Resistance. The diphtheria bacillus has less resistance to adverse conditions than the majority of the spore-free bacteria. It is more readily destroyed by light, heat, and disinfecting substances than the typhoid bacillus. In this regard it corresponds more to the frailer streptococci. Under certain circumstances the diphtheria bacillus resists drying for a long time. When buried in the false membrane or other albuminous. substances, they may remain virulent for some months.

Immunity.-Immunity to diphtheria is very largely an antitoxic immunity and persists for some months or years following a natural attack of the disease. Frequently immunity is of short duration, and second and third attacks are not uncommon. The fact that healthy persons may harbor virulent bacilli upon their mucous membrane for a long time without contracting the disease shows that other factors are involved. These predisposing causes are inflammations or lesions of any kind of the mucous membrane, depressed vitality due to bad air, overcrowding, poor food, etc. Persons vary markedly in susceptibility. During the first 6 months of life there is but little susceptibility. Children between the ages of 3 and 10 are most susceptible; after that age the susceptibility again decreases. It is known that guinea-pigs born of immunized mothers inherit a certain degree of resistance, which may explain the relative insusceptibility of children under 6 months. This may also be accounted for by the diminished danger of exposure of babies during this age, especially in those that are breast-fed. Mother's milk, even colostrum, contains protective antibodies, which are absorbed by the infant, and thus may protect it.

Prevention.-CONTROL OF OUTBREAKS IN INSTITUTIONS.-Diphtheria frequently appears in asylums, hospitals, jails, on shipboard, and similar places. Under these conditions of crowding the disease has a highly contagious tendency. It may, however, be controlled with every assurance of success by the application of well-tried measures. It is customary first of all to give a prophylactic dose of antitoxin to all the persons within the institution, including both inmates and administrative force. This, however, must be regarded more as a measure of temporary personal protection than as a radical means of stamping out the infection. It is not possible by the use of diphtheria antitoxin alone to wipe out diphtheria. The bacilli remain in the throats of the immunized and the disease continues to crop out after the antitoxic immunity has passed away, which may be a matter of only a few weeks. When diphtheria antitoxin is used as a prophylactic, the dose is 1,000 units, which should be repeated every ten days or two weeks— as long as the danger persists.

The most important measure to suppress diphtheria in an institution is to isolate all cases and all carriers. This is possible in an institution, although not very practical among the population at large.

The isolation of both cases and carriers is the most important and radical of our preventive measures. In the case of institutions, jails, ships, and similar places all those who show cultures containing organisms which morphologically resemble the diphtheria bacillus should be isolated, whether the strains are virulent or not.

The bacilli frequently grow in the mucous membrane of the nose and nasal pharynx without symptoms indicating their localization. Unless cultures are taken from the nose, many carriers will be overlooked, leaving a large loophole in our preventive measures. Ward and Henderson in a public school epidemic in Berkeley in 1907 found that all attempts to isolate infected children had no effect on the epidemic so long as they made throat cultures alone. When they took both nose and throat cultures and quarantined all the children showing positive cultures, the epidemic stopped.

Convalescents should not be released from quarantine until at least two cultures taken from both the nose and throat are negative.

In addition to the above-mentioned measures, care must be taken that the infection is not spread by the use of cups, spoons, dishes, towels, handkerchiefs, and other articles used in common. The infected discharges should be rendered harmless at the bedside, and all objects that come in contact with patients or carriers should be disinfected. A general disinfection with formaldehyde may be practiced, but in a well-ordered institution the usual cleanliness of floors, walls, and other surfaces will suffice.

CONTROL OF EPIDEMICS.-The principles which guide us for the control of outbreaks among the population at large are precisely the same as those described for the control of epidemics in institutions. The only difference is that in the population at large it is more difficult, if not impossible, to apply the one real important measure, namely, that of isolating the carriers. What is needed is a convenient and reliable method of distinguishing the virulent and dangerous bacilli from those that look like diphtheria bacilli but lack pathogenic power and danger to man.

In almost all communities diphtheria is now one of the diseases which must be reported to the health authorities. The houses are placarded and the cases isolated. There is no great objection to treating a case of diphtheria in the household provided the patient and the nurse may also be quarantined from the rest of the household. Under these circumstances and with intelligent care and disinfection at the bedside there is little danger to the rest of the family; but the great menace that some of the members of the family will harbor bacilli of a dangerous type and transmit them to others makes it advisable to treat all cases of diphtheria in a special hospital.

The prompt and early diagnosis of diphtheria has now become one

of the routine measures of board of health laboratories. This example in the case of diphtheria could be extended with advantage to the other communicable diseases for which we have satisfactory laboratory aids. Especially commendable is the general practice of refusing to lift the quarantine until two successive cultures prove negative.

Disinfection in diphtheria should be applied especially to the secretions from the mouth and nose. These may be received upon a piece of gauze and burned. For the hands and other objects bichlorid of mercury (1-1,000), carbolic (22 per cent.), formalin (10 per cent.), tricresol (1 per cent.), are efficient. As a terminal disinfectant formaldehyde gas may be used, but the ordinary fumigation, as practiced by Boards of Health, seems to have little influence in checking the spread of the disease. Evidence is accumulating that the infection usually comes from persons rather than from things. Bed linen, towels, and other fabrics should be boiled or steamed.

PERSONAL PROPHYLAXIS.-In individual cases diphtheria may be avoided by the use of diphtheria antitoxin. The antitoxic immunity, however, depends upon the free circulation of the antibodies in the blood, and as the antitoxin is gradually eliminated it cannot be depended upon to protect more than 2 or 3 weeks.

Diphtheria antitoxin is a specific and sovereign remedy. When given in sufficient amounts during the first 24 hours of the disease it reduces the mortality to practically nil. Ordinarily 500 units are sufficient for prophylactic purposes, but 1,000 units are preferable, as this amount produces an immunity of higher degree and fonger duration. When the exposure to the infection continues the antitoxin may be administered at successive intervals of about 2 or 3 weeks. Upon the first appearance of sore throat, fever, or other suggestive symptoms in persons who are exposed to diphtheria a full dose of 3,000 to 10,000 units should be administered without delay. In order to obtain the full life-saving benefits of diphtheria antitoxin, it should be given early in the disease. Time is the most important factor. When the damage to the cells has been done, it may be too late. It is not always advisable to wait for bacterial confirmation. Personal prophylaxis is further favored by the individual having his own glass, cups, spoons, towels, etc., and exercising personal cleanliness, especially concerning the hands and all objects placed in the mouth. Physicians, nurses, and others who come in close contact with the patient should guard against droplet infection.

PREVENTION OF POST-DIPHTHERITIC PARALYSIS

It has been observed that post-diphtheritic paralysis is more frequent since the use of antitoxin than before the days of serum therapy.

This is due to the fact that many cases now recover that would formerly have died. It is also due to the fact that diphtheria antitoxin is sometimes used too late, thus neutralizing only the acute effects of the toxin, but not neutralizing the after-effects of the toxon, which acts specifically upon the nerves. The prevention of post-diphtheritic paralysis, therefore, consists in giving sufficient amounts of antitoxin carly in the disease. The antitoxin does not influence the paralysis after it has once appeared.

PREVENTION OF SERUM SICKNESS

This subject may appropriately be considered here, although it is a condition that may follow the injection of any alien serum into the system. Serum sickness is a syndrome which frequently follows the injection of horse serum into man. The symptoms come on after about 8 or 10 days following the injection. They consist of various skin eruptions, usually urticarial or erythematous in character; also fever, edema, glandular enlargements, rheumatic-like pains in the joints, and albuminuria. The eruptions may be either local or general, and sometimes resemble that of scarlet fever or measles. Serum sickness has nothing to do with the antitoxin, but is caused entirely by the foreign proteins contained in the horse serum. It may be produced with normal horse serum as well as with antitoxic horse serum. The studies upon anaphylaxis have thrown much light upon the nature of this complication. The serum of some horses is much more apt to produce the syndrome than that of other horses. A serum that is several years old is perhaps less apt to produce these reactions than a fresh serum. Manufacturers of antitoxin, therefore, prefer to keep their serum in the ice chest some time before they place it upon the market, although this a doubtful expedient. The occurrence and severity of the symptoms are in direct proportion to the amount of foreign protein injected. Fortunately, this form of anaphylactic reaction soon passes away and is never serious. Under certain circumstances, however, there may be an accelerated or immediate reaction threatening in its consequence or even leading to death. Rosenau and Anderson have collected some 19 cases of sudden death following the injection of horse serum, and they know of more instances which have not appeared in the literature. This unusual and serious complication comes on within 5 or 10 minutes of the injection, and is characterized by collapse, unconsciousness, cyanosis, labored respiration, and edema. The heart continues to beat after respiration has ceased. The entire picture is an exact counterpart of the anaphylactic shock so readily reproduced by second injection of horse serum or other foreign protein in the guinea-pig. Contrary to the experimental work on the lower animals, most of the cases of

sudden death in man follow the first injection of horse serum. The serious symptoms and death in these cases are not due to any inherent poisonous property in the antitoxic serum, but result entirely from a hypersusceptibility of the individual. Just how man becomes sensitized in these cases is not known. Most of the cases, however, occur in asthmatics or in persons who gave a history of asthma or discomfort when about horses. This is a practical and important point, and should be inquired into before horse serum of any kind is injected. Horse serum should not be injected into such individuals unless the indications are clear, and then only with a statement as to the possible out

come.

In order to prevent this serious complication a small quantity may first be injected, 1 or 2 drops, and after waiting an hour the remainder may be given. Vaughan proposed 0.5 c. c. as the trial dose, but this is excessive, as some of the fatal cases have followed the injection of about 1 c. c. It is known that in man, as in the experimental cases in the guinea-pig, the severity of the symptoms bears a definite ratio to the amount of serum and the mode of injection. Thus, second injections in the guinea-pig are much more fatal when given directly into the circulation than into the subcutaneous tissue. It is sometimes advisable to give antitoxic sera directly into the circulation, but in the susceptible persons under discussion this would be hazardous.

Friedberger and Mita1 found it possible to avoid all symptoms of anaphylaxis in experimental work with guinea-pigs by injecting the serum extremely slowly. When thus introduced animals are able to tolerate an amount far beyond the ordinary lethal dose.

Historical Note. -A complete summary and bibliography of diphtheria up to 1908 will be found in the system edited by Nuttall and Graham-Smith entitled "The Bacteriology of Diphtheria," containing articles by Löffler, Newsholme, Mallory, Graham-Smith, Dean, Park, and Bolduan; Cambridge University Press, 1908.

The original clinical description of the disease is, by common assent, attributed to Bretonneau in 1826: Traité de la diphthérite. Desinflammations spéciales du tissu muqueux et en particulier de la diphthérite ou inflammation pelliculaire, connue sous le nom de croup, d'angine maligne, d'angine gangréneuse, etc., Paris.

The bacillus of diphtheria was first cultivated and adequately described by Löffler, 1884: Untersuchungen über die Bedeutung der Mikroorganismen für die Entstehung der Diphtherie beim Menschen

Friedberger, E., and Mita, S.: "To Prevent Anaphylaxis in Serotherapy' ("Methode, grössere Mengen artfremden Serums bei überempfindlichen Individuen zu injizieren''), Deutsche med. Wochenschr., Berlin, Feb. 1, XXXVIII, No. 5, pp. 201-248.