Part 34

We turn to ‘Passive Immunity’. The fact that Immunity can be transferred from one animal to another via the serum proves that the immunizing serum contains substances antagonistic to the bacterium or toxin against which immunity is conveyed. These antagonistic substances are spoken of as Antibodies. A series of very important observations on Antibodies has been made, and may in time profoundly modify not only our views of Disease but also our whole conception of the workings of the living body. We find that it is not only toxins that stimulate the formation of antibodies. Antibodies can be elicited also by the introduction into the tissues of the living body of red blood corpuscles, of embryonic tissue, and of various soluble tissue-constituents of animal or vegetable origin. We are still only on the threshold of the investigation of this subject, which may be as important philosophically as it is therapeutically.

§ 13. Some Practical Applications of Immunity.

We may now consider a few special applications of our knowledge of the defences against bacterial action.

Diphtheria is a disease in which the characteristic organisms are found only locally, and in artificially produced cases only at the site of inoculation. It therefore seemed probable from the first that the symptoms were due not to the organisms themselves but to poisons that they threw off, that is to their ‘exotoxins’. This was given demonstrational form in 1889 by two pupils of Pasteur, Pierre Roux (1853-) and Alexandre Yersin (1863-), who investigated many of the properties of these toxins. In the following year (1890) Emil von Behring (1854-1917), a Prussian Army Surgeon, and Kitasato showed that it was possible to produce a Passive Immunity against Tetanus by a serum from an infected animal, the immunity being efficient against 300 times the fatal dose of Tetanus. Their paper contains for the first time the word antitoxic. Immediately after, von Behring showed that against Diphtheria, too, immunity could be obtained by injecting serum from an animal that had been previously injected with living cultures of the Diphtheria bacillus. This epoch-making discovery of von Behring was soon given a practical application. It was found possible to induce a degree of immunity even after the onset of the disease. The first human case was a child in a clinic at Berlin in 1891. Antidiphtheritic serum was placed on the market in 1892. In a few years’ time its administration had become a routine part of the treatment of the disease. Diphtheria antitoxin is one of the greatest additions to therapeutics. With competent administration the case mortality of Diphtheria is one-half or one-quarter of what it is without the use of Antidiphtheritic serum. (Fig. 119.)

FIG. 119. DEATH-RATE OF CASES OF LARYNGEAL DIPHTHERIA IN PUBLIC HOSPITALS IN LONDON. Antitoxic serum came into use in London in 1895 and into full use in 1896. As its application became more general and as the method of administration improved the death-rate from this very grave condition progressively fell. ]

An important aspect of the reaction of the body to the Diphtheria toxin was revealed by B. Schick of Vienna in 1908. The technique of inducing it was perfected by him in 1913, and the test is known by his name. He showed that susceptibility to the disease could be detected by the behavior of the skin after injection of minute doses into it. It has thus been found that new-born infants are seldom susceptible and that the proportion of susceptibles increases up to two years of age, but that then it diminishes. The actual proportions of susceptibles, as estimated in a large number of cases in New York City in 1919, are as follows:

Of those under 3 months 15% are susceptible Of those between 3 months and 6 months 30% are susceptible Of those between 6 months and 1 year 60% are susceptible Of those between 1 year and 2 years 70% are susceptible Of those between 2 years and 3 years 60% are susceptible Of those between 3 years and 5 years 40% are susceptible Of those between 5 years and 10 years 30% are susceptible Of those between 10 years and 20 years 20% are susceptible Of those over 20 years 15% are susceptible

These figures show why Diphtheria is mainly a disease of childhood and is relatively seldom encountered in adults. They also make it evident that steps for protecting individuals against contracting the disease--‘prophylactic measures’ as they are called--need only be taken with a fraction of the population. The useful term Prophylaxis is derived from a Greek word meaning a watchman or guard. It is used to describe preventive measures against disease in general, but is more specially applied to that form of protection which is achieved through the artificial production of Immunity.

Such prophylactic measures are now available against Diphtheria. They differ from those in use against any other disease, since the substance injected is neither the living infective material as in vaccination against Small-pox (p. 184), nor is it a killed culture of the organisms as in immunization against Typhoid (p. 268), nor is it the serum of an immunized animal as in the protective measures against Tetanus (p. 267). The Toxin itself (mixed with an experimentally determined proportion of its antitoxin) is now in wide and effective use as a prophylactic against Diphtheria. The method was proposed by von Behring (cp. p. 264) in 1913. The details, however, have since been worked out in the laboratories of the New York City Department of Public Health and have been mainly the work of W. H. Park (1863-). The susceptibles are first determined by the Schick test and are then immunized against the disease. The immunization reduces the likelihood of contracting the disease to about one quarter.

Plague differs from Diphtheria in that the organisms, instead of being local, pullulate throughout the body of the victim. As in the case of most diseases of this type, the toxins of Plague are chiefly endotoxins, unlike those of Diphtheria, which are exotoxins (p. 263). Thus, the filtrate of a culture of Plague Bacilli is but little toxic and confers little or no immunity. Protective vaccines of a killed culture of Plague Bacilli are, however, prepared, and these confer considerable immunity. It is claimed that they reduce the liability to the disease by about three-quarters, and the case mortality by about one-half. Prophylactic inoculation against Plague is associated especially with the name of the Russian investigator Waldemar Haffkine (1860-), a pupil of Pasteur, who was for many years in the service of the British Government in India, the Plague center of the world.

After Diphtheria one of the earliest diseases of which the toxins were investigated was Tetanus. Kitasato found in 1891 that the filtrates of pure cultures injected into animals are very toxic. A peculiar feature is the incubation period of some days that occurs between the inoculation and the advent of the symptoms. This fact had been referred to, more than two thousand years earlier, in the Aphorisms of Hippocrates (p. 23). Moreover, it has been found that, soon after inoculation, the Tetanus toxin disappears from the blood-stream. This, it has been shown, is due to its affinity for nervous tissue, with which it rapidly enters into some sort of combination. The fact is of clinical significance and of therapeutic application.

By injection of small and progressively increasing doses of Tetanus toxin into animals, a high and long-lasting degree of immunity to the disease is produced. The serum of such immunized animals has the capacity to protect animals susceptible to the disease against an injection of a fatal dose. It is now a routine treatment to inject serum derived from an immunized horse into those who have wounds likely to result in Tetanus. Owing to the rapid disappearance of the Tetanus toxin from the blood-stream, and owing to its tendency to unite with nervous tissue, it is important to inject the serum as soon as possible after the infliction of the wound. In some cases it is advisable to inject the serum into the sheath that surrounds the spinal cord in order to give it as rapid access to the nervous centers as possible. During the Great War prophylactic doses of Antitetanic Serum were given to every wounded man after 1914. Before the practice was adopted, the incidence of Tetanus among the wounded was 16 per 1,000. After the introduction of this line of treatment as a routine, the incidence fell to 2 per 1,000. Countless lives were thus saved. Antitetanic serum should be injected as early as possible in every case of a large ragged wound, especially if contaminated with soil.

Typhoid Fever differs from Diphtheria, Plague, and Tetanus in that it can hardly be conveyed to animals. It has thus proved impracticable to produce anything in the way of passive immunity in man. On the other hand, there is no disease in which the production of active immunity by means of Vaccines of dead cultures has been attended with more favorable results. The researches which led up to the introduction of active immunization against Typhoid Fever are bound up with investigations concerning the diagnosis of the disease which are of wide importance in connection with several other diseases.

The discovery of Antibodies (p. 262) gave rise to great activity in their investigation. Among the most interesting and important of the antibodies is a group which will cause ‘agglutination’ or clumping of the disease organisms with which they are specially associated. This reaction is specific for the corresponding organisms, within certain limitations. Given, therefore, (1) a pure culture of an organism, and (2) the knowledge of the highest degree of dilution of the serum containing such an antibody that will cause agglutination of that particular organism, the physician has in his hands a means of detecting or excluding infection with that organism. The method was especially studied by the Parisian investigator Fernand Widal (1862-), who in 1896 succeeded in making it practicable for Typhoid Fever, and his name is attached to the test. It is now universally applied in that disease. Similar tests have been devised for Malta Fever and for other conditions.

There are other groups of antibodies that have been investigated. Some of these possess the power of dissolving the corresponding organism. They are, therefore, known as Bacteriolysins. Their existence gives a certain insight into the defensive mechanism of the animal body against bacterial invasion. They are sometimes of practical use in distinguishing types of disease-producing bacteria. The method is applicable, for example, in detecting certain types of dysentery organisms.

Another group of antibodies act not against bacteria but against certain specific substances. Antibodies of this type were first detected by the Belgian workers Jules Bordet (1870-) and Octave Gengou (1875-) in the year 1900. The physician avails himself of the existence of such an antibody in the test that is applied for Syphilis, which was introduced in 1904 by Ehrlich’s pupil, August von Wassermann (1866-), and is known by his name.

Of late years a special aspect of Immunity has come into view in connection with the so-called ‘Carrier Problem.’ With many diseases, acquisition of Immunity on the part of the patient implies the death within his body of the organism that has been causing the disease. There are conditions, however, in which the organisms may lurk in some individuals long after the symptoms have subsided. These persons may even contract the disease so lightly that they are unconscious of it, but nevertheless they become capable of conveying it. Such individuals are known as carriers. Evidently the existence of carriers introduces special difficulty into attempts to delimit an infective disease in any population.

Among the diseases of known bacterial origin that are sometimes conveyed by carriers are Typhoid Fever, Diphtheria, and Spotted Fever or Cerebrospinal Meningitis. A special case of the Carrier Problem is afforded by Infantile Paralysis, a disease due to ‘ultra-microscopic’ organism--since the virus is ‘filtrable’ (p. 274). This disease, like that of Cerebrospinal Meningitis, is probably transmitted by carriers who do not themselves suffer.

Typhoid Fever, Diphtheria, Influenza, Scarlet Fever, and many other conditions are often conveyed by ‘ambulant’ cases. This term is applied to those cases which, while definitely suffering from a disease, do not regard themselves as ill enough to take to their beds but continue their ordinary avocations. Such ambulant cases are not less but more dangerous to their neighbors than those more severely stricken.

The whole study of the Carrier Problem is in its infancy. It is beset with extraordinary difficulties. In the case of Diphtheria and Typhoid Fever, however, the demonstration that a suspected individual is or is not a ‘carrier’ is easy. The difficulty is to trace him in the first instance!

§ 14. The Conquest of the Tropics.

Nowhere in Medicine has the rational spirit been more triumphantly vindicated than in connection with the diseases peculiar to hot countries. The increase in the habitability of the Tropics may be traced to two main causes. First is the application of the ordinary laws of Hygiene. Second is the increasingly exact knowledge of the microbic origin of tropical diseases, leading to a more complete apprehension and a stricter application of the laws of Hygiene.

We have glanced at the great changes wrought in the social organization of temperate countries by the rise of modern Hygiene (pp. 172-78), which commenced to be felt about the middle of the eighteenth century. The death-rate then began to fall, and has fallen steadily ever since. The mid-eighteenth century marks, for temperate countries, the end of the ‘Middle Ages’ of Hygiene. But with the advent of the modern period the fall in the death-rate in temperate countries has not been the only change in the public health. Even more significant is a change in the causes of death.

Certain diseases have gradually receded from the more civilized and settled temperate countries, and are now almost unknown there. Thus, Malaria, Plague, Typhus, Leprosy and Dysentery, once of world-wide distribution, have come to be regarded as more or less distinctively ‘tropical’ diseases. A time is approaching when we shall be able to place other diseases with which temperate countries are still afflicted, such as Typhoid Fever, in the same category. The ultimate exclusion of Typhoid as a disease of civilized communities is suggested by the death-rates of England and Wales.

Average Annual Death-rate in England and Wales from Typhoid per million living.

1871-80 1881-90 1891-1900 1901-10 1911-20 1921-26 332 198 174 91 35 24

In the category of such removable diseases which, being excluded from temperate countries, are regarded as tropical are Malaria, Plague, Typhus, Leprosy, and certain forms of Dysentery. These diseases are ‘tropical’ only in the sense that it is in the Tropics that the general hygienic conditions most favorable to their development are still found. If the hygienic conditions of the Tropics could be raised to those of the civilized temperate countries--a task, it is true, of very great difficulty--these particular diseases might become as rare there as they are with us. Indeed, it is possible to foresee a world in which a number of these so-called tropical diseases will have disappeared altogether.

There are, however, other diseases that are tropical in another sense. Such diseases have seldom or never visited the shores of temperate countries, or at least have obtained no lasting foothold there, even when the conditions have been favorable to them. Among such diseases are Yellow Fever, Sleeping Sickness (which must not be confused with the so-called ‘Sleepy Sickness’), Beri-Beri, Dengue, Sprue, Kalar-azar, and a host of other less known conditions.