Infection, immunity and inflammation : a study of the phenomena of hypersensitiveness and tolerance, and their relationship to the clinical study, prophylaxis, and treatment of disease

Front matter

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By

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Preface

Since the discovery of the phenomenon of anaphylaxis in 1906, the attention of immunologists throughout the world has been directed in large measure to the study of hypersensitiveness and its relationship to other immunologic processes. Although this chapter in our investigation of disease is not yet fully written, I am of the opinion that there has now accumulated a sufficient amount of data regarding the phenomenon of tissue hypersensitiveness to the presence of foreign albuminous substances, and the companion state, in consequence of which the tissues are rendered insusceptible to symptoms of tissue irritation, to which the name ‘‘tolerance’’ is applied in this volume, to justify a more general knowledge of these facts by the practicing physician and surgeon.

Although I believe that the immunologic process, at least as it applies to the tissue reaction against colloidal proteins, is, in fact, an exhibition of digestive activity on the part of the tissue cells, I do not wish to obseure, by the discussion of the nature of the reaction which occurs between antigen and antibody, the importance of the truth that hypersensitiveness and tolerance are phenomena which are readily demonstrated both in animals and in man. An appreciation of the fact that the two states may, and often do, exist in the same individual is of the utmost importance, both in the study of clinical phenomena and in the treatment and prophylaxis of infectious disease.

Anaphylaxis constitutes the first stage in the immunologic reaction, and, although, under very exceptional circumstances, it may constitute a danger to the life of the animal or individual, it serves a useful purpose in that, in consequence of hypersensitiveness of the tissues to the complex protein molecules which constitute bacteria, the bacterial cell bodies are immediately recognized by the tissue, as irritants. The nor-

8 PREFACE mal response of the tissues to the presence of small particles of irritant substances is focal hyperemia, accumulation of leucocytes, and phagocytosis of the irritant particles.

A proper appreciation of the allergic phenomenon, as described by von Pirquet, and its relationship to anaphylaxis and tolerance, places the prevention and treatment of infection by means of bacterial or other protein preparations upon a rational basis. In the absence of a working hypothesis, the production and control of alterations in the immunologic state of the human individual become, not only difficult, but dangerous.

Since 1914, when I first brought forward the point of view expressed in this volume, the clinical study of infectious processes and the control and guidance of inflammation, whether by means of mechanical (operative) or specific immunologic methods, has confirmed, in my opinion, the accuracy of the hypothesis which is elaborated in this contribution.

No attempt has been made to include in this volume a complete bibliography. Specifie references have been made only to such publications as have been employed to illustrate a definite phenomenon, or support an hypothesis. My own views have been indicated, and, where it was thought necessary, the contrary opinions have been presented, although I have made it my aim to eliminate unnecessary argument.

Although the general subjects of infection and immunity are considered in a broad way, I have endeavored to limit the discussion to such facts and theories as are of importance to the clinical practitioner. Bacteriology is not discussed from the viewpoint of differentiation of strains of microorganisms, but a study is made of those characteristics of bacteria which determine their pathogenicity and their power to stimulate reactive phenomena on the part of the host.

In the chapters upon the application of immunity principles to the treatment of disease, and in the explanation of disease phenomena, the importance of immunology is indicated, although no attempt has been made to make the presentation of these aspects of the subject exhaustive. Serology, insofar

PREFACE 9 as it refers to technical methods for the identification of immune bodies, has been excluded. There are at the present time a number of very excellent volumes written in English, in which technical methods of serology are described and the relative importance of in vitro reactions discussed. For the presentation of the subject for the laboratory worker, the reader is referred to contributions of this nature. The author has made use of the following works with considerable freedom: Kolmer: Infection Immunity and Specific Therapy. Zinsser: Infection and Resistance. Wells: Chemical Pathology, and Physiological Reviews, 1921, Vol. 1, No.1: The Present Status of Anaphylaxis. Karsner and Ecker: Prinevples of Immunology. Vaughan: Protein Split Products. Besredka (Gloyne): Anaphylaxis and Antianaphylazis.

If this small volume, which has been written by a practicing surgeon who, for many years, has made the study of infection and the reaction of the tissues to irritants his special interest and hobby, be of value in stimulating other clinical observers to further inquiry into this fascinating and practical branch of biology, the effort entailed in its preparation shall have been adequately rewarded.

Chapter I Page

DEFENSIVE AND OFFENSIVE REACTION OF THE BoDY AGAINST IRRITANTS General Introduction, 17; Serum Reactions, 20; Cellular Reaction, 22.

Chapter II Infection And Infectious Agents

Introduction, 24; Historical, 26; Miechalaate anid Chemical Characteristics of Bacteria, 28; Chavectectetioe of Bacteria Determining Their Pathogenicity, 31; Factors which Determine Relative Virulence of Bacteria, 46; Factors Influencing Infection, 53.

CHAPTER ITI

IMMUNITY AND IMMUNIZATION . .. .

Chapter VII

More DETAILED DESCRIPTION OF THE PHENOMENA OF ANAPHYLAXIS IN THE GUINEA PIG AND OTHER ANIMALS .

Clinical Phenomena of Shock in the Guinea Pig, 84; Postmastinn

Findings in Guinea Pigs Dying in Anaphylactic Shock, 86; Ana-

12 CONTENTS

PAGE phylaxis in the Rabbit, 87; Anaphylaxis in the Dog, 88; Postmortem Findings in Dogs Dying of Anaphylactic Shock, 89; Anaphylaxis in the Cat, 90; Anaphylaxis in the Goat, 90; Anaphylaxis in Man, 90.

Chapter VIII

PHYSIOLOGY OF ANAPHYLACTIC SHOCK . . . oe Tissues Affected in Anaphylaxis, 98; The Role of the tine in Anaphylaxis, 101; Effect of ‘Aiasgiaalin Shock upon Coagulation of Blood, 103; Effect of Anaphylactic Shock upon Temperature, 104; Effect of Anaphylactic Shock upon Leucocytes, 104; Depletion of Complement in Anaphylaxis, 105; Increase in Blood Nitrogen in Anaphylaxis, 105; Lymphagogue Reactions in Dogs, 105; Nonstriated Muscle Reaction in Vitro, Schultz-Dale Reaction, 106.

Chapter XVIII

PROTEIN-LYSIN IMMUNITY. ALEXIN (COMPLEMENT) AND SENSITIZING

SUBSTANCE (AMBOCEPTOR) . .

Alexin or Complement, 199; Origin of Alinta, 200; Relationship

of Complement to Leucoprotease, 201; Multiplicity of Alexins,

203; Sensitizing Substance (Amboceptor), 203; Resistance of

Amboceptor to Heat and Desiccation, 204; Sensitizing Experi-

ments, 204; Reciprocal Activity of Complement and Amboceptor,

205; Multiplicity of Amboceptors, 205; Complement Fixation or Binding, 206; Complement Binding Reactions, 206.

Chapter XIX

AGGLUTININS AND PRECIPITINS Agglutinins, 210; Group haatinias, 211; Nature of Agetatinia Reaction, 212; Precipitins, 213.

Chapter XX

RELATIONSHIP OF ANAPHYLACTIN TO OTHER IMMUNE BODIES . . . Identity of all First Order Antibodies, 215.

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. 174

. 185

. 198

. 210

14 CONTENTS

CHAPTER XXT

PAGE

HEMOCELLULAR REACTION. THE LEUCOCYTE COUNT IN DIAGNOSIS AND PROGNOSIS .

Physiologic Variations in Onedidiig t ilalaaiiien, 921,

Chapter XXII

FocaL VASCULAR AND CELLULAR REACTION TO IRRITANTS. INFLAMMA- SOE sae fie a aera a ay ‘ Nature and Qualities of Serum, 225; Phiscinene of titkseemaitod, 226; Nature and Origin of Cells Which Take Part in the Inhisabantoiny Process, 227.

CHAPTER XXTII

CLASSIFICATION OF INFLAMMATORY REACTIONS . . ‘ Acute Inflammation, 231; Chronic Inflammation, " 933; ‘deta lomata, 236; Tuberculosis, 236; Syphilis, 237; Leprosy, 238; Other Granulomata, 241; Piotective Effect of Macephiigts upon Certain Microorganisms, 241.

Chapter XXIV Anaphylaxis In Man

Reactions to the Parenteral tatcodustion of toca ictus in oe —Serum Sickness, 243; Determination of Hypersensitiveness and Method of Desensitization, 247; Treatment of Anaphylactic Reaction in Man, 249; Clinical Examples of Hypersensitiveness to Nonbacterial Proteins, 250; Constitutional Manifestations of Infection and Reaction, 258; The Réle of Anaphylaxis in Resistance to Infection (Vaughan’s Conception), 262; Factors Determining Relative Susceptibility to Infection, 266.

Chapter XXV

APPLICATION OF IMMUNITY PRINCIPLES TO .THE PREVENTION AND TREATMENT OF DISEASE . . . ee

Serum Therapy, 270; Production and Praiaiitinn: of Antitoxie Sera, 276; Antitoxic ‘RbceinTreatessnt of Diphtheria, 277; The Prophylactic and Therapeutic Employment of Tetanus Antitoxin, 278; Antipneumococeus Serum, 283; Bacillary Dysentery, 284; Prophylactic and Therapeutic Employment of Bacterio-proteins (Vaccines) and Pollen Extracts, 287; Prophylactic Employment

of Vaccines, 290; Rabies, 291; Prophylactic Immunization Against Diphtheria, 293; The Therapeutic Employment of Vaccines, 296;

. 220

. 223

. 230

. 243

. 270

CONTENTS 15

PAGE Vaccine Treatment of Furunculosis, 298; The Treatment of Gonorrheal Infection by Means of Vaccines, 300; Tuberculin Therapy, 302; Dosage and Interval T. R. and B. E., 307; The Treatment of Hay Fever by Means of Pollen Extracts, 309; Nonspecific Protein Therapy, 312.

Chapter XXVI

THERAPEUTIC GUIDANCE OF THE ACUTE INFLAMMATORY REACTION . . 315 Clinical Inhibition of Inflammatory Reaction, 316; Clinical Stimulation of Inflammatory Reaction, 319; Surgical Removal of Irritants, 320.

Chapter I Defensive And Offensive Reaction Of The Body Against Irritants

General Introduction

Throughout the lifetime of the individual, the animal or human body is periodically exposed to the entrance of foreign irritant substances. It is only as a result of constant preparedness on the part of the tissues, that the latter are able to maintain their capacity for functioning and the body to prolong its existence.

Broadly speaking, there are two methods by which the offensive and defensive functions of the tissues are accomplished: (1) by the elaboration, on the part of the tissue cells, of soluble substances which are capable of neutralizing or destroying injurious agents; (2) by the phagocytic and lytic activity of certain of the body cells.

Since the study of these two processes requires special technical methods, and hence special training, they have been divided into two groups, both of which are worthy of, and have received by numerous investigators, most careful observation and research. The science which treats of the constitutional reaction of the body to irritants, as evidenced by the elaboration of certain soluble substances and their discharge into the blood, lymph, and other body fluids, is known as immunology.

The reactive processes, as manifested by morphologie (visible) changes at the site of the introduction of, or invasion by, irritating substances are termed inflammation. Inflammation consists, therefore, of the focal reaction of the tissues against irritants.

The larger proportion of the cells which take part in local inflammatory reactions are derived from the blood stream, into which they are discharged from the myelogenous and lymphogenous tissues, in increasing numbers, during the course of reactive phenomena. There occur during the course of infectious diseases changes in the productive activity of the tissues, more particularly of the bone marrow, as well as deviations from the normal cell content of the blood. This readjustment of blood cell precentages may be conveniently called the hemocellular reaction.

All forms of reaction, with the exception of rare instances of reflex reaction, are stimulated by the presence in the tissues, in which the reaction occurs, of some form of irritant. If we attempt to divide the causative factors which. provoke inflammatory reactions according to their physical nature, we find that in so doing, we understand, to a considerable degree, the usefulness of the individual elements taking part in the reactionary process, and, thus, are enabled to appreciate the rationale of the reaction itself.

Three main types of irritant are met with, viz.:

(a) Diffusible substances, such as toxins, alkaloids, erystalloids.

(b) Colloidal substances, proteids. These may be either (1) soluble, as egg albumen and serum protein, or (2) particulate, as bacterial cells.

(c) Insoluble and nonfermentable substances, such as carbon and the metallic elements.

As might be expected the manifold substances belonging to any group vary much in toxicity or irritant qualities; it may be noted however, that no matter what may be the relative toxicity of the foreign substance, an attempt is usually made by the tissues of the host to combat this effect and to remove the source of irritation. It will be observed, moreover, that the physical as well as the chemical nature of the

REACTION OF BODY AGAINST IRRITANTS 19 foreign substance determines the type of reactionary process exhibited.

The pathogenic effect of irritants upon the body tissue is due to a variety of injurious actions:

1. By their simple mechanical presence foreign substances, even though not in themselves irritating to the tissues, may destroy cells in their immediate vicinity and interfere with the function of the part in which they are situated, e.g., drainage tubes, projectiles, anthracite pigment, and air and other gases (such as are produced by B. aerogenes capsulatus during its growth).

2. If the irritant substance be soluble, it is carried to distant parts of the body and may cause injury to cells far removed from its point of entrance, e.g., bacterial and other toxins, and alkaloidal poisons.

3. Insoluble toxic substances may injure tissue cells in juxtaposition to them.

4. Living, growing bacteria and animaleulae may, in addition, destroy tissue as the result of their metabolic activity, e.g., muscle tissue by the B. aerogenes capsulatus, and red blood cells by the plasmodium of malaria.

Irritants not only differ in physical and biological type, but the extent of their injurious action varies to a very considerable degree, some being almost inert, e.g., catgut and most of the metallic elements; whereas others (hydrocyanie acid, tetanus toxin) are so potent that extremely small amounts lead to rapid and violent death of the individual.

As we study the reactive changes which occur in the animal body, we find, as might well be expected, that different types and degrees of irritants are met by the exhibition, on the part of the body tissues, of different methods of defense. We note, moreover, that certain substances are not antagonized in their action in any way and that the fate of the individual into whose tissues the irritant gains entrance will depend largely, or entirely, upon the amount of the substance introduced. Such we find to be the case with the alkaloidal poisons, as well as the majority of toxic mineral substances, such as arsenic, lead, and mercury. Experiments prove that repeated introduction into the animal body of certain drugs, such as the aldehydes and alcohols, as well as a number of alkaloids, is followed by the exhibition of a certain degree of tolerance to such drugs. Drug tolerance of this sort is not looked upon as an immunity reaction; nor is there any suggestion that this form of tolerance is related to tolerance to the presence of protein derivatives in the tissues.

It is pointed out later in this volume that the most important type of irritant and the one which is met by specific antibody production is that composed of protein complexes in colloidal form. Although all colloids are not antigenic, it is a fact that, so far as we know at present, all antigens are colloids. The chief obstacle to a more adequate understanding of the defensive reactions of the tissues is due to the fact that the chemistry of the colloids is as yet obscure.

Since bacteria and their derivatives constitute by far the most important group of irritant substances, they have been made the object of special consideration in this volume. The action of microorganisms as causative factors in disease is complicated by the fact that, in studying them, we are dealing with a type of irritant, the concentration of which fluctuates, - and the chemical constitution of which is very insufficiently known. ©

During the earlier studies of immunity processes, bacteria were employed almost exclusively as antigens. Later the data obtained as a result of such experiments were generalized so as to be applicable to all antigens. Since the discovery of the anaphylactic reaction, the fundamental observations have been made with nonbacterial antigens.

Serum Reactions

There are present in the body fluids, blood, lymph, etc., substances which are capable of combining with, digesting, or absorbing, specific chemical bodies, and which are known

1Any substance which stimulates the tissue cells to produce antibodies is ealled an antigen.

REACTION OF BODY AGAINST IRRITANTS 21 as antibodies. The study of the nature, method of production, and manner of action of such antibodies, is known as immunology. Substances against which specific antibodies are produced are called antigens.

The science of immunology is recognized today as one of the most important of all biologic branches of medicine, since it attempts to discover and explain the basic principles underlying protection from, and cure of, infectious diseases.?

In this chapter, it is not-my intention to discuss in detail, the nature of such antibodies, nor their method of production, but rather to draw attention, in a broad way, to the important part which they play in disease conditions. At present it is sufficient to state that the body fluids of man and animals normally contain bodies which are able to act as antidotes to many forms of toxins, and also substances which are able to alter certain solid (particulate) organic materials, notably proteins, in a manner which leads to their inactivation as harmful agencies and their subsequent destruction. It must be noted also, that, to a very considerable extent, the toxin or foreign material is neutralized by a specific substance present in the blood, and, furthermore, that under certain cireumstances of stimulation there is exhibited by the body, the ability to manufacture an enormous increase in the number of such specific antibodies.

An individual, or animal, whose tissues contain substances which lead to the immediate overwhelming of the invader, is protected against infection. The state of the body, by virtue of which it is able adequately to defend itself, is termed prophylaxis.

There is a natural prophylactic state against certain types of bacteria, which is known as natural immunity. In general, however, the immune state is developed only after the stimulation of the tissue cells, by previous successful encounter with like germs, active immunity, or by the introduction of specific

2In addition, immunologic contributions of recent years have shown that a number of previously obscure clinical entities, e. ¢., asthma, hay fever, and eczema, are the result of the reaction of the tissues to the presence of nonviable protein antigens.

antibodies contained in the serum of some other individual or animal, in which active immunization has previously been stimulated. The gift of antibodies in this manner, is known as passive immunity.

For the most part, the production of antibodies under stimulation is specific; that is to say, the activity of the antisubstances elaborated by the tissues, and discharged into the body fluids, is directed chiefly against the antigen, whether bacterial toxin, heterologous protein, or cell body, which has stimulated their production.

Cellular Reaction

In the defense of the tissues against invasion by bacteria, not only are there chemical substances produced, the action of which is inimical to the life of the microorganisms, but certain cellular and tissue constituents of the body take part in the destruction of the bacterial cell by a process of ingestion and subsequent intracellular dissolution of the bacterium. Such a process is known as phagocytosis.

In a general way, we note that certain foreign substances stimulate phagocytosis on the part of special types of cells. Exactly what the attributes of the foreign substances must be, in order that the cells may be induced to attempt their destruction, is insufficiently understood. It is evident, however, that it is because the foreign material is irritating, and hence injurious, to the tissues that this means is adopted for its destruction. The type of cell, which takes part in protective reactions, is determined largely by the nature of the irritant substances. As a general rule, markedly irritant foreign substances are the object of attack by the neutrophile polymorphonuclear leucocyte.

It may be stated that it would appear that the endolysins of certain body cells, notably the leucocytes (leucoprotease), are considerably more potent than the serum lysins.? The exhibition of phagocytic activity on the part of the cells is

3Lysins—Substances potent to cause solution of proteins in particulate rm.

REACTION OF BODY AGAINST IRRITANTS 23 thus the more effective, as well as the more economical, means of combating infection.

If microorganisms which gain entrance to the body tissues are able to adapt themselves to the conditions as regard oxygen supply, moisture, and foodstuffs—qualities which all parasitic, and many saprophytic, bacteria possess—their continued growth will depend upon the adequacy of the defensive properties at the disposal of the body.

If the combined antibody and phagocytic properties of the tissues be sufficiently potent, the invader is forthwith destroyed; no infection occurs; and no visible pathologic lesion is manifest. This phenomenon, which may be termed subinfection (Adami), is in itself harmless, and is in reality useful, as it stimulates the production of larger numbers of antisubstances.

If the number of microorganisms introduced, considered as units, be larger than the number of available units of antibacterial properties, not all of the former are destroyed, and the survivors which maintain their vitality continue to proliferate. If the capacity for antibody production be well developed, the body at once commences the manufacture of new antibodies, with the result that, although the number of units of bacteria is being rapidly multiplied and hence large numbers of antibody units are exhausted or inactivated, there eventually comes a time when the rate of production of antibacterial properties surpasses that of the multiplication of bacteria. From this instant the number of bacteria present in the tissues commences to diminish, with the result that ultimately the invaders, or at least those brought in contact with the blood stream and body fluids, are completely destroyed.

Introduction

Infection consists in the entrance into, and growth within, the animal (or plant) tissues of minute living bodies of vegetable or animal origin. The process or state of infection has been differently defined by various writers. Adami, and others, consider infection to comprise the succession of changes induced in the organism, generally, by the growth within it of microbes. Such a definition embodies not only the phenomenon of infection but also the reaction on the part of the tissue against invasion by the morbific agent; for, although it is true that, as a rule, unusual cell accumulations and immune body production follow the entrance of bacteria, protozoa, ete., into the tissues, these changes represent reactions on the part of the host, and are better studied under the headings of immunity and inflammation.

Infective agents may be divided into four main groups, as follows:

I. Bacteria.

II. Yeasts, moulds and fungi.

III. Protozoa and metazoa.

IV. Filterable viruses.

Bacteria, as a class, are commonly considered to belong to the lowest type of plant life and are closely related to, and are indeed in many instances only with difficulty differentiated from, the more simple moulds and fungi.

The protozoa represent the simplest form of animalcule. Among the higher animal forms (metazoa) the helminthes (worms) are the most important. Their activity is usually confined to the intestinal tract.

The vegetable and animal types mentioned are readily demonstrated visually and, with few exceptions, have been studied by means of animal experiment, or under conditions of cultivation in vitro. There remain a number of infective bodies whose potency in the production of disease and the induction of immunity are well established, but which, owing to their minute size, are invisible under the microscope. Since these bodies are capable of filtration through the finest porcelain filters they have been termed filterable viruses.

Practically all local pathologie lesions which are classified as inflammations, as well as many constitutional diseases, are caused by the presence, and growth, in the body of one or the other of these microscopic vegetable forms (bacteria, yeast, and moulds) or of those animaleule known as protozoa. No aspect of the study of disease is of so great importance to the practicing physician or surgeon, as an appreciation of the mode of action of bacteria in producing pathologic changes in the body, and the various means at the disposal of the body, by which it may overcome such invaders.

The different manifestations of infection, as recognized and classified clinically, represent chiefly the evidences of the reaction of the tissues of the host under stimulation by the invader. It has been found, moreover, that infection by different types and species of microorganisms, is, in many instances, followed by reactions of a specific type, and, since many pathogenic infective agents demonstrate a predilection for certain particular tissues, it is possible to recognize from the clinical manifestations alone the nature of many infecting microorganisms. Thus are diagnosed infection by the typhoid bacillus, and by the streptococcus in erysipelas, as well as invasion by the viruses of smallpox, measles, and other exanthemata.

There is a comparatively large number of affections the specific etiologic agents of which cannot be thus recognized and for whose diagnosis bacteriologic methods must be employed. The more precise methods of the laboratory permit, moreover, an earlier, as well as a more exact diagnosis than those of the clinician. In certain diseases, as in syphilis, the identification of the specific infective agent permits the employment of proper treatment, at an earlier period in the course of the disease, than would otherwise be possible.

Historical

The history of the development of the biologie science of bacteriology, as applied to the observation and treatment of disease, is of comparatively recent growth; for, although, even as far back as 1683, Leouwenhoek, a lens maker of Holland, described minute moving forms in material collected from the mouth, and, although, from time to time, observations were recorded in which more exact details of the structure of such forms were mentioned (Miiller, 1786, Ehrenberg, 1838), it was not until the early part of the latter half of the last century that Pasteur, although investigating as a chemist the cause of deterioration of certain wines, recognized and described the all-important part played by bacteria in bringing about changes in the chemical nature of their environment. Coincidently with the acquirement of this new knowledge Pasteur applied it to the study of pathologic conditions, and to the production of immunity.

Up to the time of Koch’s employment of solid culture media in the isolation of single pure strains of microorganisms, the study of the nature and properties of bacteria was accomplished only with the most tedious labor, and was rewarded with relatively meager results. From this time, 1876-1881, however, the possibilities of more precise methods of study by means of the employment of pure cultures were appreciated. Gradually, but with steady progress, a constantly increasing number of pathogenic processes have been proved to be due to bacterial activity, or to the presence of fungi or protozoa.

It is to Koch, moreover, that we owe the promulgation of a series of postulates which have been accepted as being useful and necessary in associating a given microorganism with a specific disease. According to Koch’s postulates the chain of evidence upon which this connection may be based, is:

(1) The demonstration of the microorganism in all cases of the disease, in such a relationship to the pathologic process that its causative nature seems probable: (2) the artificial cultivation of the organism in pure growth: and (8) the reproduction of disease by inoculation of the microorganism so isolated.

Although, previous to 1860, the subject of bacteriology, as such, was practically unknown to all but a very occasional worker, the fact that there was some substance, or virus, which was responsible for the development of disease processes in man, was appreciated, as is evidenced by the employment by Jenner of the exudate from cases of vaccinia to inoculate the healthy individual. In obstetrics also, White, Semmelweis, and Holmes recognized that as the result of uncleanliness, contact with infected patients, ete., cases of puerperal fever developed. Basing their actions upon these observations, they adopted methods which were strikingly modern in their nature, and which were successful in controlling markedly the incidence of this disease.

Following the appreciation of bacteria as the cause of wound infection, Lord Lister (1865) applied his knowledge of the germicidal action of certain substances, especially carbolic acid, to surgery. From this time dates the advance in surgical technic with which we are all familiar; for, although a more comprehensive recognition of the biology of bacteria has led to the discarding of some of the practices thought by Lord Lister to be necessary, the value of his work cannot be overestimated.

There are several aspects of the biology on life history of bacteria, which it is of the greatest importance that the practicing physician rightly appreciate. For instance, an adequate idea of the various factors which influence favorably, or the opposite, the life and multiplication of microorganisms, is of the greatest value, not only in the proper handling of infeectious processes, but also in prophylaxis. Again the chemical constitution of bacteria is of paramount importance, since their activity as pathogenic agents, as well as their protection from the defensive properties at the disposal of the body, depend, in large measure, upon their more intricate chemical peculiarities. An attempt will be made to prove in consideration of immunology in a later chapter, that it is largely upon the relative amount and exact nature of the protein constituents of the bacterial cell body, that the various clinical manifestations of bacterial invasion (infection) depend.

One of the most important contributions to our knowledge of the method of action of chemical germicides, as also of immune processes, is that of Ehrlich in his recognition, and elaboration, of the principle of chemotaxis or receptor affinity. According to Ehrlich’s hypothesis, the ability of any living cell to incorporate into its protoplasm chemical substances, present in its vicinity, depends upon the presence of receptors, or special unsatisfied molecules, which are capable of attracting and combining with specific substances. The normal metabolism of the cell depends upon the presence of such receptors for useful and essential food particles. Ehrlich proved that not only do cells possess affinities for useful and helpful foreign molecules, but that they also possess receptors capable of attracting and combining with injurious substances which may ultimately lead to the death of the cell.

Morphologic and Chemical Characteristics of Bacteria

Structure.—Bacteria consist of unicellular organisms which exhibit an extremely simple structure. In contrast to the more complicated morphology of higher vegetable, as well as animal, cells, bacterial cells show no differentiation into a distinct nucleus and cytoplasm; although it is probable that infinitely small masses of nucleo-protein (chromatin) material which are scattered throughout the cell body, and which constitute a large part of the total protein content of the bacterial cell, influence the life processes of the bacterium in a manner similar to that exerted by the nucleus of higher types of cells. It must be regarded as possible, however, that there may be a specially differentiated portion of the cell representing the nucleus which, so far, has not been demonstrated by the technical means at present at our disposal.