The first cases were recognized in February, 1880, just a year before the tunnel was completed. Hundreds of cases were soon verified, and all Italy became alarmed. There was much agitation in the press, both scientific and popular. The new method of diagnosis placed the helminthologists of northern Italy in an excellent position to demonstrate that the sufferers harbored hookworms. Of this fact there was no question, but as to whether the worms actually produced the disease there was much diversity of opinion. Some among a number of Italian physicians who went to the Saint Gotthard tunnel to investigate the malady were inclined to hold the adverse hygienic conditions responsible for the bad health of the men. The only scientist who steadily insisted on the parasitic origin of the anemia was Edoardo Perroncito, then professor of pathology at the veterinary school of the University of Turin.

Perroncito, who was present at the first postmortem examination made by Colomiatti, in which 1,500 worms were found in the body of a laborer who had died from anemia while working at the tunnel, immediately began extensive studies of the hookworm. Gradually, through tireless effort and demonstration, he won others to his views. Proof that the anemia could be cured by vermifuges that expelled the hookworms was the chief factor that converted leading Italian medical men, although in other places, especially in France, the bold conclusion that miners' anemia the world over was due to hookworms continued to find a great deal of opposition. After 1895 the quarrel died down, and eventually Manouvriez and Fabre, mining physicians of international reputation, were converted to the view that miners' anemia was due to hookworms. Thus had Perroncito succeeded in gaining general support for his original hypothesis.

Development of Vermifuges

Experiments with drugs for removing hookworms from the body had been carried on before the Saint Gotthard epidemic, but without satisfactory results. Bozzolo and Pagliani, in their report on the Saint Gotthard tunnel in 1880, confessed that "no method is known at present for killing, rendering inactive, or expelling hookworms. All known anthelmintic remedies have been tried without success. The urgent need of a vermifuge was recognized. Perroncito and Bozzolo, both members of the Turin Academy of Medicine, were prominent in the discussion, and the two became eager rivals in the search for an effective drug.

Perroncito, who had observed the enormous resistive power to most chemical agents that hookworm larvae possessed, nevertheless noted that in a one-half-of-one-per-cent solution of thymol immature larvae died

immediately, while mature larvae lived only eight to ten minutes. In a well-prepared extract of male-fern (Extractum Filicis Maris Aethereum), mature larvae died even more quickly-in from five to ten minutes. This led to a trial of the drug, followed by Perroncito's announcement that by repeated administration of fresh extract of male-fern he had succeeded in reducing the number of hookworms harbored by two patients, though he pointed out the futility of expecting one or two doses of the drug to remove all hookworms from the intestine.

This announcement by Perroncito was also received with considerable scepticism. Bozzolo stated that his studies of vermifuges had yielded negative results, and that it was better to stress prophylaxis; Concato proposed giving up the idea of killing the parasite, thinking it better to stress attempts at building up the system; and Bizzozero thought the transfusion of blood into the peritoneal cavity might restore the patients' health. But in spite of the adverse comment, Perroncito's method of treatment was taken up in certain parts of Italy; cures were reported; and eventually the Italian government began to use male-fern in treatments given at government expense.

Bozzolo, in 1879, had tried thymol as a vermifuge for hookworm anemia among the brickmakers in northern Italy, but the doses used were too small to be effective. Later he increased the dose, and in 1881 announced that he had succeeded in curing six patients, some of whom could not tolerate male-fern. Lutz, in Brazil, immediately began the use of the drug, and in 1883 pronounced it preferable to male-fern. Gradually it came into favor in Italy and elsewhere, until, in an article written in 1912, Bozzolo was able to give an extended account of the success with which it had been used throughout the world.

Hookworm Disease in Mines

From the Saint Gotthard tunnel, which was completed in 1882, hookworm disease spread over Europe. The tunnelers sought work in European mines, and seemed to revive an epidemic of the malady that had existed in these mines, at intervals, for centuries. The disease became most severe in the sulphur mines of Sicily; in the gold and silver mines of Hungary; in the coal mines of Germany, Holland, Belgium, and France; in the lead mines of Spain; and in the tin mines of England.

In Germany an energetic campaign, conducted from 1903 to 1914, was attended with striking results, reducing the rate of infection, which had reached the high point of 13.1 per cent in 1903, to 0.17 per cent in 1914. Infected miners were treated, new employes who carried hookworms were excluded from underground work, sanitary conveniences were introduced;

and all of these measures were strictly enforced. As the rate of infection was reduced, the work of examining underground miners decreased, but the reverse was true of the examination of applicants for employment. The latter activity assumed such vast proportions that several million microscopic examinations were made from 1903 to 1913.

An illuminating discussion preceding the campaign produced, from 1896 to 1903, a considerable body of literature in Germany. Questions of fundamental policy were discussed; physicians took sides; the daily press became interested; and ultimately both the Prussian Diet and the Imperial Reichstag concerned themselves repeatedly with the problem. In 1903 the controversy ended with a victory for the sponsors of an extensive and thorough hygienic program.

In Belgium the methods employed were about the same as those in Germany, with the marked exception that coercion by government was replaced by co-operative effort developed through educational work among the men, about 35 per cent of whom were illiterate. In the Liége district, where the disease was most severe, the rate of infection was reduced from 22.8 per cent in 1902 to 1.2 per cent in 1913. The result was achieved chiefly through treatment, little progress being made in installing sanitary conveniences.

Prompt action on the part of the Dutch government, before the disease had become severe in the mines of that country, permitted the campaign to be largely prophylactic, mild, and comparatively inexpensive, instead of curative, drastic, and expensive, as in Germany and Belgium. Results were secured by co-operative effort in which the mine-owners splendidly performed their part. The rate of infection was reduced from 25.1 per cent in 1904 to 0.3 per cent in 1913.

Interest in France was aroused by alarming reports concerning the spread of hookworm disease in the mines of Belgium and Germany. An invasion was feared. A survey made in 1904 disclosed a varying amount of infection in the mine districts, but the situation was considered by no means alarming. In 1911 certain sanitary laws were passed and treatment was provided at the expense of the mining companies, with compensation for time lost from labor. No systematic campaign was conducted.

In Italy the workers in the Sicilian sulphur mines bore the brunt of the disease. It was discovered here as early as 1882. A survey in 1898 revealed an infection of about 50 per cent, but no campaign was undertaken. Another investigation in 1912 indicated that conditions had grown worse rather than better. In 1914 an experimental campaign was begun in two Sicilian mines and a considerable reduction in infection was brought about, chiefly by means of treatment. Some work was also done in a small

sulphur-mining center in the Romagna, on the Italian mainland, where a campaign of disinfection and treatment is said to have decreased the incidence of the disease from 38.2 per cent in 1908 to 0.3 per cent in 1914. Conditions in Austria were not favorable for the development of the parasite, owing largely to the dryness of the mines. English mines, too, were for the most part exempt, except the tin mines in Cornwall and Devon, where sporadic work in examining the men was undertaken and some sanitary reforms were introduced, though the infection was never serious enough to call for drastic action.

At present Hungary and Spain are centers of the most severe mine infection in Europe. Certain Hungarian mining sections whch have been infected for centuries are still a standing menace, although in one section (Brennberg) heroic efforts have been made to stamp out the disease. In Spain very little has been done. The rate of infection appears to be highest in the lead mines of Linares, where it ranges from 50 to 90 per cent and where conditions are in every way favorable for the further spread of the disease.

The infection in a mild form is also found among the non-mining population of certain European countries. Thus, it has been discovered among brickmakers in Holland and Germany, and cases from tropical countries are occasionally imported into England. But the climate of the northern European countries is too cold for the hookworm to propagate extensively on the surface. Except underground, widespread infection is present only in Italy and perhaps in certain sections of southern Russia and the Balkan states. In Italy it is found on the surface in brickyards, truck farms, and rice-fields, and in general among people whose work brings them into contact with the soil. Except for thorough discussion and an attempt to get the state to manufacture thymol, little has been done in Italy to control the disease, although the harm it works to agricultural interests has been repeatedly pointed out.

Discovery of Dermal Infection

Many conflicting views were originally held as to the process by which human beings acquired the infection. One of the earliest was the belief that hookworm larvae might be transported by air currents or in dust. Experiments made by von Schopf in Hungary about 1888 apparently confirmed this view, which arose indirectly from Perroncito's erroneous theory that desiccated mature hookworm larvae revived if placed in a moist medium, and was not finally overthrown until a great deal of controversial matter had been published.

The part played by animals, especially the horse, in the distribution of hookworm disease, also gave rise to discussion, and in some of the mines of Hungary horse-haulage was discontinued. Increased experimentation has, however, made it seem extremely unlikely that any domestic animals are carriers of either Ancylostoma duodenale or Necator americanus. The species of hookworms found in domestic animals differ from the human hookworms and, with the single exception of Ancylostoma ceylanicum, which is parasitic to the dog and has been found in small numbers in East Indians, they do not inhabit the human body.

It was at first thought that the worms could enter the body only by way of the mouth, being acquired in the main from contaminated food. That this mode of entry was possible was shown provisionally by Leuckart in 1866 and proved experimentally by Leichtenstern in 1887. But in 1898 Arthur Looss, professor of parasitology at the government medical school at Cairo, accidentally discovered that a hookworm culture spilled on his hands produced dermatitis. Later, when he found hookworm ova in his feces, he concluded that he had been infected through the skin. In succeeding years he proved experimentally his theory of dermal infection, according to which hookworms in their larval stage may enter the human body through the skin-at any place, but preferably between the toes, or wherever else the skin is tender. His communications on the subject aroused a great deal of criticism, but in the end his views not only as to the acquisition of infection through the skin but also concerning the intricate migratory path of the hookworm larva after it enters the human body were established in every detail.

This discovery revolutionized methods of control. Measures were henceforth directed toward avoiding contact between the bare skin and infected mud or water. Warnings against going barefoot and against leaky or wet shoes superseded those against contaminated food. All writers now agreed that the most common and only important mode of infection was by way of the skin.

Close of a Period

The period of research and investigation which opened so brilliantly with the discoveries at the Saint Gotthard tunnel, culminated in 1911 in the publication of Looss's monograph on the hookworm, in which all the scientific knowledge of the parasite then available was carefully summarized and much new light shed on its life-cycle and anatomy. During the period following the construction of the Saint Gotthard tunnel-that is, from about 1880 to 1898-according to Zinn and Jacoby, who collected the literature, some 500 papers appeared on the hookworm, on hookworm