Typhoid fever considered as a problem of scientific medicine

Preface

This treatise is an attempted exposition of the problem of typhoid fever. It aims to treat historically the development and present status of our knowledge concerning this important malady as viewed from the standpoint of its mechanism. It is not primarily designed to aid directly in the clinic or the laboratory, but should serve to point out the relations of one to the other, to indicate the dependence of practice on theory, and the happy applicability to human need of investigation that may have seemed to aim merely at the gratification of intellectual curiosity.

There are numerous admirable clinical treatises on typhoid fever, such as those of Curschmann, of Vincent and Muratet and of McCrae. The purely laboratory and the public health aspects of the disease are well summarized in such works as those of Kutscher, of Chapin and of Whipple. This book aims to strike a balance between these sources of information, following the life history of the typhoid bacillus rather than the manifestations of the disease it produces, in order to gain insight into the nature of the problem as a whole.

No attempt has been made to make this work encyclopedic in character, although the references to original sources are sufficiently ample to lead a prospective investigator to full sources of information. Although we may have succeeded in maintaining correct proportions in our estimate of the accuracy and value of facts, methods and theories that have been shaken down by time into their proper relations to one another, we shall unconsciously or wilfully have exaggerated the importance of recent contributions. We may well have overemphasized the importance of modern investigations in respect to antityphoid vaccination and specific therapy in typhoid fever through personal enthusiasm. The data on these aspects of typhoid fever are so ample and so recent that a critical summary of their essentials seems desirable, even though somewhat premature.

In addition to the use that has been made of all the general treatises and original sources of information to be cited, particular indebtedness is felt to Charles Murchison's "Treatise on the Continued Fevers" as furnishing the backbone of the discussion of the earlier historical aspects of typhoid fever. The author wishes to express his thanks to Dr. John N. Force, Miss Ruth Stone and Miss Helen Dunbar for suggestions and aid in preparing the manuscript.

CHAPTER I A GENERAL SURVEY OF THE DEVELOPMENT OP KNOWLEDGE CONCERNING TTPHOn>

FEVER

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Progress in the Differential Diagnosis of Typhoid on the Basis of Symptomatology and Morbid Anatomy 1

Development of the Conception of Contagion in Typhoid Fever 6

The Advent of Bacteriology and Its Importance in the Explanation and Prevention of Typhoid Fever 8

CHAPTER II TYPHOm FEVER AS A CAUSE OF DEATH AND DISABILITY

The Significance of Typhoid Fever in Mortality Statistics 13

Chronological Changes in the Typhoid Death Rate 15

Typhoid Fever in Armies 21

The Present Economic Loss from Typhoid 22

Chapter III The Typhoh) Bacillus

Bacillus Typhosus as the Cause of Typhoid Fever 25

The Cultural Characteristics of Bacillus Typhosus 25

Biological Peculiarities Which Serve to Differentiate the Typhoid Bacillus

from Other Bacteria 28

The Toxins of Bacillus Typhosus 31

Mutations and Variations in Bacillus Typhosus 34

Chapter IV The Modes Of Infection In Typhoh) Fever

Transmissibility of Typhoid Fever and General Conceptions of Its Modes

of Infection 39

Sources of Infection from the Typhoid Patient 42

The Typhoid Bacillus at Large 45

Routes Followed by the Typhoid Bacillus from one Individual to Another 46

Contact Infections in Typhoid 46

Direct Contact 46

Indirect Contact and Its Several Channels to the Individual 47

Water Infections in Typhoid and Its Several Routes in Reaching the

Individual 50

Relative Importance of Various Routes of Infection 56 riii CONTENTS

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General Factors Which Influence the Occurrence of Typhoid Fever 56

Extrinsic Factors 56

Intrinsic Factors 58

Chapter V The Pathogenesis Op Typhoid Peveb

General Symptomatology of Typhoid Fever 61

The Incubation Period 63

The Portal of Entry 66

Localization of the Typhoid Bacillus in the Body During the Course of

the Disease 70

The Cause of the Fever in Typhoid 72

Metastatic Foci of Typhoid Bacilli 73

The Bone Marrow in Typhoid 74

The Gall Bladder in Typhoid Fever 75

The Toxins of the Typhoid Bacillus in Their Relation to the Disease

Process 77

The Complications in Typhoid 78

Complications in General and Causes of Death 78

Hemorrhage and Perforation 79

Relapses 81

Experimental Typhoid Fever in Animals 83

Chapter VI The Diagnosis Op Typhodd Feveh

Clinical Diagnosis and Its Limitations 87

Laboratory Diagnosis of Typhoid Fever 88

Detection of the Typhoid Bacillus in the Body 88

Isolation of the Bacillus from the Blood 89

Isolation of the Bacillus from the Stools 94

Isolation of the Bacillus from the Bile 97

Isolation of Typhoid Bacilli from the Urine 98

The Differential Diagnosis of Bacillus Typhosus 98

Diagnosis of Typhoid Fever Based on Specific Reactions on the

Part of the Patient 100

Serum Reactions 100

Agglutination 101

Fixation Reactions in Typhoid 105

The Bactericidal Property of the Serum of Typhoid Patients. . 106

Tropins or Opsonins in Typhoid Serum 106

Methods of Diagnosis Depending on Evidence of Localized Hypersusceptibility in the Patient 107

Diagnostic Reactions Dependent on Changed Metabolism in Typhoid Fever 107

CONTENTS ix

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Changes in the Leucocyte Count in the Course of Typhoid Fever. . . 108 Summary of the Diagnostic Value of the Various Laboratory Tests. . 109

Chapter VII The Sequels Of Typhoid Fever And The Carrier Condition

Sequels After Bacteriological Cure Ill

Typhoid Sequelae Due to Persistence of the Typhoid Bacillus in the Body 113

Localized Pyogenic Foci 113

Gall Bladder Infection 114

Jaundice and Cholecystitis 116

Gall Stones 117

The Carrier State 119

Classification of Typhoid Carriers 120

Urinary Carriers 120

Carriers in Recovered Typhoid Cases 121

Convalescent 121

Chronic 122

Precocious or Incubation Period Carriers 123

Healthy Carriers 124

Importance of Carriers as a Source of Typhoid Fever 126

General Facts in Reference to Carriers 128

The Detection of Carriers 129

Chapter VIII General Measures Of Prevention Of Typhoid Fever

The Prevention of Typhoid Fever at Its Source 131

Prevention of the Extension of Typhoid Fever from Typhoid Patients . . 132

Prevention of Extension from Typhoid Carriers 135

The Detection of Carriers 136

General Methods of Dealing with Recognized Carriers 136

Treatment of the Carrier State 138

The Suppression of Typhoid Infection in Its Transit from one Individual

to Another 141

Measures of Protecting Possible Victims of Typhoid Infection 142

Chapter IX Natural And Acquired Resistance To Typhoid Fever

Evidence for Natural, Individual and Racial Immunity from Typhoid. . 145

Immunity from Typhoid Acquired by Recovery from the Disease 147

Recurrence of Typhoid Fever 147

The Nature of Protection Afforded by Recovery from Typhoid. . . . 149

The Typhoidin Test in Typhoid Recoveries 151 x CONTENTS

Chapter X Artificial Immunization Against Typhoid Fever

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Historical Aspects of Typhoid Immunization 155

Preparations of the Typhoid Bacillus That Have Been Used as Vaccines 156

Killed Cultures of the Typhoid Bacillus 156

Bacterial Extracts 158

Living Cultures of the Typhoid Bacillus 159

Sensitized Cultures of the Typhoid Bacillus 159

Methods of Administration of Typhoid Vaccine 164

The Immediate Effects Following Antityphoid Inoculation 166

Chapter XI The Protective Value Of Vaccination Against Typhoid Fever

Statistical Value of Results of Vaccination Available 172

Vaccination in Armies 173

Results in the English Army 174

Results in the French Army 177

Results in the French Navy 178

Results in the Russian Army 178

Results in the Italian Army 179

Results in the Japanese Army and Navy 179

Results in the German Army 180

Results in the United States Army 181

Results in the United States Navy 182

Antityphoid Vaccination in Institutions 184

Vaccination Among Physicians and Nurses 184

Vaccination Among Laboratory Workers 185

Results of Typhoid Vaccination in Civil Communities 185

Typhoid Fever in the Vaccinated 186

Paratyphoid Fever in Typhoid Vaccinated Individuals 189

Multiple Vaccination 191

Duration of the Protection Afforded by Antityphoid Vaccination 192

CHAPTER XII Diseases in Man and Animals Produced by Bacteria of the Paratyphoid

Group 198

Clinical Differential Diagnosis of Paratyphoid Fever 202

The Laboratory Diagnosis of Paratyphoid Fever 204

Blood Cultures in Paratyphoid Cases 205

Diagnosis of Paratyphoid Infections by means of Agglutination Tests. . 208

The Incidence of Paratyphoid Fever 209

Epidemiology in Paratyphoid Infections 211

Prophylaxis in Paratyphoid Infections 212

CONTENTS xi

Chapter XIII The Treatment Op Typhoid Fever

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The Influence of Diet in Typhoid Fever 214

Hydrotherapy in Typhoid Fever 215

Treatment of Typhoid Fever by Means of Sera 217

Use of Serum of Recovered Cases 217

Autoserumtherapy 217

Specific Immune Sera 217

Antiserum of Chantemesse 219

Besredka's Antiserum 219

Rodet's Antiserum 220

Vaccine Treatment in Typhoid 221

Comparative Results with Various Vaccines and Different Modes

of Administration 221

Intravenous Vaccine Therapy 222

Non-Specificity of Vaccine Therapy in Typhoid 235

The Mechanism of Cure in Intravenous Vaccine Therapy 236

Chapter XIV Suggested Methods Of Advance In Solving The Typhodd Problem 240

BIBLIOGRAPHICAL INDEX OF REFERENCES QUOTED 245

CONSIDERED AS A PROBLEM OF SCIENTIFIC MEDICINE

TYPHOID FEVER CONSIDERED AS A PROBLEM OF SCIENTIFIC MEDICINE

Chapter I

A~ r GENERAL SURVEY OF THE DEVELOPMENT OF ~ KNOWLEDGE CONCERNING TYPHOID FEVER

Progress in medicine depends on the gradual recognition and separation of disease entities. Differential diagnosis must precede all rational means of prevention and therapy, and in each of these phases of progress the older methods of bedside observation and experience have been increasingly supplemented by methods of laboratory precision. No disease illustrates better the successive stages of scientific medical advance than typhoid fever, which as a cause of death and economic loss has been one of the world's greatest scourges. A survey of the useful knowledge that we have gained in respect to this disease is at once of historic interest, as bearing on medical progress, and of promise to those who trust in "Man's redemption of man."

PROGRESS IN THE DIFFERENTIAL DIAGNOSIS OF TYPHOID ON THE BASIS OF SYMPTOMATOLOGY AND MORBID ANATOMY

The disease we now recognize as typhoid or enteric fever is one of those continued fevers which was for centuries confused with other lasting fevers of somewhat similar appearance. Even today mistaken diagnoses are frequent, unless the most modern methods of laboratory aid are resorted to. Among those fevers which may be confused with typhoid may be mentioned recurrent fever, septic infection, malaria, tuberculosis, trichiniasis, and, particularly, typhus fever. The recognition of a disease entity like typhoid is, of course, more readily made in face of an epidemic than in an individual case. In the gradual differential recognition of typhoid fever we find certain characteristics which have been evident from the first. One of the most striking things about typhoid fever is its seasonal occurrence, and we find that Hippocrates, in the course of two successive autumns, met with many cases of a fever of the continuous type, characterized by diarrhea, offensive watery stools, bilious vomiting, tympanites, abdominal pain, red rashes, epistaxis, sleeplessness, and in some cases a tendency to coma, delirium and subsultus, irregular remissions, and a lengthened duration, accompanied by increasing emaciation. Galen classified under the larger grouping of Hemitritceus a variety of bilious fever which may also have been typhoid.

We may continue our historical survey by dividing the criteria of differentiation into two rather arbitrary groups. First of all, may be cited those criteria which are based on purely clinical, observational grounds, and on the basis of experience, and, secondly, those criteria which depend on the recognition of definite changes in anatomic structure. It is obvious that chronologically these two groups of observations will overlap to a considerable extent, but the separation may serve to show the limitation of each type of investigative procedure.

Following the observations of Hippocrates and Galen, which have been mentioned, Spigelius in 1624 noted the occurrence of a fever characterized by the presence of abdominal pain, diarrhea, with sometimes melena, absence of crisis, and occasional relapses. In 1659 Thomas Willis * of England was first to make an attempt at separation of typhoid fever from typhus or febris pestilens, with which it was still destined for many years to remain confused. He made his differentiation on the basis of the fact that typhoid fever is less contagious, has little or no eruption, an imperfect crisis, and is prone to local complication. In 1734 Ebenezer Gilchrist described typhoid fever under the name of "nervous fever," which he characterized by its long duration, the occurrence of diarrhea, abdominal pain, blood in the stools, epistaxis, and "partial sweats which gave no relief." A further and more complete separation between typhus and typhoid fever was made by Langrish in the following year, who separated the two diseases under the headings of "slow, nervous fever," and "malignant, continued fever." A further amplification of this separation was made by Huxham (1739), who described the two fevers as "slow, nervous fever," on the one hand, and "putrid, malignant, petechial fever," on the other. About the year 1850 a discussion arose between Sir John Pringle and Professor De Haen of Vienna, in reference to the advisability of bloodletting in fevers. This discussion is now of no particular interest as bearing on treatment, but served to bring forward a point in differential diagnosis between the eruptions of typhus and of typhoid. It appears that Pringle was describing bloodletting in typhus fever, whereas the cases which De Haen had treated were typhoid. It remained for Pringle to recognize the fact that they had been describing two different forms of disease, and he makes the statement that the miliary fever or typhoid of De Haen occurs in all ranks of people and is characterized by a petechial and miliary eruption, whereas the fever which he had been studying, the malignant fever, occurs only among people who are crowded together in such close and foul places as military hospitals, jails, and transport ships. In 1772 Dr. Macbride of Dublin spoke of "febris nervosa," a protracted fever attended by diarrhea, as different from the putrid, continual fever which was contagious and accompanied by a florid eruption which gradually passed into petechise.

We may now turn to the differentiation of typhoid fever on the basis of changes in anatomic structure, at once a surer and more scientific basis of classification. It appears that the lesions of typhoid fever were first referred to by Spigelius in 1624, who called attention to an inflammation and sometimes gangrene and sphacelus of both large and small intestines. In 1682 Willis 2 made these observations much more definite by describing, in the less contagious of the two diseases which he attempted to differentiate, pustules like those of variola and ulcers in the small intestines, accompanied by swelling of the mesenteric nodes. In 1696 Baglivi called this fever "febris mesenterica" on account of the enlargement of the mesenteric glands which he found associated with the intestinal inflammation. He also separated the disease from typhus or febris pestilens. Hoffmann in 1699 described gangrene and sloughing of the small intestine as associated with typhoid. Lancisi in 1718 first described typhoid perforation, which, however, he incorrectly attributed to the presence of certain lumbricoid worms in the intestines. In a form of fever which he refers to as Lent or symptomatic fever, Strother in 1729 described inflammation and an "ulcer fixed on some of the bowels." The characteristic lesions of typhoid were more definitely localized by Riedel in 1748, who described "febris intestinalis," accompanied by gangrene of the lower ileum. A definite and full description of the characteristic intestinal lesions of typhoid fever is usually attributed to two German investigators, Roederer and Wagler (1762). After a careful inspection of the original treatise, we agree with Murchison, however, that it is practically certain that these investigators were not dealing with typhoid at all. In their thirteen cases, the post-mortem appearances of which are described with great minuteness, we find no description of ulceration of the ileum, whereas the lesions described are almost entirely confined to the stomach or to the large intestines. It is probable, then, that the German investigators were in reality dealing with an epidemic of typhus, complicated by dysentery, as Murchison has suggested. It appears that the intestinal lesions of typhoid did not escape the keen observation of John Hunter, as is shown by two preparations in his museum at the Royal College of Surgeons, one of which was later figured in a publication by Matthew Baillie.

It remained, however, for a group of French investigators in the early part of the nineteenth century to describe with fullness and accuracy the lesions which we now recognize as being characteristic of typhoid. In 1804 Prost described ulcerations in the mucosa of the intestines and also a mild type of inflammation, which, however, was in all probability a simple post-mortem change. In 1813 Petit and Serres described in their "Fievre entero-mesenterique" lesions which were limited to the lower ileum and were specific, differing in many particulars from the ordinary type of inflammation which occurs in simple enteritis. They believed, moreover, that these lesions preceded and were the cause of this fever. In 1826 Bretonneau described typhoid under the name of "dothienenteritis," which he found characterized by lesions localized in the agminated and solitary glands of the ileum. He thought, moreover, that this disease was due to a poison, transmissible from the sick to healthy individuals, which suggestion may be regarded as the first definite contribution to the means of transmission in typhoid fever. Bretonneau further made the important observation that there is no definite relation between the severity of the disease and lesions produced. These observations were confirmed and amplified in the same year and independently by Hewitt of London, who also described the lesions of the solitary and agminated follicles. The further observations of Louis in 1829 and of Chomel (1834) served still further to separate typhoid from simple gastro-enteritis, and also to point out the lesions of the lymph follicles.

We find, then, at the beginning of the nineteenth century that a pretty clear picture of typhoid fever had been developed, at first on clinical grounds, and later on the basis of post-mortem appearance. There remained, however, for several years confusion between the two diseases, typhus and typhoid, owing largely to the fact that few observers had been able to compare them at first hand. We have mentioned the criteria of differentiation on a purely clinical basis by Willis and Huxham, and other similar observations were also made by Hildenbrand in Germany in 1810, who separated

"contagious typhus" from "non-contagious, nervous fever," a separation which was further amplified by the work of Schoenlein in 1839, who gave names to the two diseases, which still unfortunately persist in Germany, namely, "typhus exanthematicus" and "typhus abdominalis." The objection to these terms lies not in their original form but in the abbreviation of "typhus," which is frequently used indiscriminately for typhus and typhoid.

The valuable anatomic work of Bretonneau, Louis, and Chomel was not immediately of great service in the separation of typhus from typhoid, owing to the fact that the French investigators had no opportunity of studying typhus fever, a disease which in their time prevailed primarily in England. They were, indeed, inclined to regard typhus in England as identical with the French typhoid fever, and they regret that no careful anatomical observations were made by the English observers. Dr. H. P. Lombard of Geneva in 1836, on the basis of study of fever both in France and England, concluded that in England there were two types of disease present: first of all, the contagious typhus; and, second, a sporadic disease identical with the typhoid fever of the French. It remained, however, for William Gerhard in 1837 to establish beyond doubt the differential criteria between typhus and typhoid fever, on the basis of his own experience in both diseases in France and in Philadelphia. Gerhard maintained that the typhus of Philadelphia was identical with British typhus fever and with the jail, ship, petechial or spotted fever, and that it is eminently contagious. On the other hand, the enteric or typhoid fever of the French is rarely communicated from one individual to another. He showed that the lesions of Peyer's patches and of the mesenteric glands invariably present in the latter were never found in the former, and remarked that English observers erred in regarding the intestinal disease as a mere complication of typhus. He insisted on the marked difference between the petechial eruption of typhus and the rose-colored spots of typhoid fever, and he showed that a peculiar train of symptoms very different from those of typhus were associated with the intestinal affection, and that the distinctive characters of the two diseases were such as should not allow them to be confounded in practice. Shattuck of Boston studied cases of both diseases in France and England and separated the two in London. Confirmatory observations were made by Valleix (1839) and by Rochoux (1840) in France, and by Barlow in England (1840). Sir W. Jenner l - 2 in London between 1849 and 1851 further confirmed and amplified the distinction between the symptoms of the two diseases as previously laid down by Gerhard and others. By careful analysis of cases admitted into the London Fever Hospital, he showed that the two fevers did not prevail coincidently and that the one did not communicate the other. He also adduced cases to prove that an attack of either fever protected the patient from subsequent attacks of the same malady but not from the other. Perhaps the most important bearing of these facts is their indication that the two diseases are not only different, but are due to distinct causes.

It was possible, then, early in the nineteenth century to recognize typhoid fever as a disease entity on the basis of clinical observation and post-mortem examination. No clear understanding of the exact nature of the disease was, however, possible until the isolation of its specific bacterial cause, nor could the certain recognition of the disease in any particular case be assured in the absence of such knowledge. And, if the individuality and the recognition of typhoid fever is dependent on bacteriology, much more so is accurate knowledge concerning its method of transmission and effective prevention.

DEVELOPMENT OF THE CONCEPTION OF CONTAGION IN TYPHOID FEVER

There were, however, several observations in the pre-bacteriological days which were of extreme significance, and, indeed, of practical importance in understanding and in controlling this disease. Up to the nineteenth century the general belief was that typhoid fever was not contagious. This relative non-contagiousness was, indeed, one of the earlier differential points in diagnosis between typhus and typhoid. Early in the nineteenth century, however, Leuret (1828), Gendron (1834), and Bretonneau (1829) in turn gave definite reasons for regarding typhoid as transmissible from one individual to another. In 1850 Piedvache summarized the facts, and concluded that the disease is to a limited extent contagious. In 1856 William Budd 1 began a series of publications on the nature and mode of transmission of typhoid fever, which constitute one of the most notable contributions to our knowledge of this disease. He not only proved conclusively by careful epidemiological studies that the disease could be transmitted through the feces of a typhoid patient by means of water or milk contamination to healthy individuals, but repeatedly emphasized that this is the usual way in which the disease is propagated. He regards typhoid fever as contagious in the broader sense of the term, using Piedvache's definition that any transmission of a disease from a diseased individual to a healthy individual, whatever may be the method, constitutes contagion. The poison of the disease, according to Budd, resides in the diarrheal discharges of the patient, and epidemics are usually caused by contamination of the water supply with such dejecta. "This method of reproduction is not only a characteristic but the master fact in the history of typhoid fever," he says. He discards, after careful discussion, the putrefactive decomposition idea of Pettenkoffer and the pythogenic theory of Murchison, and shows that the disease is essentially self-propagating. He believes he was able to prove this method of contagion, owing largely to the fact that his practice was in the country, where such sewage contaminations are more likely to be traced than with the more complete methods of sewage disposal in cities.

Budd, in addition, laid down definite rules which he proved to be effective in checking and preventing epidemics. It is very interesting, moreover, to find that he distinctly foresaw the possibility of spread of the disease from the dejecta of those who had entirely recovered from any active manifestations of the malady. In view of this now recognized, important carrier condition, it may be of interest to cite his exact words in this connection. Budd says (p. 118): "The precise date at which the fever patient ceases to give fever to others is not so easy to define. But I have seen so many instances in which fever has broken out in a family living in a previously healthy neighborhood soon after the arrival of a convalescent, that I am quite sure that patients so far recovered cannot always be safely allowed to mix with others without precaution. In the case referred to all traces of actual fever had disappeared and diarrhea had long ceased."

Murchison 2 added certain additional facts to the contagiousness of typhoid fever through the feces, although his theory of transmission was marred by the introduction of the idea of a spontaneous origin of the disease through fermentative processes outside the body. He further subscribed to the importance of a transmission of typhoid by means of polluted milk.

Of historical interest in this connection is the so-called ground-water theory of Buhl and of Pettenkoffer in reference to the spread of epidemics of cholera and typhoid fever. The theory, although no longer accepted in its entirety, doubtless throws some light on the spread of certain epidemics of these diseases. According to Pettenkoffer, the contagion of these two maladies would require a ripening stage in the earth, and the actual spread of the epidemic itself depends on the falling of the ground-water with consequent spread of these ripened contagia from the superficial water supplies.

THE ADVENT OF BACTERIOLOGY AND ITS IMPORTANCE IN THE EX- PLANATION AND PREVENTION OF TYPHOID FEVER

The year 1880 may be given as marking the advent of the science of bacteriology, and typhoid fever was one of the first of the human infectious diseases to yield the secret of its specific animate causation. In the few years preceding 1880 several observers had described the occurrence of certain micrococci in the tissues of cases of typhoid fever. The bacillus, however, which we now recognize as the cause of the disease was not discovered until 1880. The first observations of Bacillus typhosus in the tissues may be attributed to three independent investigators, namely, Eberth, Klebs, and Koch. Credit of priority in the discovery of the microorganism is generally given to Eberth, but it may well be that injustice has been done in the general acceptance of this priority. It is of interest, therefore, to examine the investigations of these authors in some detail. On April 22, 1880, appeared the first contribution of Klebs l on the nature of typhoid, in which he describes his findings in twenty-four fatal cases of the disease. In each of these cases he found short rods, and also in certain places filamentous but unbranching bacterial structures in the various tissues of the body which are peculiarly associated with the malady. He found these organisms in Peyer's patches, in the mesenteric lymph nodes, in the blood vessels, and also in the pia of certain meningeal cases of the disease. The organisms were not found in the intestinal wall of normal cases. They were found in definite relation to what he describes as "a leucocytic proliferation" in the necrotic areas caused by the disease.

In July of the same year Eberth ! published his findings in typhoid. In the majority of cases of the disease which he investigated he found short bacterial rods in various organs of the body, which diminished in number with the progression of the disease. He states that these rods at times possess spores and do not stain well with the ordinary aniline dyes. From the illustrations which accompany his article it would appear certain that he was dealing with the Bacillus typhosus, although the sporogenous forms which he likewise depicts are misleading. In the year 1881 Koch l published photomicrographs of the bacterial findings in various infectious diseases, among them typhoid fever, in which the characteristic microorganism appears with convincing clearness. Both Eberth 2 and Klebs agree that the bacterial or rodlike forms which each of them had in turn described are identical. The difference in their findings would seem to rest in the description by Klebs of threadlike forms of from fifty to eighty micra in length, which we do now recognize as characteristic of the growth of the typhoid bacillus, at least in the body. Somewhat similar forms have been described in culture media. This type Klebs regards as a second stage in the development of the rodlike form. Klebs may well have erred in describing a type of microorganism which may have been a secondary invader; it is evident, however, that he really did see the same typhoid bacillus that Eberth describes. Since criticism is made of his description of this threadlike microorganism, it may also be pointed out that the sporogenous microorganism described by Eberth is likewise inaccurate. At all events, the threadlike forms described by Klebs seemed to him subsidiary to the rods which alone are mentioned as occurring in the various organs of his twenty-four protocols. Klebs unquestionably should be credited with suggesting the accepted name (B. typhosus) for the etiological agent in typhoid fever.

It would seem also that at least some credit should be given to Klebs for his attempt, and, perhaps, success in cultivating Bacillus typhosus outside of the animal body, although the usual credit for this discovery is given entirely to Gaffky (1884). In Klebs' second communication in 1881 2 he describes his method of preparing and sterilizing gelatine culture media, his inoculation of such media from the mesenteric lymph nodes of a case of typhoid fever, and he further notes the occurrence of rodlike forms in the turbid culture growth which results from the inoculation. Gaffky objects to accepting Klebs' results largely on the basis that he had described threadlike forms as existing in the disease, and also owing to the fact that he, Gaffky, failed to produce lesions in animals with his pure cultures similar to those that had already been described by Klebs. Klebs had described the production of hemorrhagic infiltration without ulceration in the cecum of rabbits following injection of his culture of the microorganism. Although Gaffky failed to obtain such results with his cultures, it is now known that they may be produced with pure cultures and toxins of the typhoid bacillus, although they are not specific in nature (Arima, 1 Gay and Clay pole x ). Klebs, then, may well have grown Bacillus typhosus and, indeed, may have grown it in pure culture, although it remained for Gaffky to demonstrate the purity of the culture, as he was able to do by the employment of solid culture media. Gaffky remarks on the absence of spores in his artificial cultures of the microorganisms, and also comments on its growth on gelatine and potato.