Immunity and specific therapy

Preface

IN writing this book I have attempted to give a connected and symmetrical outline of the chief facts definitely known with regard to the method in which the body protects itself against infections, and of their applications in the diagnosis, prevention, and treatment of disease. It is not written in support of the views of any particular school of thought, and, when dealing with subjects still under discussion, I have tried to give a fair and impartial, though necessarily succinct, account of each of the rival theories. The factors in many of the problems of immunity are so complex, and our knowledge of the subject grows and alters so rapidly, that it is quite impossible to deal with it dogmatically at the present time. I have kept in view, as far as possible, the requirements of the physician and surgeon who may require an epitome of the theoretical basis of the modern methods of diagnosis and treatment, now assuming so much importance, and of the student who desires a general survey of the subject before commencing more advanced studies.

My best thanks are due to Mr. H. K. Lewis for the ready and courteous way in which he has acceded to all my suggestions and requirements ; to Drs. Whitfield and Briscoe, from whom I have received some valuable suggestions; and to Professor Herbert Jackson, of King's College, for kindly reading the sections dealing with the more purely chemical and physical questions and for much useful information connected therewith. I have also to thank Sir Almroth Wright and Drs. R. W. Allen, Eyre, and Bolduan; Messrs. Macmillan and Co., Kegan Paul and Co., and the proprietors of the Lavcet, British Medical Journal, and the St. Bartholomew's Hospital Journal for permission to use illustrations from their publications.

Contents

CHAPTER PACE

GLOSSARY . . ' . . ix

I. INTRODUCTORY AND GENERAL . ... I

Chapter I Introductory And General

IMMUNITY is the power which certain living organisms possess of resisting influences which are deleterious to others. In its widest form it includes the power of resisting poisons, adverse physical influences, and diseases of all kinds. Thus, many men can and do acquire some degree of immunity against nicotine, alcohol, and other poisons ; some bacteria are immune to temperatures which are quickly fatal to others ; and some individuals and races have a very real immunity to gout and other metabolic diseases to which their less fortunate brethren are more prone. In any complete discussion of the subject these forms of immunity would require some consideration, but in what follows we shall, in the main, limit ourselves to the investigation of immunity against the diseases of bacterial origin. In doing so we must not be thought to consider the other diseases — metabolic and what not — as being unimportant. The very reverse is the case, and the subject which calls most urgently for research at the present day is the nature and mechanism of immunity against malignant tumours, and of this we have recently acquired a little knowledge. But the diseases other than those of bacterial origin will not be dealt with, for the simple reason that our knowledge of their intimate causes is still unknown, and until they are discovered, and until the physiological disturbances of the economy which occur in these diseases are more fully known, the nature of the corresponding immunity is obviously extremely difficult of study. The bacterial diseases are quite different, for here

2 INTRODUCTION

the causes are fully known ; the diseases themselves can be reproduced (in most cases) at pleasure, and the physiological disturbances which take place are fairly well investigated. There are, of course, gaps, and those not inconsiderable, in our knowledge ; but, on the whole, the nature of these diseases is nearly as well ascertained as the present state of normal physiology will allow. Further, we can not only reproduce the diseases, but we can reproduce in most cases any degree of immunity to them which we may require for purposes of protection or research, and we can investigate the differences between the cells and fluids of the immunized person or animal and the corresponding parts of a normal organism, and we can attempt to correlate them with the production of the immune state. We have, therefore, a very large amount of information on the subject, and although this information is at present incomplete, we have already obtained results of the highest practical and theoretical importance ; and the value of these results leads us to believe with confidence that our methods are right, that we are on the right track, and that a solution of the problems that have at present baffled research will come in the near future.

As denned above, immunity is a function of all living material, and one of the highest importance. Biologists have compiled lists of the essential properties of living protoplasm — nutrition, reproduction, and the like — but have not realized that immunity to bacterial action is the first necessity for continued life. Consider for a moment a small water animal — say a hydra — occurring in water which naturally contains saprophytic bacteria. Whilst the animal lives these organisms do not affect its protoplasm in any way, the latter being immune to their action ; but on the animal's death rapid putrefaction occurs, and in a few hours its protoplasm is broken down by bacterial action: the immunity has ceased. Immunity to putrefactive bacteria is therefore a condition of life in the lower animals. But the same is true in every respect for those of a higher grade, man included. From the moment of birth we are surrounded with air containing bacteria which are not pathogenic in the ordinary sense, but which only fail to be so because of the inherent power of immunity to saprophytic bacteria, which is a fundamental property of all living material. Apart from this, the organisms present in the air, alimentary canal, skin, etc., would flourish as rapidly as they do in a corpse, and life would only be possible for a few hours, or perhaps minutes. Readers of one of Mr. Wells's ingenious romances may perhaps remember how the strange beasts from Mars which invaded this planet died rapidly, being evolved in a region in which there were no bacteria, and in which this power of resisting their action had not been developed. The example is a striking one, and is strictly scientific, though we may wonder how the rotation of nitrogen, in which bacteria play so essential a part, is brought about in Mars ; for this process of the breaking down of dead proteids by bacterial action, and the preparation of its nitrogen for use in plants, is essential for continued life on the planet. Without decomposition all the combined nitrogen of the world would soon become locked up in the dead bodies of animals ; plants would starve and die, and animals (which are all dependent, directly or indirectly, on plant nitrogen) would likewise become extinct. It is a most marvellous natural phenomenon that these putrefactive bacteria should be found wherever life occurs, and wherever their aid may be required to deal with the protoplasm when dead, and that this same protoplasm should have acquired such potency in resisting their attacks whilst still alive. Absence of bacteria or absence of immunity are alike incompatible with animal life.

Considerations of this nature lead us to a short discussion of the difference between the pathogenic and non-pathogenic bacteria, and we find that there is, theoretically, none. Any bacterium will produce disease if it grows in the tissues of the living body, and all bacteria1 will do so if the necessary degree and form of immunity is not present. A pathogenic organism is one which can grow in the living tissues, and it can do so only because those mechanisms of immunity which are sufficient in the case of the saprophytic bacteria are powerless to resist it ; but in most cases, as we shall show, a higher degree of immunity can be produced artificially, and the microbe in question then becomes non-pathogenic to that particular animal. So, too, with the bacteria ordinarily regarded as non-pathogenic. Under certain circumstances, some of which are known and some still unknown, the resistance of the body or of a part of it may be broken down to such an extent that these organisms may gain access, flourish, and give rise to disease. Thus, B. proteus may give rise to phlebitis, growing in the thrombosed vein, and giving off toxins which have an injurious action on the tissues.

1 Bacteria growing only at very high or very low temperatures, or on media very poor in nitrogen, perhaps excepted.

4 INTRODUCTION — PATHOGENICITY

As a matter of high theory, therefore, there is no fundamental distinction between pathogenic and non-pathogenic bacteria, and we can imagine circumstances in which the tissues are vulnerable to attack by almost any microbic species. Practically, however, we shall consider an organism as pathogenic when the immunity of the animal which it attacks is not so perfectly developed that its presence in the tissues is but transient and unaccompanied by any noticeable ill-effects, but in which there is a balanced contest of longer or shorter duration between the injurious powers of the microbe and the defensive mechanism of the host, accompanied by more or less injury to the tissues and disturbances of the physiological economy of the latter, and resulting either in the death of the invader or of the patient. All grades occur. In most staphylococcic infections the chances are enormously on the side of the host, and the immunity is sufficiently high to localize the process before it has gone far. In typhoid fever the natural immunity and the pathogenic power of the organisms are more nicely matched ; the contest between them is of long duration and doubtful issue. And in some forms of human disease, but more especially in artificial infections of animals with highly virulent cultures, the power of immunity seems almost nothing, the bacterium growing apparently unchecked and death occurring within a few hours. We say that these organisms have different degrees of pathogenicity, but it would be equally correct to say that there are different degrees of resistance against them, since an organism that is highly virulent towards one animal species may be quite harmless to another, so that pathogenicity is not an inherent property of certain bacteria.

Thus far we have considered the resistance of the host as if it were fixed and definite, but this is not the case. It has been known from time immemorial that certain diseases — especially those due to infection — are followed by a greater or smaller degree of immunity, so that a second attack is unlikely — at any rate, for some time. Smallpox, scarlet fever, and measles are amongst the most striking examples, and in them the protection given by the disease is in most instances absolute and lifelong. This is known as acquired immunity, and we shall enunciate it as a law that all recovery from infective disease is due to, and followed by, some degree of acquired immunity, though this may be slight, transient, and perhaps local.

Take, for example, a case of pneumonia, a disease which may occur repeatedly and at short intervals in the same person. Pneumococci are widely distributed, and are almost universally present in the mouth ; the necessary exciting cause, therefore, is always at hand. Under ordinary circumstances the power of resistance is sufficient to ward off the infection, but when this barrier of immunity is broken down by certain adverse circumstances— by excessive fatigue or starvation, by cold, or by an overdose of alcohol or other poison — the pneumococcus gains access to the tissues, and infection1 occurs. The balanced contest spoken of above then takes place. The pneumococcus grows in ' the lungs and blood and produces a toxin, which tends to reduce the general health and the resistance of the body still further; and looking at the problem only from this side, it would appear that the process would go on until all the immunity was broken down, and the pneumococcus could flourish unchecked. This, indeed, might perhaps happen did not death supervene and bring with it conditions unfavourable for the growth of this organism. But all this time the tissues of the host have been reacting, and (in non-fatal cases) sooner or later a condition is brought about in which the noxious power of the coccus and the immunity of the patient are exactly level, so that the disease neither advances nor retrocedes ; and the process goes still farther, and the patient develops such a degree of resistance as will not only render him immune to the spread of the infection, but will suffice to sterilize his tissues of the pneumococci which have already gained access. In other words, there has been an acquisition of immunity; the patient has become immune to the pneumococcus, and it is this, and this only, which has brought about the cure of the disease.

This process may be represented very diagrammatically, as shown on p. 6.

The line ag represents the degree of immunity to the organism in question, the pneumococcus. At b some event takes place (e.g., exposure to cold) by which the resistance is lowered to such a degree that infection can occur. This takes place at c, with the result that the immunity falls still farther. At this time the bacteria begin to flourish in the tissues in increasing numbers. This is represented by the ascending line i. The immunity falls and bacterial action increases until a certain point is reached,

1 I have elsewhere defined infection as the access of living, virulent, pathogenic bacteria to a region whence their toxins may act on the tissues of the body (Rose and Carless's " Surgery," sixth edition et seq., chap. i.).

6 RECOVERY FROM DISEASE

when the reserve forces of the patient have been brought into action, with the result that the immunity rises (from d to e). Somewhere during this rise (not necessarily or probably at its commencement) the contest turns in favour of the host ; the bacteria are rapidly destroyed, and the disease is cured. Usually, but not necessarily, there is a rise to a level higher than the previous normal one (e to/), of longer or shorter duration, and then a reversion to the normal g. If exposure to cold again takes place, a fresh infection may now occur.

Now it must be emphasized that natural recovery from disease only takes place in virtue of an acquisition of immunity to the infecting agent, and in no other way ; and, further, that, except in a few instances, medical treatment simply aims in aiding this phenomenon. If we exclude the various sera and vaccines, there k

FIG. i.

are but two therapeutic agents which have a direct curative effect — mercury in syphilis and quinine in malaria.1 In these diseases the physician can apply a direct remedy, but in other cases the aim and object of treatment is to support the patient's strength until the natural development of acquired immunity takes place, and in some cases to aid this development by certain empirical means. It is found that all agents which tend to improve the general vitality and facilitate the performance of the normal physiological processes have this action ; hence the importance of suitable food in amounts and at intervals suited to the patient's complaint, of fresh air at a proper temperature, of the removal of pain, and other symptoms which tend to impair the patient's

1 Arsenic and some other drugs in the treatment of various protozoal infections (trypanosomiasis, etc.) may also be included. It is interesting to notice that all the diseases directly combated by simple means are protozoal in origin.

strength. These agents are all-important in medical treatment 9 but in themselves they are useless, and they only act by hastening the evolution of the immunity, without which the disease must necessarily progress to a fatal issue. This is well seen in the few diseases in which the development of immunity, in face of a natural infection, is but slight, or perhaps altogether absent, such as leprosy or hydrophobia. Here ordinary medical treatment is powerless, and all our hopes for the future are concerned with the discovery of a direct specific remedy.

It is this connection between immunity and recovery that renders the subject so important to the physician, and the neglect with which its study is treated by the general members of the profession a matter of such profound regret. In our medical education at the present day we pay, and rightly, much attention to the study of physiology, for without a knowledge of the processes of the healthy body we can hardly hope to diagnose and treat its derangements when diseased; and our physicians are in many cases competent physiologists. But it is equally important to understand the method in which the diseased body combats and cures an infection ; and, although our knowledge of this is as yet imperfect, it is increasing day by day, and results of the greatest interest to the practising physician have already been obtained. And I, for one, think that an intelligent appreciation of what is actually taking place in the body, of the conservative and adverse forces, and of the conditions necessary for cure, will always be of value to the therapist, although it may not give any definite information as to what drug is to be prescribed.

Let us revert to the subject of NATURAL IMMUNITY. We may define it roughly as the immunity possessed by a certain individual in virtue of its belonging to a given animal species ; it is inherent to a greater or less extent in all members of that species, and is not dependent on any event taking place during the life of the animal in question. In most cases it is present at birth, though this is not absolutely essential.

Examples are numerous. The lower animals are immune to the gonococcus, and, with few exceptions (the higher apes), to syphilis also. On the other hand, most of the diseases of the lower animals do not affect man — fowl cholera, canine distemper, and rinderpest are a few of many examples. In some cases all animals, with a few exceptions, are immune : this is the case with the venereal diseases, and in some of the protozoal infections of

8 NATURAL IMMUNITY

the lower animals. In others different types of the infecting organism occur, and a given species is susceptible to one, immune to others ; for example, there are three, and perhaps more, varieties of tubercle bacillus, which resemble one another in many points, and which attack respectively man, cattle, and birds, and each animal species is more or less immune to bacilli from animals far removed in the scale.

In general terms, the immunity or susceptibility of different animals depends to some extent on their zoological affinities. Thus man is pre-eminently susceptible to the Spirochata pallida, the anthropoid apes less so, but still not immune, and the lower animals entirely refractory. Rinderpest affects cattle, sheep, goats, and other ruminants, and South African horse-sickness horses, asses, and mules. But to this rule there are numerous exceptions : thus, almost all warm-blooded animals are susceptible to anthrax, but the Algerian sheep and white rat are relatively immune, the wild rat being susceptible. And of the domestic animals we find cattle to be highly susceptible to tubercle, whereas goats, though closely allied zoologically, are almost immune.

Natural immunity does not exist to an equal degree in all individuals of a species. This is well seen in man during an epidemic, where, of a certain number of persons who are exposed to an infection (and, as far as we know, receive the same dose of the materies morbi), some escape the disease altogether, some have a slight, and others a severe, attack, whilst yet others die rapidly. Sex has some influence here, but it is usually difficult to trace, since the males and females of a community are in most cases exposed to an infection in varying degree.

Age is of more importance, and, in quite general terms, we may say that the younger the infant the less its immunity. Certain diseases, such as measles, scarlet fever, and whooping-cough, are rarely seen except in infants, and this is not altogether due to acquired immunity preventing a second attack in later life. Epidemic diarrhoea due to bacilli of the dysentery group is rarely seen — in this country, at least — except in the early years of life, and the same is true of cerebro-spinal meningitis and some other diseases. It is also interesting to notice that the variation in immunity may take a qualitative rather than a quantitative form. The best example is in the case of the pneumococcus. This organism is the chief cause of suppurative processes of whatever region in infants, whereas in adults it is (except in certain regions) a decidedly rare cause of abscesses and other pyogenic processes. It is evident that the form of immunity which prevents the pneumococcus from gaining access to the tissues and giving rise to abscess formation is in abeyance in the young and well developed in the adult ; yet the two are more nearly equal in their resistance to this organism in its role of a producer of pneumonia. There are also very marked differences in regard to local immunity in the two ages, but of those we shall speak subsequently.

Natural immunity must not be regarded as a fixed and definite quantity, since all individuals vary enormously in their resisting powers against various diseases at different times and under different conditions. The factors which tend to break down the immunity against any or all infections may be referred to as the banal causes of the diseases in question. They are not in themselves sufficient to lead to these diseases, but when they come into action and an infecting agent is present the disease will arise. Hence they are often referred to as predisposing causes of disease, and to the lay public they are the actual causes, since they are usually open and obvious, and the real infecting agent is, of course, unknown They are of the utmost importance in preventive medicine, and wherever the probability of an infection is apprehended, a study of the patient's surroundings and habits may often lead to the giving of advice by which these banal causes of infection may be avoided and the disease warded off. In general these predisposing causes are a study for the physician rather than for the pathologist, and in some cases we are quite in the dark as to the method in which they act. Their study cannot be conveniently undertaken here before the mechanisms and processes of immunity have been described, but it will be useful to enumerate some of the more important.

Of these cold and wet, especially in combination, are unquestionably the most important. The exact way in which they act is not definitely known, but there are materials for a number of suggestions. Thus, as we shall have abundant opportunity of seeing, immunity is to a very large extent a function of the leucocytes, to which are specialized cells to which the defence of the body is entrusted. Now the functions (movement and phagocytosis) which can be easily investigated are found to be dependent in a very high degree on temperature, acting best at the temperature of the body, or slightly above ; and it is highly probable that

10 COLD, WET, AND FATIGUE

the more subtle functions of the leucocytes may be similarly depressed by a low temperature. The exposure of the skin to cold, especially if the animal heat be abstracted more quickly by evaporation of moisture on the surface, will lead to a cooling of the blood which circulates through it, and hence to a slight, though appreciable, cooling of the whole blood. This, it is true, is soon compensated for, and no great amount of cooling of the whole body occurs; but even so, it is quite possible that the periodical chilling of the leucocytes during their repeated passages through the cold skin may be sufficient to diminish greatly their functional activity, and to lower the resistance to a point at which infection can occur, and when once pathogenic bacteria have gained a foothold, the resistance will for a time tend to decrease. There is also some evidence going to show that exposure to cold may lessen the production of the defensive substances which occur in the blood (alexin, antibodies, etc.), though this is not fully proved. It is worthy of note that the loss of immunity due to the action of cold and wet on one part of the body (such as the feet) is a general one, and may result in a nasal catarrh, an attack of pneumonia, acute rheumatism, etc., according to the nature of the infection at hand. It is not necessarily a local infection of the chilled region. This is very well shown experimentally. Fowls are immune to anthrax, but are rendered susceptible if they are kept for some time standing in cold water ; and this acquired susceptibility is then a general one, and not merely of the feet.

Cold and wet, as is well known, have less action when accompanied by energetic muscular exercise, so long as this does not reach the extent of undue fatigue. This is not because less heat is lost during exercise. The reverse is the case. The suggested explanation is that the muscular metabolism leads to an increased production of heat, and at the same time the cutaneous capillaries are dilated and the heart accelerated, or that the circulation of blood through the skin occurs quickly ; further, the internal temperature of the body may actually be raised several degrees. The result is that the temperature of any given leucocyte never falls much below normal, if at all, since it comes from the internal regions where the temperature is raised, passes rapidly through the skin, and returns again to the interior of the body.

The effect of fatigue, either alone or in conjunction with cold and wet, is also well known, and is one reason for the excessive mortality from disease of armies in the field. It is less explicable,

INTRODUCTORY AND GENERAL II

but may probably be connected in some way with the presence in the blood of katabolic products of muscular activity, which have an injurious action on the cells of the tissues in general and on the leucocytes in particular. Further, the metabolic products formed during the action of the muscles are acid in reaction, and it is found that some at least of the protective substances which occur in the blood (alexins and opsonins) act best in an alkaline medium. This diminution of immunity after muscular fatigue is manifested in animals as well as in man. White rats which have been made to work in a revolving cage are more susceptible to anthrax than normal white rats, the pre-existing immunity being broken down.

Insufficient or unsuitable food is a factor of importance, especially, perhaps, in the aetiology of tuberculosis. It is, however, rarely seen alone — in this country, at any rate — and in the poorer classes its effects are usually complicated by insufficient clothing, uncleanly habits, and by insufficient ventilation of their houses. For this reason we may perhaps be led to exaggerate its importance ; and whilst it is, of course, true that semi-starvation, in common with other weakening influences, does pave the way for infective processes, we do not find that a supply of food restricted enough to cause a marked reduction of the bodily strength and some degree of anaemia is necessarily associated with any infective disease, though the patient may live under conditions in which infective material is present in abundance. This is well seen in fasting men, in hysterical anorexia, and in patients with impermeable cesophageal strictures. The blood, it may be pointed out, is not one of the tissues that suffers first in starvation, and its importance to the body in many ways is so great that it is kept in good functional activity whilst other regions waste quickly.

It is probable that insufficient food lowers the resistance of the body in certain directions rather than in others. In the East plague follows famine with some regularity, but there is little or no connection between famine and cholera. But in these latitudes at the present time the disease most commonly due to bad or insufficient food is tuberculosis. Formerly it was relapsing fever, or, as it was sometimes called, famine fever, a disease which is now almost extinct as a result of the general cheapening of foodstuffs.

It is worthy of note that the number of leucocytes per cubic centimetre diminishes in starvation, and is generally lower in the badly-nourished than in the well-fed ; and these cells, as we shall see, are pre-eminently concerned in immunity, and this in a great

12 EFFECTS OF A VITIATED ATMOSPHERE

many ways. It was recognized long ago that post-mortem wounds are much more dangerous when received whilst fasting than during the process of digestion, and it is possible that this may be due to some extent to the increased number of leucocytes which occur in the blood during the process.

Exposure to a vitiated atmosphere, if of long duration, is a most potent cause of the breaking down of immunity, and when considered on a large scale, and in view of its effect on the general death and disease rate, is probably of greater importance than all other causes combined. It is especially important in connection with tuberculosis, and nothing is more striking than to notice its effect on the peasantry of some regions, in which, in spite of exposure to abundant fresh air during the daytime, and a supply of food which certainly does not fall below the physiological minimum, and is usually more abundant, phthisis and other tuberculous diseases are rife. These affections are in general common in cold and windy climates, and less prevalent in warmer countries, and there is little doubt that the main reason for this is the habit which dwellers in cold countries frequently contract of hermetically sealing all entrances to their rooms to keep out the cold. But this is frequently seen in warmer regions, and even throughout the South of England there is an almost universal opinion amongst the lower classes that night air is injurious. This is probably a survival from the time when malaria was indigenous in this country.