, we observe a feature of the utmost 
importance. This is that the animal of experiment 
never exhibits a single trace of illness which can be 
attributed to the immediate or early effects of the 
first infection. No matter how large the dose and 
no matter how inoculated, the first bacilli will 
never bring about any visible change in the guinea 
pig’s or rabbit’s general health. Immediately after 
the infection, and for days and several weeks, these 
animals are as lively and eat as well and have the 
same muscle tone as though nothing unusual had 
happened to them. It is only in the fourth, fifth 
or sixth week after inoculation that they begin to 
show a falling off in health. 
All these constitute the more apparent features 
of what we may call the essential or native or 
inherited response of susceptible animals to tubercle 
bacilli—that reaction which meets a first infection. 
Put a little more sharply, they are (1) extreme 
sluggishness of reaction, (2) lack of inflammatory 
phenomena, (3) predominance of proliferative phe- 
nomena, with the consequent formation of discrete 
nodule or tubercle, and (4) total absence of intoxica- 
tion or any symptoms. 
But as soon as infection is established and tuber- 
cles are formed, the capacity of these animals to RESISTANCE 
81 
react to tubercle bacilli or any of their dissoci- 
ated protein constituents is changed. For instance, 
the series of events is quite different following 
reinfection. 
Then-—that is, after reinoculation of an already 
tuberculous animal—both local and constitutional 
changes take place with great promptness and 
celerity. We may perform such reinfection on the 
same animals to which we applied tubercle bacilli 
a few weeks before and which responded as we have 
described in the preceding paragraphs. But now 
we observe (1) extreme rapidity of appearance and 
development of tissue changes at the points where 
new bacilli focalize, (2) redness, swelling and even 
tissue death, in other words, inflammation, appearing 
at these points within a few hours after reinfection, 
(3) more vigorous and accelerated proliferation of 
fixed-tissue cells which, however, is abortive and 
soon reaches an acme beyond which it does not 
progress, and (4) rapid intoxication of the animal, 
with illness within a few hours and, often, death in 
less than a day. 
Although a few men, as long as a half-century ago, 
had observed this changed habit of reaction, which 
tuberculous infection confers, we really remained in 
ignorance of it until 1906, when Pirquet announced 
his skin test of tuberculosis to the world. We first 
really learned something about it through the appli- 
cation, not of living tubercle bacilli, but of their 
derivative, tuberculin. 82 
RESISTANCE 
Tuberculin contains nothing virulent or alive. 
It has in it products of tubercle bacilli, usually in a 
soluble form. If an animal is without tuberculous 
infection it will tolerate tuberculin with the same 
facility as it would a mixture of glycerin and broth 
that is without products of tubercle bacilli but in 
other respects resembles tuberculin. It will remain 
well if large amounts of tuberculin are put beneath 
its skin or into its belly or a vein. It will exhibit no 
local response, no swelling or redness or soreness, 
to tuberculin applied to its skin through a scratch 
or with a needle into the skin. In other words, a 
nontuberculous animal will not react to a single 
application of tuberculin, either immediately or 
ultimately. The essential or native or inherited 
reaction of animals to tuberculin is nil. 
Not so that of the tuberculous animal, however. 
Infection with tubercle bacilli endows animals with 
something besides tubercle. It changes their whole 
manner of meeting the application of tuberculin. 
It “trains” their tissues to react to tuberculin with 
inflammation and their body to react with intoxi- 
cation. A minute amount of tuberculin put into the 
skin of a tuberculous animal will provoke redness, 
swelling and soreness at the point within a few hours; 
injected beneath the skin or into the belly or a vein, 
it will prostrate the animal with fever and malaise. 
To sum up then: Anatomic tubercle, consequent 
to the introduction of tubercle bacilli, so changes the 
animal body that its tissues react differently from the 
normal to the application of any soluble protein prod- 83 
RESISTANCE 
ucts of tubercle bacilli or to the reintroduction (reim- 
plantation) of living or dead bacilli. 
This newly acquired attribute of tissues has been 
aptly denominated as allergy (a\\ov + e'pyov or 
different action), a term coined by Pirquet. As we 
learn more about allergy, we are coming to realize 
that it plays a prominent and at times a preponderant 
part in all the phenomena of tuberculosis. Appre- 
ciation of its manifestations are demanding that 
we look at many phases of tuberculosis from new 
points of view. It is desirable that in this essay 
I restrict a discussion of allergy to an inquiry into 
its probable relations to resistance to tuberculosis. 
But even this limitation will encroach on pathologi- 
cal and clinical phases of the infection. And, lest 
I should otherwise run the risk of obscurity and 
incoherence, I deem a digression on the nature and 
characteristics of allergy necessary in this place. 
1. Conditions necessary for the development and 
recognition of allergy: These have already been 
touched upon. No dissociated substances of tuber- 
cle bacilli have ever to a certainty brought about 
the allergic state. Only tubercle bacilli—living or 
dead—have produced it. Allergy due to dead bacilli 
is inconstant, feeble and transitory; that set up by 
living bacilli in a previously normal animal is re- 
markably invariable, marked and durable. In other 
words, there exists no allergy without tubercle. 
The allergic state is recognized by the allergic 
reaction, that is, the rapid inflammatory responses 84 
RESISTANCE 
mentioned above, to the proper substance necessary 
to elicit it (antigen). The proper antigen is living or 
dead tubercle bacilli or any dissociated product of 
these which contains protein (tuberculin). Thus, 
while dissociated tuberculoprotein cannot give rise to 
the allergic state, the true allergic reaction is apparently 
set in motion only by tuber culoprotein, whether dis- 
sociated or contained in intact bacilli. Therefore, 
until the contrary is proved, we would class allergy 
among bioreactions to protein. 
2. The time relations of allergy: According to the 
virulence and dosage of the infecting bacilli, the 
first manifestations of allergy are to be elicited in an 
animal (guinea pig) at from six to twenty-five days 
after first infection, that is, at about the time of the 
first development of tubercle. The same relations 
apparently hold in man (Hamburger, Hess). All 
experimentation indicates that it persists as long 
as specific tubercle remains in the body. 
3. The variations and fluctuations of allergy: The 
capacity for allergy varies greatly in several animal 
species. Man is apparently the most sensitive 
animal: at any rate, he will react to the smallest 
doses of tuberculin—and presumptively, therefore, 
to the smallest numbers of tubercle bacilli. The 
sheep is highly allergic (Roemer). The guinea pig 
has a much lower capacity for tissue hypersensitive- 
ness than man or the sheep. For instance, no 
guinea pig, however tuberculous, will react to 
tuberculin applied through a scratch or scarification 
a la Pirquet. It will, however, react very consist- RESISTANCE 
85 
ently and vigorously to the intracutaneous applica- 
tion of the proper amount of tuberculin, an amount 
which is far in excess of that capable of eliciting a 
response in man. The rabbit is the least sensitive 
of all animals commonly experimented with: its 
skin reactions are inconstant and comparatively 
feeble. 
Experiment shows that allergy follows quantita- 
tive and qualitative curves, that is, variations of 
degree and intensity, which are roughly parallel 
with the development and progression or retro- 
gression of infection. Studies, published by me 
several years ago, pointed out very sharply that 
allergy in guinea pigs inoculated with virulent human 
bacilli began at about ten to fifteen days after infec- 
tion and increased progressively with the evolution 
and extension of infection until the animals became 
moribund. It proceeded differently, however, in 
guinea pigs that had been inoculated with relatively 
avirulent human bacilli, which, while arousing the 
formation of tubercle, did not kill the animals. 
The latter were frequently tested and studied 
through a period of almost two years. Their allergic 
course was about as follows: Allergy first appeared 
a few days later than in the virulently infected 
animals; autopsy showed that tubercle also de- 
veloped more slowly. With the growth and pro- 
gression of tubercle, allergy increased to a marked 
and constant degree, but it never reached as high 
a point as in the virulently infected animals. After 
about forty days it reached a “plateau” which it 86 
RESISTANCE 
held for a long time—for months. Then, while 
physical examination and autopsy were revealing 
that tubercle was receding and was being arrested, 
allergy began to diminish. It continued to fall 
until it became very slight. In no case, however, 
did it disappear, that is, return to the base line or 
level represented by the native or original capacity 
of the animals to react. Autopsy with microscopic 
examination of tissues of these slightly reacting 
animals, 697 days after infection, showed only very 
sclerotic and very well invested tubercle in lymph 
nodes related to the point of inoculation. 
Highly instructive was the behavior toward rein- 
fection of these animals with falling allergy. They 
were given a second inoculation of living tubercle 
bacilli, 669 days after their first infection. This 
new infection promptly and markedly intensified a 
diminishing power to react. 
We are therefore led to believe that in life, and 
under the influence of infection (tubercle), the 
allergic state is continually fluctuating, now lazily, 
now sharply, with the amount and pathological 
condition (competence of investment, opportunities 
for focal absorption, etc.) of tubercle. It is height- 
ened for longer or shorter intervals by extension or 
metastasis of infection, or by reinfection; or it is 
becoming feebler as the sum total of sclerosis keeps 
ahead of the sum total of degeneration or fresh 
extension; all this, so long as the physiological 
activities of the animal remain fairly stabilized. 
Our methods for estimating these relations of quan- RESISTANCE 
87 
tity and quality are so crude that finer variations of 
allergy in the human being are either impossible 
of detection or equivocal of interpretation. But 
it is not to be doubted that these fluctuations are 
going on continually in whoever carries tubercle. 
At this place, also, I would merely refer to the 
well-known diminution of allergy which attends 
intercurrent febrile diseases, pregnancy, perhaps 
fatigue, etc., in tuberculous animals. It is impor- 
tant to remember, likewise, that during the height 
of a general tuberculin reaction and for a short time 
after it, allergy may fall to the vanishing point. 
It may similarly be greatly blunted during certain 
phases of acute tuberculosis. 
1+. The tissues affected by the allergic state: Allergy 
is best known and usually recognized through the 
easily obtainable inflammatory reactions of the 
skin and mucous membranes of persons with tuber- 
cle. But all studies made thus far would indicate 
that all the tissues of a tuberculous animal are 
allergic (Trudeau and Nichols on the lung, Leon- 
Kindberg on the kidney, Paterson on the pleura, 
Soper on the liver, etc.). Whether at a given time 
all the tissues are allergic to the same extent is an 
important question that has not yet been investi- 
gated—probably because of the very great potential 
source of error in any experimental technique which 
would approach this problem. 
5. Tuberculous foci are highly allergic: While the 
comparative allergic capacity of the several unin- 
volved tissues of a tuberculous animal is a problem 88 
RESISTANCE 
awaiting investigation, there is no question about 
the much greater reacting quality of tuberculous 
foci, or, perhaps more accurately, of tissues con- 
taining tubercle, if these be compared with non- 
tuberculous tissues of the same animal. As is well 
known, foci of tubercle anywhere in the body react 
with acute inflammation to tuberculin put into the 
body at a remote place. This focal reaction is 
nothing else than an allergic reaction. The amount 
of tuberculin which reaches foci, under these condi- 
tions, must often be extraordinarily minute: the 
results are frequently intense, even violent, as may 
be learned from the animal of experiment. A very 
small amount of tuberculin, superficially and di- 
rectly applied, will inflame a tuberculous ulcer 
(Sternberg); or, allowed to drain by skin lymphatics 
to a patch of lupus, may induce a violent reaction 
in the latter. When tuberculin is given subcutan- 
eously and thus becomes distributed throughout the 
body by lymph and blood, whole organs which 
harbor tubercle may rapidly undergo hyperaemia, 
congestion or the more advanced grades of inflamma- 
tion, even though their visible tubercle is slight and 
isolated. In general, it may be said that the com- 
petence of investment of a given tubercle will 
govern its capacity to react: old, sclerotic processes 
are much harder to throw into reaction than are 
young or softening ones. 
6. Trauma not necessary to elicit allergy: Because 
the skin or mucous membrane must be punctured 
to bring about the reaction, it may be thought that RESISTANCE 
89 
reaction will occur only when a tissue is wounded. 
But focal reactions, and the inflammations following 
the introduction of reinfecting bacilli by way of the 
blood, at points where these focalize in internal 
organs, teach us that reaction may take place with- 
out the application of trauma; unless, indeed, in 
the latter event the focalization (embolization) of 
bacilli highly resistant to outside influences may be 
conceived as a traumatizing act. 
7. Variations of intensity of the allergic reaction: 
The reaction may run the entire gamut of inflamma- 
tory intensity. It may be anything from a very 
faint and transitory redness and swelling to the 
most violent necrosis, with haemorrhage and rapid 
sloughing (Koch phenomenon). We are very likely 
correct in assuming also that below the limits of 
visibility reactions may occur which are so slight 
that they comprise the outpouring of only a few cells. 
Sometimes the reaction may be delayed: instead of 
appearing from six to twelve to twenty-four hours 
after the application of tuberculin or bacilli, it 
becomes manifest only from two to four days 
thereafter. Not infrequently the reacting area pre- 
sents a centre which is blanched and pallid while the 
periphery is pink or red. 
8. Factors which influence the intensity of the 
reaction: The most prominent analyzable factors 
are the degree of allergy at any time and the amount 
of antigen (tuberculoprotein, tubercle bacilli). High 
allergy with much tuberculin or many bacilli at a 
point make for prompt and vigorous reaction. 90 
RESISTANCE 
High allergy with few reinfecting bacilli or low 
allergy with large numbers may give rise to only 
moderate or slight reactions. There is one factor, 
which has never been studied experimentally, but 
which undoubtedly has a definite influence on the 
intensity of the reaction of the skin. This is the 
amount and character of skin pigmentation; for 
instance, the pigment-free skin of albino guinea pigs 
reacts much more vigorously than colored skins, 
from light fawn to black. Another factor which 
may presumably affect the capacity for allergy is a 
constitutional one of heredity,—that individual, 
family and racial variation of native reactivity to 
irritation which we have already discussed. Since 
the presence of pigment or the tissues’ ability to 
form pigment is an inherited factor, it takes its 
place with whatever other qualities make up the 
hereditary factors of allergy. 
Here then is an acquired type of tissue reactivity 
to tubercle bacilli and its derivatives. Besides the 
native way of meeting the bacilli rather leisurely, 
there is the exaggerated and explosive method of 
allergy which comes to all animals with the develop- 
ment of tubercle. Allergy is thus a specific state 
brought into being with specific substances and 
released by specific substances. How and to what 
purpose does it function in tuberculosis? 
As one ponders the various characteristics of the 
allergic state and reaction in tuberculosis, the forces 
that bring them into being, the changes which they RESISTANCE 
91 
themselves set in motion, the modifications which 
they undergo and the agencies which mould these 
modifications, the more one is inclined to bring 
allergy into relation with specific immunity to 
tuberculosis; particularly if at the same time one 
happens to be familiar at first hand with the mani- 
festations of allergy and specific immunity as these 
display themselves in animals of controlled experi- 
ment. 
For it happens that anatomic tubercle brings 
about other deep-seated changes in the animal body, 
besides allergy or specific hypersensitiveness. For 
twenty years it has been recognized that animals 
with tubercle can withstand relatively enormous 
numbers of living virulent tubercle bacilli, as com- 
pared with normal animals. That is, animals 
acquire a specific immunity which is one—and only 
one—of the elements of resistance to tuberculous 
infection. 
Ever since the discovery of the tubercle bacillus 
(1882) there have been unceasing efforts to attain 
active (and passive) immunization against infection 
through the use of almost numberless derivatives 
and variants of tubercle bacilli. But competent 
and unbiased observers are agreed that only one 
procedure is uniformly successful. This consists 
in preliminary infection with living tubercle bacilli. 
In other words, we will not admit to-day that specific 
immunity ever exists without tubercle in the host. 
If we treat nontuberculous normal animals with 
dissociated derivatives of tubercle bacilli, such as 92 
RESISTANCE 
those contained in the various tuberculins or those 
obtained in relatively pure state by chemical 
methods of extraction and cleavage, we can get 
various responses on the part of the animals in the 
form of “bodies” detectable in their blood serum or 
in exudates elaborated by them. Such serum and 
exudate “immune bodies” or “antibodies” com- 
prise precipitins, agglutinins, aggressins, opsonins, 
complement-fixing bodies, anaphylactin, etc. Every 
one of these has been obtained by the method just 
mentioned, that is, without the intervention of 
infection with living tubercle bacilli. But we do 
not find that these animals, even with a high serum 
content of such substances, display a heightened 
resistance to infection by living tubercle bacilli, 
and it need hardly be emphasized that a resistance 
above the normal is an absolute requirement of any 
state that we would call specific immunity. 
At the same time, we can easily and regularly 
render animals undeniably immune to infection by 
producing tubercle in them with living bacilli and 
yet find that the serum of these immune animals is 
without the “antibodies” referred to above. We 
must therefore conclude that whatever their function, 
and this is thoroughly obscure, it has no direct 
connection with resisting infection. 
Out of a wealth of experiment and investigation 
of the immune state in tuberculosis have come 
several features which appear with such uniformity 
and consistency that we are justified in formulating RESISTANCE 
93 
them as the laws of specific immunity to tuberculous 
infection. They may be summarized as follows: 
1. Specific immunity exists only in animals which 
at the same time have tubercle provoked by tubercle 
bacilli. 
2. It first appears about the time of the first palpable 
development of the foci of infection. 
3. It persists, in some degree, as long as infection 
remains. 
4. It diminishes with the subsidence and healing 
of infection. 
5. It increases with the extension and evolution of 
infection. 
6. It probably disappears with the enucleation of 
all foci. 
7. It varies in degree directly with the virulence of 
the immunizing microorganism; or, otherwise ex- 
pressed, with the amount and activity of infection in 
the host. 
It is of the utmost significance that the conditions 
and characteristics of allergy exactly parallel those 
of specific immunity; and this circumstance is true 
of allergy alone, among all the specific changes of 
reaction which may be artificially brought about 
in animals through the bacillus or substances de- 
rived from it. For we find that 
1. Allergy is never observable unless tubercle is 
present. 94 
RESISTANCE 
2. It appears coincident with the establishment of 
tubercle. 
8. It continues as long as tubercle persists. 
If.. It falls with the retrogression and healing of 
tubercle. 
5. It increases with the extension or repetition of 
infection. 
6. It probably disappears with the eradication of 
infection. 
7. It varies directly with the intensity of the disease, 
which is in turn dependent, not wholly, but in large 
measure, on the virulence of the bacilli concerned. 
This close and direct parallelism of allergy and 
specific immunity at once suggests that immunity 
is a function of allergy. As to the character of the 
mechanism, set in motion by the allergic reaction 
to accomplish an increased protection against 
infection, opinions will no doubt differ, inasmuch as 
the underlying forces of allergy are as yet thoroughly 
obscure. 
While Koch was making his first investigations 
with old tuberculin (1890) he observed the operation 
of allergy at its highest. Without grasping the full 
significance of what he saw, he put on record how 
guinea pigs which always tolerated first virulent 
infections (tubercle bacilli) without immediate 
visible effect would react violently to reinfections if 
these were made superficially; how the point of 
reinfection (skin) would inflame within a few hours, 
become rapidly necrotic, break down, be cast off RESISTANCE 
95 
as a slough, and then appear as an ulcer which 
healed; how, also, animals in which all this occurred 
suffered no invasion from the bacilli of reinfection, 
while portions of the same suspension of germs 
inoculated as a first infection into normal, “control” 
animals rapidly brought about disease and death 
of the latter. This rapid ulceration followed by a 
slough and healing wound at the point of reinocula- 
tion has ever since been known as the Koch 
phenomenon. 
Koch appreciated the immunity part of the 
“phenomenon.” His idea of the cause of the non- 
occurrence of generalized infection from the second 
inoculation was that in the sloughing process the 
bacilli which he had put beneath the skin were 
cast out, and, with relatively few or none left 
behind, actual reinfection was prevented or made 
weaker. This idea still bobs up in explanations of 
the mechanism of specific immunity. It cannot be 
tenable, however; for it can easily be demonstrated 
that even when sloughing and ulceration do not 
occur'—and this is the usual thing when dosage is 
small or moderate—reinfection does not “take” or 
does not proceed far. Again, if reinfection is done 
by way of a vein, the bacilli carried to internal 
organs will make slight headway under circum- 
stances where sloughing and ulceration cannot 
enter into the course of events. 
Another view, held by Rist, Paterson and others, 
is that during the inflammatory phases of the 
allergic reactions there are released and brought into 96 
RESISTANCE 
play, at the sites of reinoculation, substances which 
disintegrate and dissolve the bacilli,—so called lysins. 
This has the merit of being a reasonable interpretation 
and of squaring with our present conceptions of meth- 
ods by which tissues dispose of living foreign par- 
ticles. Yet direct scientific demonstration of these 
hypothetical lysins in tuberculosis has thus far been 
very incomplete and unsatisfactory. 
Personally, I cannot conceive of the allergic 
reaction going on without the intermediation of 
some kind of lytic action; yet I am disinclined to 
accept the lysin hypothesis without reserve and at 
its full face value until I can exhibit the lysins in a 
way that is free from criticism, and this I have thus 
far failed to do. 
There is yet another at least plausible view which 
one may take of the allergic mechanism as it concerns 
immunity. It embodies a mechanical explanation 
of end effects, not fundamentally different from the 
one which I have put forward in seeking for a more 
exact comprehension of the way in which other 
phases of resistance were brought about. Although 
it conceives that actual protection against the spread 
of infection is afforded by and through certain 
physical obstacles which the operation of allergy 
puts in the path of tubercle bacilli and thus impedes 
their spread, it does not seek out the basic springs 
of allergy and leaves these to the investigator of 
biophysical and biochemical reactions. My con- 
ception would put the case something as follows: RESISTANCE 
97 
In a normal, nontuberculous, nonallergic animal, 
because of the leisureliness of native tissue reaction, 
tubercle bacilli, when first inoculated, are able to 
spread over a comparatively large territory and to 
many remote parts of the body with relative facility. 
I have shown by experiment how in the guinea pig, 
after subcutaneous infection, bacilli may reach the 
centre of drainage of foreign particles, that is, the 
tracheobronchial lymph nodes, in four days or less. 
This means that, given sufficiently large initial 
dosage, bacilli in variable numbers can be carried 
throughout the body and form many loci of infection 
(though not necessarily of quickly apparent lesion) 
before competent tissue reactions (tubercle) are 
interposed to bar their transit and progress and 
before the infection has established the allergic state 
in an animal. 
In the allergic animal, on the other hand, rein- 
fecting bacilli, wherever they come to a pause in 
tissues, are met by an immediate tissue reaction— 
inflammation'—which tends to put a more decisive 
stop to their progress and limit their activities. In 
other words, they are more likely to be partially 
arrested in situ and at once; while in the normal 
animal they are given opportunity to multiply and 
spread before the latent reacting capacities of the 
tissues are sufficiently aroused to deal with them 
effectively. 
Or, to state the matter in still another way: The 
tuberculous allergic animal responds with exag- 
gerated or overreaction to specific irritation and 98 
RESISTANCE 
throws up a barrier against the bacilli much more 
promptly and actively than normally and before 
the bacilli can get well under way. 
There are studies on the larger effects of pure 
inflammation in general which lend some color of 
probability to such a view. Pawlowsky, for in- 
stance, has pointed out that an inflamed territory 
is a fairly efficient impediment to direct infection. 
If he first inflamed a guinea pig’s knee joint with a 
sterile irritant, such as turpentine, alcohol or quinine, 
staphylococci which he then introduced into the 
joint would not disseminate beyond it, although 
twenty-four to forty-eight hours after the injection 
of staphylococci into a normal joint he could re- 
cover the microorganisms from the blood and organs 
of the guinea pig. Isayeff has also shown “that the 
peritonitis by a variety of sterile irritants such as 
a foreign blood serum, bouillon or normal salt 
solution, temporarily increases resistance to subse- 
quent intraperitoneal inoculations of bacteria.” 
The refractoriness to infection of inflammations of 
the type of the chronic leg ulcer is familiar; as is the 
circumstance that acute septic infections, like 
erysipelas, are not nearly so prone to settle in 
inflamed wounds as in those of the type of clean 
surgical incisions or slight cuts, abrasions and 
breaks of the surface which exhibit scarcely any 
inflammatory features. 
It may be well also to recall that the end result 
(or shall we say the purpose?) of every inflammation 
pursuing a normal, uninterrupted and complete RESISTANCE 
99 
course is fibrosis, to eventuate in the repair of the 
injury or irritation which called into action the 
cycle of inflammation. It is fair to assume that 
with the very beginning of exudation which initiates 
inflammation, the secondary response, which will 
soon follow and be noticeable as fibrous proliferation, 
also gets under way under the spur of the stimulus 
—a physical injury, bacteria, or what not. We 
should therefore expect that in allergy, which is 
revealed to us as a newly acquired intensification of 
a native reaction, there are protective elements 
besides those provided by the sharp exudative 
features of acute inflammation: there should be in 
addition an accelerated and exaggerated tendency 
to fibrosis which, all will agree, is a potent factor 
in resistance to tuberculosis. 
I had always thought that this new capacity for 
inflammation represented the entire transformation 
which tissues experienced in respect to allergy, until 
recently, when more detailed studies showed me 
unerringly that in the allergic animal there is, if 
compared with the reaction to first infection, also 
an earlier response with that type of proliferation 
which results in the formation of characteristic 
early tubercle. What is observable upon reinfec- 
tion is first, an almost immediate acute inflamma- 
tion, then a fading out of the redness and diffuse 
oedematous wheal-like swelling, followed by the 
rapid appearance of nodule which arises in a non- 
inflamed background. These nodules are the real 
tubercles and antedate by several days those which 100 
KESISTANCE 
develop in the control animals (given a first infection 
at the same time). This difference is sharp and not 
to be mistaken if dosage of bacilli is gauged right: 
if too many bacilli are used and allergy is high, 
reaction is so intense and prolonged in the allergic 
animals that events are telescoped and not unrolled 
in proper sequence, while in the normals tubercle 
formation comes into view so early that it approxi- 
mates the time of appearance in the allergic animals; 
thus the tendency to prompter proliferation in the 
allergic may be overlooked. If we view the ana- 
tomic response of tubercle as a defensive tissue reac- 
tion to foreign bodies, as we have every right to do, 
we accordingly find that the proliferative or tuber- 
cular or resisting reaction is likewise much more 
active in the allergic animal. 
In one respect the allergic reaction impresses the 
observer as being an exaltation of the native capacity 
to respond to tubercle bacilli, and, if we view tubercle 
formation as fundamentally a defensive process 
against foreign body irritation, then specific im- 
munity would appear as a newly acquired and higher 
evolution of the body’s native way of,, resisting 
infection. In accordance with such a point of view, 
it would seem as though all susceptible animals 
possess their own definite and peculiar normal 
reacting capacity to tubercle bacilli; a capacity 
which is within certain limits uniform for a species 
and which consists, in one particular, in a given irrita- 
bility of the body’s fixed-tissue cells to bacillary 
stimulation. It is significant, also, that these cells RESISTANCE 
101 
will react more vigorously and extensively to large 
first infections than to smaller ones: the time of 
first visible appearance of tubercle can be advanced 
several days ahead of normal, if quite large inocula- 
tions are used. 
But infection “trains” or “sensitizes” these cells 
(in our present ignorance of underlying forces it is 
hard to find more precise words), so that their 
native irritability becomes greatly enhanced. When, 
therefore, reinfections occur, these cells react to 
even very small numbers of bacilli with the speed 
and vigor that characterize their response to very 
large first infections. The immediate inflammatory 
reaction is perhaps the expression of a new attri- 
bute—one that is foreign to the normal, nontuber- 
culous animal, although it is true that when dosage 
of first infection is enormous a rapid outpouring of 
serum and polymorphonuclear leucocytes follows it. 
But this is an altogether different thing from the 
inflammation of allergy, as observation and experi- 
ment will show. It is a response to the large 
amount of protein represented by excessive num- 
bers of bacilli and is comparable to the second out- 
pouring of polymorphonuclear leucocytes which 
later attends the rapid disintegration of caseous 
tissue and the formation of pus. It comes on 
rapidly and disappears just as rapidly. 
We begin to flirt with new ideas of the nature *of 
specific immunity as we become more and more 
attentive to what happens when other acid-fast 
bacilli are introduced into tissues and as we cogitate 102 
RESISTANCE 
its meaning in relation to phenomena such as we 
have been describing. The face of all this may be 
deceptive; but I believe that a search after 
relations may serve its purpose even though it lead 
us astray. 
If you hunt diligently enough you will find ac- 
counts of more than fifty acid-fast bacilli. All 
except the several tubercle bacilli and the leprosy 
bacillus are called saprophytic or nonpathogenic. 
But, strictly speaking, there are no nonpathogenic 
acid-fast bacilli. All so called nonpathogens will 
provoke tissue change; and that the latter is some- 
thing more than a mere foreign body reaction, such 
as attends the encystment of inert particles, is 
indicated by the response of the body to their 
introduction with allergy and other biological 
changes (precipitins, agglutinins, etc.). 
It is true that they will not set up progressive 
disease in mammals: we therefore call the latter 
natively immune and the bacteria nonvirulent. 
Yet they will arouse lesion in mammals and must 
be considered pathogenic to that extent. Their 
inoculation into normal animals is followed by 
rapid tissue response. Within four or five days, and 
sometimes two days, local swelling and bubo of 
adjacent lymph nodes are visible. All changes are 
much more inflammatory (exudative) than those first 
following first infection with tubercle bacilli, viru- 
lent microorganisms. These changes quickly reach 
their acme,—as a rule within a week or ten days; 
and by the end of two or three weeks they have RESISTANCE 
103 
disappeared and the part has returned to normal. 
After first focalization, the bacilli do not spread 
through the body. Unless enormous and repeated 
inoculations are made the animals remain in good 
health. 
What seems significant is that the native reaction 
of tissues to nonpathogenic acid-fast bacilli re- 
sembles superficially and in broad outline the 
response of allergic and immune animals to virulent 
acid-fast bacilli. It is similar to the latter in that 
it is comparatively rapid and that inflammatory 
features predominate over proliferative ones. We 
find that to those germs, which the final issue teaches 
us to call avirulent, the reaction, the native tissue 
reaction, is rapid, acute and vigorous, and patho- 
logical effects begin by being comparatively florid, 
soon come to a standstill and rapidly subside and 
disappear; while to those germs (tubercle bacilli) 
which experience compels us to call virulent, the 
native tissue reaction is indolent and comparatively 
delayed—acuteness and vigor begin only after about 
two weeks, when, because of the first infection, the 
tissues have been “trained” to allergy. 
We ask ourselves whether the native immunity 
of animals to nonpathogenic acid-fast bacilli dwells 
in an inherent vigor of reacting capacity to them; 
or whether susceptibility to virulent tubercle bacilli 
is the expression of a congenital inability to meet 
first infection with the promptness that is necessary 
to localize the germs within narrow limits and 
prevent their decisive multiplication. Infection 104 
RESISTANCE 
with virulent bacilli endows animals with relative 
immunity, but only when and after their bodies 
have taken on new powers; after their tissues have 
been trained, as it were, to behave in a way that 
resembles their conduct toward saprophytic acid- 
fast bacilli,'—to react with celerity to fresh invasions 
by tubercle bacilli and to substitute, in a measure, 
the speed of exudative (inflammatory) response for 
the leisureliness of proliferation. 
We have also to deal with another phase of specific 
immunity and of allergy which must undoubtedly 
be of great importance in any infection in which 
there is a more or less continuous migration of 
germs from one part of the body to another or 
many repeated acts of infection from without 
(exogenous infection) or from parent foci within 
(endogenous or autogenous reinfection). 
Broadly speaking, in any process of active im- 
munization there occurs a variable incubation 
period after a first application of immunizing agent 
(antigen) and then a rising curve of increased resis- 
tance (immunity) to the specific germ of infection. 
In time this curve reaches a certain maximum or 
high level (plateau) which may continue for a longer 
or shorter time. If the application of antigen is 
repeated during the period of immunity, there is an 
immediate and very sharp drop in the animal’s 
resistance to the particular substance. Resistance 
may fall to a point which is lower than the native 
resistance of the animal; or, to put it another way, 
the animal’s susceptibility may for a space be RESISTANCE 
105 
unusually and abnormally great. In the course of 
specific immunity, therefore, we meet with the para- 
dox that at certain times and under the repeated 
influence of the immunizing agent, resistance is less 
than in the normal, nonimmunized animal. The 
phenomenon is well known and is perhaps best 
known as the negative phase of immunity. It can be 
shown that reinfections made during the negative 
phase are particularly dangerous. This period of 
negative phase lasts from a few hours to several 
days, and is then succeeded by a much more rapid 
rise of immunity than before and by an immunity 
that goes to a still higher level. 
Allergy is similarly responsive to various in- 
fluences. We have already seen that the reacting 
capacity of the tissues (skin) of tuberculous man and 
animals is blunted by such events as the general re- 
action to tuberculin, pregnancy, measles, influenza 
and other febrile diseases, acute tuberculosis, terminal 
tuberculosis, and the last cachectic stages of exhaust- 
ing illnesses of many kinds. A child known to react 
to a Pirquet application of tuberculin in health will 
fail to react during the clinical course of measles, or 
if stricken with tuberculous meningitis or acute 
generalized tuberculosis. It has generally been 
taught that in the latter affections and the agonal 
stages of many diseases allergy is lost completely. 
My own experimental observations and recent work 
by Ilapp and Casparis lead me to believe that this 
is not strictly true, and that what is more likely is 
that every person or animal with tubercle, no 106 
RESISTANCE 
matter what the constitutional condition, can be 
made to react to tuberculin, provided enough 
tuberculin is given. In other words, there may occur 
a very great diminution of reacting capacity, but 
the latter is never entirely gone as long as tubercle 
remains. 
A satisfactory explanation of why allergy should 
undergo these modifications has not yet been ad- 
vanced. Most theories proceed from what may be 
called the “antibody exhaustion” hypothesis. It is 
held that the specific antigen (immunizing or allergy- 
provoking substance) stimulates the body to elabo- 
rate specific antagonistic substances, which pass 
under the name of “antibodies” or “immune bodies.” 
An actively immunized or allergized animal will 
possess an excess of these and upon the introduction 
of new antigen (tuberculin or tubercle bacilli) there 
occurs a reaction between units of antibody and 
antigen which results in the inflammatory reaction 
of allergy. Florid or very progressive infection 
provides antigen to an excess that at last stimulates 
the body to exhaustion—to that point when it can 
no longer respond with antibody; or the excess of 
antigen “uses up” all available antibody and thus 
exhausts it. In either event, there is no antibody 
left to react with whatever antigen (tuberculin) 
we may apply in these cases, and no reaction results. 
In nontuberculous affections, the resources of the 
body have enough to do in combating whatever 
disease or condition is menacing, and for this reason 
can devote none of their powers to respond with KESISTANCE 
107 
specific antibody to an antigen of tubercle bacilli: 
here again, there is an exhaustion or a nonproduction 
of antibody and the application of tuberculin passes 
without reaction. 
I have never been able to entertain the “antibody 
exhaustion” view. It has always been my experi- 
ence that, no matter how refractory to tuberculin 
a very ill animal might be, it would always manifest 
some reaction to a large enough dose of tuberculin; 
and it was impossible for me to reconcile this plain 
observation with any idea of an exhaustion or non- 
production of specific reacting substances in the 
animal. It appeared to me rather that under the 
influence of any condition which brought about great 
or sudden depression or exhaustion of bodily (con- 
stitutional) function, the normal reaction of the tis- 
sues to any and every irritant was altered. Highly 
anaemic tissues, for instance, will not respond at 
all with the same characteristic inflammation to a 
bruise or a cut or a burn as will normal tissues. 
Typical bodily reactions are conditioned on two 
factors, namely, the integrity of the stimulus and 
irritant and the integrity of the mechanism con- 
cerned in reacting. As I conceive it, whatever gives 
rise to the inflammatory response of allergy is a 
noxious degradation product of tubercle bacilli 
(or a derivative) which results from an antigen- 
antibody reaction and is an irritant for tissues. 
If the body is functioning normally in respect to 
response to irritation the result will appear in the 
acute inflammation with which we are familiar. 108 
RESISTANCE 
If, for any reason, specific or otherwise, function is 
depressed or abnormal, there can be no characteristic 
tissue response, even though an antigen-antibody 
reaction occurs and gives rise to the substance or 
substances capable of arousing inflammation. 
This opinion is borne out by an incident which I 
have already mentioned, namely, the failure (in- 
ability) of the skin of acutely ill guinea pigs to react 
to first infection with tubercle bacilli with the forma- 
tion of characteristic nodular tubercle: in this case 
animals lose their native capacity to react typically. 
I have also had brought to my attention the follow- 
ing case which is highly significant: 
A child in the service of Doctor John Howland 
of the Johns Hopkins Hospital was sick with what 
was clinically generalized miliary tuberculosis, and 
failed to react to several Pirquet tests. It was also 
profoundly anaemic and for this reason was trans- 
fused. After the transfusion it reacted vigorously 
to new Pirquet tests, to which the former nonre- 
acting areas also at once responded with inflam- 
mation. The child died and at autopsy was found 
to have generalized miliary tuberculosis. 
In other words, a transfusion of blood brought 
an abolished reacting capacity up to normal. All 
experimental efforts to transfer the antibody of 
allergy by injecting the blood serum of an allergic 
animal into a nonallergic one have turned out 
negatively. We cannot therefore conclude that 
in the above instance we put into the sick child’s 
body by transfusion a reacting substance which it 
lacked. We must assume that it possessed this RESISTANCE 
109 
all along and that when the first Pirquet tests wore 
given an antigen-antibody reaction went on in its 
tissues and gave rise to the inflammatory irritant. 
We must assume further that it failed to react with 
inflammation to the irritant because its tissues’ 
capacity to react had been disturbed (depressed?) 
by disease. A transfusion of normal blood restored 
for a time this ability. 
Tuberculous infection assumes and gains impor- 
tance and momentousness as it spreads within the 
body. This spread is nothing more or less than 
reinfection from within. As soon as first tubercle 
is formed, its possessor becomes allergic and specifi- 
cally immune. Therefore, after about ten days 
from the first infection all new focalizations of 
bacilli within the body take place in allergic and 
immune soil. But it must be kept in mind that in 
many instances the conditions of such reinfections 
must be vastly different from any that an investiga- 
tor has yet reproduced by experiment or any that 
he conceivably might reconstruct. In nearly all 
experimental work on immunity and allergy, if 
we apply antigen repeatedly, we space our new 
injections and inoculations so that they fall within 
the period of high immunity and allergy. In the 
course of many natural infections reimplantations 
of bacilli are taking place at many different times: 
there may be sufficiently long intervals so that new 
infections occur when immunity and allergy are at 
their peak; or, presumably, reinfections may be 
repeated so frequently and at such short intervals 
that some fall within the period of negative phase 110 
RESISTANCE 
and anergy. If they occur during the latter they 
come upon the tissues at times of depressed or no 
reaction (tissue reaction) and, therefore, when new 
barriers of inflammation or proliferation will be 
either absent or inefficient. After negative phase 
and anergy pass, after the measles or acute febrile 
disease is over, tissue reactivity comes back, per- 
haps with intensification, yet it is then called upon 
to meet the irritation of germs which have spread 
to new points or have been transported out beyond 
the boundaries of old foci to enlarge these or may 
have perhaps multiplied while reactivity was de- 
pressed or in abeyance. 
Something like the above is my present very rough 
and very imperfect conception of the mechanism of 
allergy and specific immunity. The gist of it is 
that immunity and allergy are both specific antigen- 
antibody processes which, through their operation, 
originate and yield a stimulating or irritating product 
which is specific. But the capacity of the body to 
react is not specific: it is the same capacity which 
will respond to any comparable irritation with the 
same pathological changes—that is, acute inflam- 
mation, heightened fibrosis and accelerated tuber- 
culoid proliferation. In depression or exhaustion 
states the tissues cannot react typically to any 
irritant, and therefore they respond only feebly 
or not at all to the application of antigen. The 
actual mode of protection against the spread of 
infection probably does not differ fundamentally 
from the native resources of resistance which the RESISTANCE 
111 
body possesses: through immunity and allergy the 
tissues’ native capacity to ward off and wall in 
bacilli is simply exalted in greater or less degree. 
No tuberculin or dissociated product of tubercle 
bacilli has yet been shown to protect or raise native 
resistance against infection, that is, implantation of 
tubercle bacilli: only living tubercle bacilli, capable 
of arousing tubercle, exert this effect markedly. 
Therefore, no tuberculin can be looked upon as being 
a prophylactic or preventive agent against a first in- 
fection. On the other hand, tuberculin has antigenic 
properties in that it will affect foci already present 
(focal reactions) or noninvolved tissues (skin, etc.) 
of tuberculous animals. By virtue of these qualities 
tuberculin may set in motion processes which may 
result in apparent immune effects, a phase of resist- 
ance which must await discussion later. 
It remains to pass in review and examine the 
effects of resistance, particularly those of allergy, 
as these are displayed in the natural evolution of 
tuberculous infection and disease. I have long 
thought that an understanding of allergy and its 
proper application will lead to a better appreciation 
of much that has been obscure and that it will 
resolve features that have been confused and chaotic 
into fewer and simpler concepts. 
Allergy undoubtedly furnishes the key which 
bids fair to unlock the outstanding riddle of tuber- 
culosis—the mystery which so baffled early observ- 
ers and so long delayed a more rational concept 112 
RESISTANCE 
of the disease; that led Virchow into the quagmire of 
the duality dogma and pushed Niemeyer to that 
absurd though logical conclusion of Virchovian 
doctrine—that “the worst thing that can happen to 
a consumptive is that he become tuberculous.” 
How understand the mystery of the enormously mul- 
tiplex and multicolored pathological background 
as all parts and variations of one and the same dis- 
ease due to a single cause—how understand it before 
the cause could be known? How explain it after 
the single cause, the tubercle bacillus, lay bare? 
Through what variables is there produced a patho- 
logical framework which may run the entire scale 
from almost pure tumor formation to purest inflam- 
mation, with all proportionate combinations of 
these elements, and punctuated with effusions of 
every type, the deposition of salts and the irregular 
formation of cartilage and even bone? 
Well, all this has had its explanations. It is—so 
it has often been maintained—the virulence of the 
bacilli concerned which will determine the type of 
pathological response in particular cases. Almost 
innumerable virulences have of necessity been 
postulated to explain how almost innumerable 
anatomic conditions may be set up. Yet the net 
result of many studies on virulence has been to 
emphasize all the more for tubercle bacilli a fixity 
and constancy of bacillary type and qualities which 
is almost unique among the microorganisms of 
disease. Differences have been described, it is true, 
but always woefully insufficient to throw light on RESISTANCE 
113 
differences of anatomic effect. Again, no investi- 
gator has ever been able to correlate distinctive 
features of anatomic change in particular cases with 
differences of bacillary attributes. 
It has also happened that the realm of pathogenic 
bacteria in general has been drawn upon in attempts 
to understand better why caseation and liquefaction 
and inflammation and acuteness and so forth in one 
case and not in another. Tubercle bacilli of them- 
selves, so many have said, can go just so far in 
provoking the anatomic changes of the disease tuber- 
culosis. They will arouse the production of nodular 
tubercle and perhaps take part in the formation of 
that peculiar type of tissue death, caseation, though 
not all will admit their part in the latter. When, 
however, it comes to disintegration and liquefaction 
of tissue—the formation of pus—and those inflam- 
matory features which make tuberculosis acute and 
are expressed in the spitting of blood, the hectic 
fever and the drenching night sweats, then other 
germs—the pus-formers—must step in to bring 
about all this. Hence, our “mixed infection” view 
of tuberculosis which has been quite popular. It is 
really nothing more or better than the doctrine of 
Virchow and Niemeyer put into the jargon of a later 
day. It attempts to explain bacteriologically what 
the men of sixty years ago illumined morphologically. 
It has a single circumstance to support it and this a 
mere association without proof of any causal rela- 
tionship, while all positive facts and many negative 
ones are against it. 114 
RESISTANCE 
The “mixed infection” concept has attracted 
attention and support because germs of known 
pathogenic types have been found in the secretions 
of known tuberculous people and also in their tuber- 
culous foci. It has gained in force because some 
features of diseases, due to these “secondary” 
microorganisms alone, resemble some features of the 
more acute types of tuberculosis. At a loss to 
explain how a single etiological agent, the tubercle 
bacillus, can bring about so many variations of 
disease, some students have derived from the asso- 
ciation mentioned a synthesis of action and effect. 
Now the occurrence of pathogenic germs other than 
tubercle bacilli, in secretions such as the sputum of 
the tuberculous, of itself certainly need not mean 
that these germs are contributing to the disease 
represented by the tuberculous process. Nor need 
it mean that they are setting up another disease, 
apart from the tuberculosis, though this may and 
frequently does occur in the tuberculous. The 
occurrence of streptococci or pneumococci in old 
tuberculous foci in the lungs themselves, if this 
can be demonstrated at autopsy, cannot without 
other evidence be interpreted as meaning that they 
set up tissue change or took part in the clinical 
tuberculosis. 
Spontaneous pneumothorax is usually the result 
of a tear in a diseased part of the pleura overlying 
a pulmonary cavity. For the most part, such 
cavities are old and would present the ideal tuber- 
culous foci in which other germs might flourish. If RESISTANCE 
115 
mixed infection, in the real sense of infection (not 
of contamination or association of other bacteria), 
were at all common, we should expect regularly to 
find other germs than tubercle bacilli in the exu- 
dates which accompany spontaneous pneumothorax; 
for all the pus-forming cocci are rapid “growers” 
compared with tubercle bacilli. It is remarkable, 
no less than it is significant, that, when these pneu- 
mothorax exudates do contain bacteria, in the very 
large majority of cases only the tubercle bacillus is 
present. 
But, altogether apart from such negative evidence, 
tubercle bacilli alone can bring about practically 
every type of anatomic change to be met with in 
tuberculous infection. Thoroughly controlled ex- 
periment will demonstrate beyond the slightest 
ground for adverse criticism that necrosis, every 
kind of acute and chronic inflammation, and pus 
will follow tuberculous infection. No one questions 
that the ordinary cold abscess with pus is brought 
about through the action of any other germ than 
the tubercle bacillus; or the psoas abscess (before 
operation) which may communicate with a caries 
of the spine; or the kidney abscess which sheds off 
tubercle bacilli into otherwise sterile urine. Then 
why assume that the lung abscess of tuberculosis 
needs another germ for its formation? 
Experiment will clearly disclose this: That first 
infection during its first few days practically always 
proceeds in the uniform manner which I have 
already described, no matter what the dosage of 116 
RESISTANCE 
infection; that the process involves largely the fixed 
tissue; and that the result is discrete tubercle. But 
after animals have been made allergic, pathological 
response to reinfection can be an enormously 
variable affair; and, as has also been mentioned 
before, it must be remembered in this connection that 
shortly after first infection has occurred the host 
becomes allergic because of it, and extension of 
infection within the host will take place in allergic 
soil. 
In any series of infections and in natural infections 
the dosage of bacilli can alway be a variable. But 
in experiment we can make dosage a constant. 
We can make the type and strain of germ also a 
constant. We can also make the method of inocula- 
tion a constant. In other words, we can readily 
perform infections in which every factor concerned 
with the germ is the same for all animals inoculated: 
we can give a large number of the latter exactly 
the same amounts of the same suspension of living 
bacilli in the same place at the same time. What 
will be the result in several animals? 
It all depends on the animals. If the animals are 
normal and are receiving a first infection, and our 
technique is good, the results are roughly similar. 
But if they are allergic they may vary greatly. 
We may use guinea pigs of various degrees of 
allergy, depending on original dosage and time since 
infection, and these we may look upon as variables. 
The response which we may observe will be ex- 
tremely diversified, depending upon the degree of KESISTANCE 
117 
allergy at any particular time. There may result 
anything from mild inflammation to extensive and 
violent necrosis, followed by sloughing (if the 
inoculations are made into the skin). In all the 
allergic animals the immediate changes will also 
be quite different from those observed after infec- 
tion of the normal animals. They will tend to be 
inflammatory. Intravenous inoculations may re- 
sult within a few days in as purely exudative pneu- 
monias as one ever sees, with interstitial tissue 
apparently thoroughly passive and air cells filled 
with serum, fibrin, leucocytes and some red blood 
cells. I have, on occasion, as a result of an inocu- 
lation of this kind, seen the leucocytes, which filled 
the alveoli, crammed with tubercle bacilli. Now 
these bacilli were put in by a vein a few days earlier 
and were no doubt carried out into the alveoli with 
the exuded leucocytes. But observations like these 
have made me wonder whether, after all, ulceration 
of a pulmonary focus is always necessary for the 
appearance of tubercle bacilli in the sputum—any 
more than it is necessary for the occurrence of 
pneumococci in the sputum of lobar pneumonia; 
whether, in acute tuberculous pneumonia, bacilli 
might not gain the sputum by being carried out into 
the air cells with the exudate. Of course, if rein- 
fecting dosage is also variable, the results in allergic 
animals can be even more diversified. 
Is the peculiar necrosis, the coagulation necrosis 
of Weigert, the caseation, of tuberculosis an allergic 
effect? It may occur with extreme rapidity, as now 118 
RESISTANCE 
and again happens when the contents of cavities 
are discharged into midlung; when, in other words, 
large numbers of bacilli are brought to bear suddenly 
on highly allergic soil. Or it may develop slowly, 
in small foci, where a few bacilli are disintegrating 
slowly, and a gradual sensitization and intoxication 
are taking place in situ. Tuberculin and tubercle 
bacilli are necrotizing for tuberculous, that is, allergic 
animals; they have no such effect on normal, non- 
tuberculous animals;'—as can easily be proved by 
skin injections and inoculations. We may also 
recall the Arthus phenomenon, that is, the rapid 
appearance of necrosis after a second injection of horse 
serum into the same area of the skin of a rabbit 
where horse serum had been injected before. Al- 
though this particular question has long engaged 
my attention, I shall not attempt to answer it. 
In passing, however, it may be added that the 
idea that caseation, like white infarct, is a result of 
tissue anaemia, occurring in a thrombosing infection 
and in avascular foci, is very vulnerable. The fre- 
quent early occurrence of caseation in very minute 
miliary tubercles, the centres of which must surely 
be in nutritional communication with surrounding 
healthy tissue, is against it for one thing. 
As I conceive it, every inflammatory feature of 
tuberculous infection is a manifestation of allergy'— 
of immunity; and will begin to appear only after a 
primary infection has taken place. I think we may 
safely say that every acute tuberculous process is 
the result of reinfection in tuberculous soil—either RESISTANCE 
119 
a reinfection that is set up in an existing focus or a 
reinfection from an existing focus into new territory. 
It is plain that serous membrane disease—tuber- 
culous pleurisy and peritonitis with and without 
effusion, tuberculous hydrops of joints, tuberculous 
meningitis—must be reinfection phases, in the sense 
that they represent extensions or metastases from 
foci elsewhere in the body. Their acuteness and 
severity and the amount and character of their 
effusions will depend on degree of allergy and size 
and concentration of dosage at the time of reinfection. 
Acute tuberculous pneumonia is most frequently 
met with lower down than the summit of the lung, 
and is usually brought about by spread of infection 
from older pulmonary foci in upper lobes; an origin 
from ulcerating root lymph nodes, discharging 
infection into the larger bronchi, must be a much 
rarer event. Miliary tuberculosis, localized or gen- 
eralized, another acute type, is always the result of 
reinfection from older foci. In miliary disease we 
find many small and discrete areas which, as experi- 
ment will disclose, show acute inflammation in 
their early stages, but in which the inflammatory 
features may have subsided by the time death 
ensues and the tissues are observed at autopsy. 
Miliary infection arises from the widespread and 
scattered distribution of bacilli to very many loci, 
when very small numbers of bacilli exert their 
effects on tissues of variable allergy; while many 
areas of acute tuberculous pneumonia result from 
the aspiration of material from older foci, and are 120 
RESISTANCE 
large and massive because large numbers of bacilli 
are brought to bear within a comparatively small 
compass. In chronic apical tuberculosis of ordi- 
nary type, that is, chroriic infiltrating tuberculosis, 
it is likely that tubercle spreads with extreme slow- 
ness and by short excursions of bacilli by way of 
lymphatics, as well as by growth of tubercle by 
concentric apposition. Fibrosis is always fairly 
well developed; and bacilli which set up fresh foci 
are relatively few at any one time. The infection 
may proceed with only slight pneumonic features, 
inappreciable to ordinary physical examination and 
too insignificant to reach a level of clinical acuteness. 
Tendeloo discusses at length the importance and 
nature of what he calls the collateral inflammation 
of tuberculous processes. He points out how tis- 
sues may be acutely struck with inflammation where 
tubercle bacilli localize, and throughout a wide 
territory, which extends beyond the actual place of 
bacillary focalization; and how the peripheral 
inflammation may rapidly subside, to leave only the 
“nucleus” of infection—the baeilli-containing centre 
—which may then go on to caseation or fibrosis or 
both. There is also no doubt that the entire process 
may undergo complete resolution, with restoration 
to normal, as I have frequently observed in experi- 
ments with immunized guinea pigs. 
Tendeloo’s conception of this type of infection, 
pathologically, is that it is determined by dosage 
and virulence of bacilli; and he nowhere mentions 
tissue allergy as being a factor in its production. RESISTANCE 
121 
Yet it is exactly comparable with what we notice 
when we experimentally reinfect the skin of a 
tuberculous or allergic animal and fail to observe 
when we infect the skin of a normal, nonallergic 
animal; and there is no doubt that Tendeloo’s 
collateral inflammation is an expression of allergy. 
We would repeat, therefore, that the acute 'patho- 
logical phases of tuberculosis always mean reinfection; 
and again refer to the fact that from about ten 
days on, after a first infection, an animal becomes 
allergic by reason of this primary infection and is 
then capable of exhibiting acute processes, provided 
direct extension of infection or reinfection to other 
parts of the body occurs. We would also emphasize 
that in allergic animals reinfection may be caused 
by so few bacilli that the allergic reaction is so mild 
as to pass unnoticed, or reinfection may occur after 
long periods of quiescence, as undoubtedly happens 
frequently in human beings, when allergy is com- 
paratively low. 
Since the clinical features of disease are for the 
most part but expressions and reflections of under- 
lying anatomic change, through the derangement of 
function which these bring about, we may now go 
one step further and suggest that acute clinical 
tuberculosis is always the expression of reinfection. 
If a man falls suddenly ill with the more intense 
features of the disease it means that there has been 
a rapid fresh extension or metastasis of infection 
from already present foci, whether these latter were 122 
RESISTANCE 
or were not known to exist. I have yet to see an 
animal become acutely ill following a first inocula- 
tion of living, virulent tubercle bacilli'—even of 
excessive doses of a milky suspension introduced 
by a vein. I have yet to observe a tuberculous 
animal not show acute illness following a similar 
introduction of smaller doses of reinfecting bacilli. 
This brings us at once to the matter of intoxication 
which makes up so large a part of the clinical side of 
tuberculosis and which expresses itself in so varied 
a way. The subject is intricate; but it is at the same 
time so important that it must receive some atten- 
tion here. Intoxication brings on the constitutional 
symptoms of tuberculosis. It is these'—their oc- 
currence, their vigor, their responsiveness to outside 
agents—which become so prominent in the diagno- 
sis and prognosis of pulmonary tuberculosis and in 
any estimation of activity or latency of infection. 
Any consideration of the nature of intoxication 
must revolve around the primary question of what 
causes it in tuberculosis. No evidence has ever 
been forthcoming that the cause is a specific toxin, 
in the accepted meaning of the term, for no one has 
ever satisfactorily shown that any constituent or 
product of tubercle bacilli acts as an essential 
poison, in the sense that it will adversely affect the 
well being of normal animals. Yet excessively small 
doses of derivatives of tubercle bacilli or small 
numbers of intact tubercle bacilli themselves will 
set up symptoms of violent illness in tuberculous 
animals. RESISTANCE 
123 
We find, in broad outline, intoxication occurring 
under two very different and distinct conditions. 
It appears spontaneously during the natural course 
of tuberculous infection, either with or without the 
contributory influence of unusual environment. 
It is also, as I have said, brought on artificially by 
the action of tuberculin, a specific product of the 
bacilli, or by the living bacilli themselves. So far 
as can be determined by observation of symptoms, 
it is likely that the intoxication of ordinary active 
tuberculosis and that of the general tuberculin 
reaction do not differ in kind, however much they 
may vary in intensity and duration. 
In my discussion of the relation of tubercular 
investment to symptoms, I pointed out how the 
symptoms, in other words, the intoxication, of 
ordinary tuberculosis must surely develop from the 
bodily absorption of materials from tuberculous 
foci,—of elements which comprise the products 
either of bacilli or of whatever cells enter into the 
constitution of foci, in variable proportions and in 
a variety of physical and chemical states, contingent 
upon the processes of proliferation, exudation, 
degeneration and repair which may be going on at 
any time. 
There are also the best of reasons for believing 
that the intoxication of the general tuberculin 
reaction results in large part, if not wholly, through 
the operation of the same proximate mechanism. 
These reasons are (1) that the general tuberculin 
reaction cannot be evoked in nontuberculous animals, 124 
RESISTANCE 
(2) that it is always accompanied in a tuberculous 
animal by a focal reaction, (3) that it does not occur 
in the latter unless focal reaction takes place and 
(4) that close observation of accessible foci will 
demonstrate unerringly that focal reaction begins 
before the first manifestations of the general reaction. 
In several other contributions I have already 
reported the results of experimental studies which 
lead me to believe that the intoxicating substance 
of tuberculosis is in large part a nonspecific material 
and not necessarily derived from the bodies of 
tubercle bacilli. I am led to believe that any tissue 
products, normal or abnormal, when thrown into 
the circulation in excess in unit time, will poison an 
animal. Deep-seated chemical changes, (ferment 
action, cleavage, etc.) are very likely going on in 
tuberculous foci with greater or less rapidity all the 
time. In the natural evolution of infection, intoxi- 
cation is to a great extent a nonspecific process, 
brought about by the absorption of focal materials 
in amounts large enough to produce symptoms. 
But if tuberculous animals are given tuberculin in 
overdose or suffer reinfection with large enough 
numbers of bacilli, then intoxication is set in 
motion through an immune or allergic process, 
although again the actual]poisonous material ab- 
sorbed is largely nonspecific and does not differ from 
that which causes the ordinary intoxication of 
tuberculosis. . $ 
Because they are allergic, tuberculous foci react 
with inflammation to new implantations of tubercle RESISTANCE 
125 
bacilli or to applications of tuberculin. This reac- 
tion is an immune phenomenon. Its physiological 
effect is to inflame the foci of tubercle and the tissues 
surrounding them and this inflammation contributes 
to the dissolution of focal products and to the 
facility with which they are absorbed. 
In the vast majority of cases of human tubercu- 
losis, reinfection, extension, metastasis, proceeds 
with so few bacilli concerned that no appreciable 
acute explosion occurs and relatively slight new 
lesion results. Such instances, the commonest 
events in human tuberculosis, do not resemble what 
we usually bring about in experimentation. But 
when large amounts of material are let loose sud- 
denly over a single area or are scattered broadcast, 
then we begin to see approximately what we ob- 
serve in our laboratory animals following our 
ordinary methods of study. It is such events that 
provide for us our clinical cases of acute tuberculous 
pneumonia and generalized miliary tuberculosis. 
In both these types of clinical disease, previously 
healthy men may fall ill abruptly; sometimes in 
miliary tuberculosis even with a rigor. Intoxica- 
tion of varying degree dominates the entire early 
phase of the illness; at first localizing signs are few 
or they may be entirely absent. The patients may 
experience an early clinical course which in essen- 
tials does not appear materially different from that 
observed in tuberculous guinea pigs or rabbits 
reinfected with moderate doses of living bacilli 
intravenously. Within a very short time'—four 126 
RESISTANCE 
to six hours'—such animals become very ill, with 
fever, dyspnoea and thorough failure of muscle 
tone, and their appearance is one of extreme misery. 
Many die in from twelve hours to two days after 
reinfection; the survivors slowly come back to their 
previous health. 
If we section the dead animals we get the clue to 
what has been happening; indeed, where tubercle 
existed the whole organ may be inflamed. In other 
words, foci have been “reacted” by the reinfecting 
bacilli (just as they would be “reacted” by tuber- 
culin). But there may, in addition, be many other 
acute changes throughout the body: the lungs and 
other organs may have many small, sometimes 
confluent, areas of acute inflammation, sometimes 
even with haemorrhage, where bacilli in sufficient 
numbers have embolized. 
In such animals there is no doubt that the acute 
illness, the intoxication, is caused in part by the ab- 
sorption of the same focal substances which arouse the 
symptoms of ordinary tuberculosis; in these cases 
under the influence of acute reaction brought about 
by reinfecting bacilli. The symptoms of reinfection 
are an intensification, as a rule, of those of the 
chronic case. They no doubt have causes besides 
the one just mentioned. There may be a rapid 
outpouring of inflammatory elements wherever new 
bacilli lodge, and part of the intense intoxication may 
be due to absorption of these freshly exuded mate- 
rials, as may conceivably happen in the lobar pneu- 
monia which comes on abruptly, with rigor and RESISTANCE 
127 
prostration, with a precipitate formation of con- 
gestion and inflammation. A certain amount of the 
intoxication may also be caused by the absorption 
of products originating from the rapid destruction 
and dissolution of reinfecting bacilli lodging in 
hypersensitive soil. But I am inclined to ascribe 
a comparatively small part of the intoxication to 
these particular materials, especially when I think 
of several features of intoxication in human tubercu- 
losis. 
We frequently meet, for instance, with few symp- 
toms of intoxication in patients who are expectorat- 
ing unusual numbers of bacilli; in some cavity 
cases, for example. In these, of course, we may be 
dealing with well walled off cavities which permit 
but slight absorption of focal material which is, 
besides, being readily evacuated: even though it 
could be shown that bacillary elements are the 
actual poisonous substances, we would understand 
why such patients present few symptoms. On 
the other hand, some patients with rapidly caseating 
and disintegrating tubercles labor under profound 
intoxication; yet, as is well known, their lesions may 
contain few bacilli. As Koch pointed out long ago, 
bacilli, again, are not a prominent feature of certain 
stages of generalized, miliary tuberculosis, a condi- 
tion marked clinically by great intoxication, and 
pathologically by innumerable foci of cellular pro- 
liferation and exudation with relatively slight 
focal investment. 128 
RESISTANCE 
At all events, there can be little doubt that the 
immune or allergic state exerts marked effects on 
the symptomatology of tuberculosis. It is brought 
into action whenever new localizations of bacilli 
are to be dealt with. The tissues react vigorously 
with anatomic results which contribute to the 
illness. Acute inflammation arises where the new 
bacilli focalize for the time being, and something 
is released from the bacilli which may in addition 
react with existing, older foci, inflame these and set 
up those conditions which promote focal absorption; 
hence, sudden access of intoxication or intensification 
of whatever symptoms have been present. If there 
is anything essentially poisonous in the bacilli 
themselves and this is absorbed, it probably con- 
tributes but slightly to the intoxication. 
For the broad and indisputable fact remains that 
the normal nontuberculous animal tolerates living 
tubercle bacilli or their derivatives without illness, 
while the tuberculous animal, made immune and 
allergic by its infection, is at once profoundly 
affected thereby. The symptoms of tuberculosis, 
particularly if they are intense and acute, must 
therefore be regarded as immune phenomena. 
They arise out of the effort which the body makes 
to resist infection, to meet it with unusual vigor, 
to check the advance of the bacilli and to destroy 
these. In the struggle the patient may die, sacrificed 
to the performance of the special function which the 
body is exercising at the time. Nature is always 
lavish in responding to an immediate need. Pleu- RESISTANCE 
129 
risy with effusion, at bottom, is without question a 
phase of resistance to reinfection; so is the inflam- 
mation of tuberculous pneumonia, or the exudation 
of even tuberculous meningitis. The fact that the 
body may overdo or that the combat goes on in a 
peculiarly dangerous location, so far as the general 
economy is concerned, and that the patient may 
be made gravely ill thereby or even be deprived of 
life, detracts nothing from the certainty that it is 
his resistance which is fashioning the catastrophe. 
If a hundred normal guinea pigs are subjected to a 
given dose of virulent tubercle bacilli, every one 
will bear the infection at first as though nothing had 
happened; for several weeks they will appear as 
lively and as unaffected as ever. But in from two 
to three months every one will have died of general- 
ized tuberculosis. If, however, a hundred guinea 
pigs with slight and well-borne tubercle are given 
similar doses as reinfections, all fall ill almost at 
once and perhaps a number will die within two or 
three days; but all of those which survive will be 
alive two or three months afterwards and will have 
overcome their second infection—the infection which 
was ultimately fatal when it was made to be a first 
infection. When we get to speaking of a patient 
who is becoming acutely ill with tuberculosis as a 
person who is losing his resistance we are being 
misled by appearances and are speaking outside the 
facts—at least, if our criterion of facts be that which 
can be sharply demonstrated, and if our gauge of 
resistance be an increased ability to ward off or to 130 
RESISTANCE 
localize infection. There are exceptions; but it is 
incontrovertible that in infections vigor of symptoms 
goes hand in hand with resistance. For the time 
being, the patient with “stormy” illness may be the 
sickest pneumonic and his exceptional derangement 
of function may kill him; but it is the more com- 
fortable patient with low reacting capacity, with 
depressed leucocyte count, that we are always 
hopeless about. We have learned that he always 
dies. He really has no resistance and his placidity 
of reaction shows it. 
By way of recapitulation I may put my view of 
the intoxication of tuberculosis as follows: 
The course of active tuberculosis in itself repre- 
sents, no doubt, a wellnigh irresolvable complex. 
There are no doubt cases, many of them, which dur- 
ing the entire period of activity evolve and recede 
without bacilli ever being conveyed to points out- 
side of the active focus and setting up reinfection 
elsewhere. There are other cases, again many of 
them, in which it is plain that massive reinfections, 
localized or disseminated, are taking place. There 
are still others, perhaps the majority of cases, in 
which the infection progresses through reinfection, 
occasionally or frequently repeated, by comparatively 
few bacilli, which have been transported by way of 
lymph or blood or visceral duct. 
In all three types of cases intoxication will take 
place from nonspecific focal materials. In the 
first type, constitutional symptoms will appear 
whenever there arise those conditions of focal RESISTANCE 
131 
investment or physiological activity, or both, which 
will make possible the absorption of sufficient focal 
materials. In the second type there will also be 
this type of intoxication; but intensified and acute 
because of the sudden release of large amounts of 
focal material set free and absorbed during and by 
reason of an immune reaction which results in focal 
inflammation, a reaction which is followed by the 
implantation of bacilli at new places in the body 
(in other words, a tuberculin effect). There is, in 
addition, an acute intoxication, set up by the rapid 
inflammation of reinfection in situ and in part 
perhaps by products arising from the rapid degrada- 
tion of bacilli. In the third type there will be non- 
specific focal intoxication, with the acute type added 
whenever reinfection is extensive enough to call 
forth symptoms; for, just as we find that there is a 
limit of tuberculin dosage below which effects on the 
body are inappreciable, so there is a line of reinfec- 
tion below which its immediate effects will proceed 
without being detectable. 
I must believe further that acuteness of constitu- 
tional symptoms always means reinfection, that is, 
infection rapidly or suddenly enlarging its bounda- 
ries and encroaching upon and extending into healthy 
tissues, or infection conveyed from one point to 
another. It is always an expression of the. allergic 
or immune phase of tuberculosis. Experimental 
evidence allows no other opinion and clinical ex- 
perience abundantly bears it out. 132 
RESISTANCE 
In bringing this account of resistance to tubercu- 
losis to a close, I may attempt a brief explanation of 
the action of tuberculin, in conformity with the 
point of view that has colored this entire concept 
of resistance. When speaking of tuberculin, I have 
in mind the many derivatives of tubercle bacilli 
(usually dissociated products) which go by this name. 
At the end of my analysis of the nature of re- 
sistance I stated that tuberculin has no immunizing 
action in the sense that it will protect against in- 
fection. Since Koch’s first astonishing claim in 
1890, and even before, if we recall the earlier work of 
H6ricourt and Richet, Courmont and Dor, Grancher 
and Martin, and others, there has been no lack of 
experimenters to maintain the contrary. The litera- 
ture of tuberculosis teems with recitals of the suc- 
cessful protection of animals of all kinds against 
tuberculous infection with many different products 
of tubercle bacilli. But it is surely not unfair to any 
claimant to suggest that the lapse of time with its 
accumulated trials and experience of the various 
methods has not borne out the promise originally 
held forth for a single bacillary constituent. To- 
day, if we are unbiased, we can admit successful 
immunization by only one method and that is 
through living bacilli, through preliminary infection. 
Yet, after infection is established, tuberculin at 
once begins to exhibit marked effects on the body. 
Moreover, its action at bottom is seen to be a 
specific one, even though all steps of the extensive 
and intricate mechanism set in motion by tuberculin RESISTANCE 
133 
need not be specific. Because of an alleged immuniz- 
ing influence, it has long been used in the treat- 
ment of established infection, with the idea that, 
in some way or other, it endowed the infected body 
with added powers of resistance. All clinical ex- 
perience leaves no doubt that through the intelli- 
gent and repeated application of tuberculin an 
infected body’s tolerance to it can be enormously 
increased: this fact has strengthened the idea that 
tuberculin is a true immunizing agent. At the 
same time unchanged susceptibility of the tuber- 
culin-treated, nontuberculous animal to infection 
has prevented our accepting tuberculin as a specific 
raiser of resistance. If tuberculin is not an active 
immunizing agent, then our task is to explain how 
the tuberculous body’s tolerance to it is brought 
about or why an increased tolerance to it accompa- 
nies its repeated use. 
It is well understood that in practice tuberculin 
cannot be used indiscriminately. Clinical experience 
and controlled experiment have both taught us that 
it is not safe for all tuberculous animals. Out of 
our experience we may formulate that it is altogether 
harmful in acute disease and that it is applicable in 
direct proportion as the symptoms of intoxication 
are in abeyance. We have come to lay down such 
general rules as that it should not be administered 
to patients with temperature over 100° or with other 
evidences of more than mild clinical activity. 
The reason for all this must be evident. It is a 
specific quality of tuberculin that it enters into 134 
RESISTANCE 
reaction with tubercubus tissues and with non- 
involved tissues of tuberculous animals. Its intensity 
of reaction depends on the allergic irritability of 
both types of tissues. This allergic irritability 
depends on the activity of the existing infection. 
This activity depends largely on focal investment, 
that is, the relative fibrosis of whatever tubercle is 
in the body. With poor or insufficient fibrosis there 
will be more activity, higher allergy, and greater 
susceptibility to tuberculin. As fibrosis becomes 
better, susceptibility to tuberculin will diminish; 
as foci stand more “naked” or new foci are estab- 
lished, susceptibility will increase. In other words, 
as tubercle recedes tolerance to tuberculin rises; as it 
progresses, tolerance declines. 
It is also true that the facility with which tuber- 
culin will enter into reaction with foci depends on 
the amount and character of focal fibrosis; that is to 
say, that foci with more and better fibrosis will 
withstand larger subcutaneous injections of tuber- 
culin without reaction than will processes with less 
or poor fibrosis. At the same time, the vigor of 
reaction is expressed largely in intensity and extent 
of focal inflammation. Too much may be bad for 
an animal already laboring under very acute or 
active infection. But this inflammation can, of 
course, be anything from transient hyperemia to 
violent exudation and necrosis. In mildly active 
and sluggish processes a certain amount of inflam- 
mation may be of service; for it may stimulate the 
fibrosis, which always follows it, just enough to RESISTANCE 
135 
close in completely what were insufficiently invested 
foci. 
Now, our guide of so-called tolerance to tuber- 
culin is the ease with which a reaction, usually a 
constitutional reaction, to it can be induced. Since 
the constitutional reaction is the effect of the focal 
reaction, this is only another way of saying that 
our index of tuberculin tolerance is the responsive- 
ness of focal reaction. As the latter remains absent 
with increasing doses of tuberculin it means, if a 
focus has never reacted, that we have not yet 
reached the dose of tuberculin large enough to 
“react” it. If it has reacted to a small dose and 
then fails to react as we continue to give larger 
and larger amounts, it means that the foci are 
becoming better fibrosed. If the successive appli- 
cations of tuberculin fail to throw the foci into 
vigorous reaction, they may, by inducing very mild 
and unnoticeable reactions, contribute to the fibrosis, 
the healing, through these repeated mild stimula- 
tions. It may be impossible to demonstrate all 
this in hidden and inaccessible pulmonary tubercle, 
but it can be followed at every step in such ob- 
servable infection as that of the rabbit’s eye or 
guinea pig’s skin. 
Experiments on anaphylaxis disclose that the 
nontuberculous animal cannot be made less sensitive 
to tuberculin through repeated application of it. 
It becomes more sensitive, or hypersensitive, as we 
say. There is no rigidly analyzed evidence to lead 
us to believe that the body of the tuberculous 136 
KESISTANCE 
animal can be made less sensitive to tuberculin 
through repeated and graduated dosage. To re- 
peat: Tuberculin effects on the body which we observe 
in practice are focal effects. Tuberculin action that 
manifests itself to us is a focal action. Tuberculin 
tolerance is focal tolerance. Tuberculin tolerance is 
increased as focal tolerance to it rises, and tuberculin 
can contribute to this enhancement by contributing 
to focal fibrosis through mild stimulation. After 
our long discussion of the part which focal invest- 
ment plays in resistance, the application of this 
concept to resistance where it touches the pathology 
and symptomatology of tuberculosis is plain. 
I leave this analysis of resistance to tuberculosis 
with a feeling of regret and with a sense that, while 
I may have struggled at times with unpardonable 
minutiae and repetition in making my position clear, 
I bring to an end a task incompletely performed and 
perhaps none too lucidly presented. 
The nature of the subject has allowed nothing but 
the most meticulous and precise assembling and 
statement and restatement of evidence. At the 
same time, still more elementary treatment of it 
would have put upon me the necessity of a wealth 
of definition and description which would surely 
have enveloped leading outlines in an almost im- 
penetrable haze. The phenomenon of resistance to 
tuberculosis is intricate; how complicated, how in- 
volved in faulty concepts, how cluttered up with 
semblances, only those who have given much time RESISTANCE 
137 
to direct observation and reflection and brooding can 
appreciate. My main concern has been to search 
for a single and solid something which stands out 
plainly in resistance to tuberculosis and is at the 
same time not steeped in verbiage and is of itself 
not merely the trappings of resistance. 
Yet the reaction of tissues, native, acquired, fixed 
or modified, is not the really fundamental thing in 
resistance. I have tried to lay bare in and through 
what process resistance works, and rises and falls. 
But tissue cells are the pieces through which the 
motive forces work, and I have said very little 
about fibroblasts and endothelium and leucocytes, 
lymphocytes, mononuclears, and so on; and it will 
no doubt some day be found that their interaction 
and relative weights are perhaps much more in- 
volved than the grosser tissue reactions which they 
bring about—in proliferation and exudation, in 
fibrosis and necrosis. Still further in the future 
lies the complete and comprehensible demonstration 
of the energies, the biochemical and biophysical 
impulsions and repulsions which set all the cells 
into play. And beneath all is life—whatever its 
essence may be. 
All this goes into the making of resistance— 
resistance revealed to us in the crude yet unequiv- 
ocal circumstance that the natural history of 
tuberculous infection is never exactly the same in 
any two animals.