History

A man who was struck from behind by a sharp dart a little below the neck had a wound which did not look serious because it did not go deep. But sometime later when the point had been extracted the patient was seized with backward-bending convulsions like those of opisthotonus. His jaws were locked, and any liquid that he attempted to swallow was returned through his nostrils. He died on the second day.

So Hippocrates recorded an obvious case of tetanus. At least one other case is recorded in the same volume. In Diseases III, the general case is given: "[W]hen tetanus occurs, the jaws become as hard as wood, patients cannot open their mouths . . . their backs become rigid . . .he suffers great pain . . .generally dies on the third, fifth, seventh or fourteenth day — if he survives that many, he recovers." Further it is noted that "the patient is drawn backwards . . . his pains are violent. . . his elbows become flexed . . . he holds his fingers in a fist. . . vomits through his nostrils. If one survives for fourteen days, he recovers." The treatment regimens varied: "pepper, black, hellbore, fat bird soup, vapour baths, cold water baths," and "phlobotomy relieves lumbar tetanus."

But the terseness of the aphorism "A convulsion supervening upon a wound is deadly" may mark the more general outcome of a case of generalized tetanus. Certainly Aretaeus (Adams 1956), writing some 700 years later, found tetanus to be "An inhuman calamity! An incredible sight! A spectacle painful even to the beholder! An incurable malady!" He believed the prayers of spectators for the death of the patient to be useful, "being a deliverance from the pains." He also pitied the attending physician's inability to afford relief, "for if he should wish to straighten the limbs, he can only do so by cutting and breaking those of a living man." It is a "great misfortune of the physician." Aretaeus, after an excellent clinical description of the disease, urged a wide variety of therapeutic maneuvers, including special diets, forcing liquids, a quiet house, phlebotomy, massage with oils, fomentations, cupping, specific treatment of any wound, and more.

The clinical descriptions have not been bettered. Therapy has changed, but it is possible that the number of survivors "after the fourteenth day" may not have markedly improved. William Osier (1892), in his seminal text, noted the clinical and epidemiological data given above, cited Hippocrates, and summarized the unchanged clinical findings. He found an 80 percent rate mortality within 4 days. Therapy had improved: The nasogastric tube was in use for feeding and hydration, morphine for sedation, and chloroform for muscle relaxation. He emphasized antiseptic care of the wound. It is fair to say that from Hippocrates to Osier - and to today — there have been no changes in diagnostic techniques, and there has been only a small reduction in mortality rates in established cases. Tetanus is a disease that must be prevented, and prevention had to begin with isolation of the organism and advances in immunology.

Isolation of the Tetanus Organism

The discovery of the tetanus organism was part of the microbiological revolution that proved the theory that a specific organism caused a specific disease. In 1884 Arthur Nicolaier produced tetanus-like symptoms and death by injecting soil samples into animals. He isolated a rod-shaped bacillus and suggested that it secreted a toxin resembling strychnine in its action. He did not isolate the organism in pure culture. Neither did D. Rosenbach in 1886, although he was able to produce classic tetanus in guinea pigs by injecting tissue from a fatal human case. He did describe the "drumstick" appearance and correctly deduced that these were terminal spores. It remained for Shibasaburo Kitasato to isolate the organism in pure culture, in 1889, from a fatal case of a soldier in Berlin. He described the anaerobic culture requirements, said he had confirmed Nicholaier's observations, and also concluded that the clinical effects were due to a toxin. The study of tetanus toxin and antitoxin followed directly and in parallel with the research of Emil Behring and Kitasato on diphtheria toxin, a much more important disease.

Tetanus Toxin and Antitoxin

Tetanus and diphtheria investigations provided the framework upon which Behring built his understanding of the principles of serum therapy. In an 1892 (1892b) paper, he argued that the serum of a patient should contain material protective and curative for another individual with the disease. In a series of studies, he and his co-workers proved this point in animal studies, but did not recommend serum use in humans until the mechanism of action was better understood. They noted that even if treatment of the animal began very early, at least 1,000 times as much antitoxin was needed to cure as to protect before infection, and that, as the symptoms became general, the antitoxin was useless in any amount.

The availability of horse antitoxin soon led to clinical trials, with widely varying results. Analysis eventually showed that antitoxin had to be given very early in the disease; that dosage - empirical at first - was critical; and that it was essentially useless once the toxin was fixed to neurons and the patient was symptomatic. As Henry Parish (1965) and E. Haberman (1978) both suggest, better understanding of wound care and more aseptic surgery accompanied the rising rate of successful use of antitoxin and a decreased death rate, especially in selected populations like soldiers.

Given that soldiers often have fought in well-manured farmland and do not have clean skins, and that until very recently armies lived in close proximity to horses used for transport and cavalry, it is not surprising that tetanus was a common problem in wounded soldiers. In 1808, for example, the rate of tetanus before immunization was 12.5 per 1,000; by contrast, the rate was only 0.04 per 1,000 in World War n (Boyd 1958).

It was World War I that saw the general introduction of early, near-universal use of antitoxin, accompanied by meticulous debridement of wounds. The effect of these measures may be seen in the British army. There was an incidence of 8 per 1,000 wounded from August to October 1914. As improved wound management and routine antitoxin use developed, the rate fell to 1.5 per 1,000 wounded. World War I patients, perhaps because the antitoxin produced a forme fruste, had a syndrome of "local tetanus" - not fatal, and usually confined to one extremity. U.S. forces, entering the war in 1917, had the advantage of the experience of their allies and thus had an incidence of only 0.16 per 1,000 wounded. Allergic reactions to horse serum occurred, more commonly after repeated doses of antitoxin.

Tetanus Toxoid

Although Arthur Silverstein (1989) credits Paul Ehr-lich with the first discussion of toxoids, the practical use of formaldehyde to produce a toxoid (a formalin-inactivated antitoxin) was introduced for tetanus by Gaston Ramon in 1927 following the preliminary work by P. Descomby in 1924. As opposed to the passive immunity conferred by antitoxin, the toxoid produced an active immunity that would protect against tetanus. Also in 1927, Ramon along with Charles Zoeller tested the immunogenicity of the toxoid in humans, and later worked out the duration of immunity and the timing and effect of booster doses.

A fluid toxoid was in use because of its harmless-ness and its efficacy (although it caused more local reactions than does the modern aluminum phosphate absorbed vaccine). This toxoid, a combined diphtheria-tetanus toxoids vaccine, was given to infants in parts of France in the late 1920s and, by regulation, to French soldiers in 1931.

Immunization with the much more epidemiologi-cally important diphtheria toxoid began in the 1920s in parts of the United States and just before World War II in Britain. The absorbed tetanus toxoid was used by the armies of Britain, France, and Canada by 1939; the United States began its use in 1941. During World War II, the American army had 5 fatal tetanus cases (2 in nonimmunized patients) and 7 nonfatal cases (all in immunized patients) in over 500,000 wounded soldiers. The reaction rate to the immunization series of three doses was 21 per 100,000, none fatal.

After World War II, the routine use of a combined vaccine of diphtheria and tetanus toxoids (DT) was urged for childhood immunization. Soon the triple vaccine, with pertussis added (DPT), became legally required for school admission in the United States. Childhood immunization programs in Europe vary, but tend to be on similar schedules and under similar laws. Nonfatal anaphylactic reactions occur at a rate of 1 per 1.5 to 2 million doses. The benefit/risk ratio for tetanus immunization is thus extraordinarily good. A worldwide infant and child immunization campaign, coupled with a booster upon injury, would essentially eliminate the disease as a clinical entity.

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