In addition to these the role of provocative agent has been often attributed to physical hardship and psychic emotion.

Moreover, the disease has been observed to break out rather commonly after change of residence. Travelers coming from the interior to the coast seem to be especially frequently attacked.

Finally, quinin plays a very important part. This drug has undoubtedly the power of producing blackwater fever in predisposed individuals. It signifies but little when we read that the inhabitants of these malarial regions have held quinin in suspicion for a long time, since it is well known that the laity are very free with their post hoc ergo propter hoc, and since the whole history of quinin represented one constant struggle before it was generally recognized, but when the same conclusion is reached by physicians of large experience, it is a very different matter.

The peculiar fact was first reported by Tomaselli in Catania, and soon after by Karamitsas, that there were persons who every time they took quinin, even in very small doses, manifested a severe fever paroxysm with hemoglobinuria. All these people had suffered repeatedly from malaria , or were at the time of observation in a condition of chronic infection. Some of these reacted in this way every time that quinin was administered, even after they were free from malaria for some time, while others showed only a temporary idiosyncrasy, which they lost after recovery from the malaria. Tomaselli insists that he has never met in Sicily a genuine or rather a pure case of hemoglobinuric bilious malaria, inasmuch as he has always found it manifested by patients only after the administration of quinin. Yet Tomaselli does not doubt that in other places cases of this character arise apart from the action of quinin.

Ughetti goes further than Tomaselli, and asserts that there is no such thing as febris biliosa haemoglobinurica, and that all such cases are to be regarded as quinin intoxication.

Similar assertions have been made by Monneret, Duchassaing, Briquet, Karamitsas, Moscato, Plehn, Kohlstock, R. Koch, and others, and in fact the majority of recent observers who have had actual experience of the disease. Pellerin reported that in Guadeloupe both the publicvand the physicians were forced to attribute, blackwater fever exclusively to the action of quinin. Cartier reported the same from Diego Suarez; more than this, the people will take no quinin on account of their fear of hemoglobinuria. Cartier also mentions that the female Creoles refuse quinin on account of their belief that it causes metrorrhagia and abortion.

Murri and Grocco have made some interesting investigations on this subject, which we will take up later. Baccelli likewise gave it his attention, and reported that among numerous cases he never met one of quinin hemoglobinuria. He contends further that quinin hemoglobinuria has nothing to do with malaria (for further details, see below). Bastianelli expresses a similar opinion.

Tomaselli, to whose investigations we are indebted for the theoretic as well as practical knowledge of the injurious effect of quinin in malarial persons, maintains that the predisposition to this quinin idiosyncrasy is congenital; further, even hereditary, for he often observed that brothers and sisters or near relatives showed the same peculiarity.

From these contradictory opinions it is evident that the role of quinin in the production of malarial hemoglobinuria is a complicated one, not yet fully understood. Nevertheless, several points have been brought out that may act as a basis for further investigation.

It may first be regarded as settled that cases of malarial hemoglobinuria have occurred in people who had immediately previously taken no quinin. It is also assured that there are persons who suffered from previous attacks of malaria who later, without a blood examination, to prove the continuance of the infection, manifested a hemoglobinuria with their fever paroxysm every time, or at least usually after taking quinin. This condition may be designated as postmalarial quinin hemoglobinuria. Finally, there are a large number of cases of virulent malarial infection that ran their course without striking symptoms up to the time quinin was taken, that immediately-i. e., three to six hours-after the administration of this drug manifested a fever paroxysm with hemoglobinuria.

In the first two categories, that is-(1) attacks of hemoglobinuria during acute malarial infection (without quinin); (2) attacks of hemoglobinuria as a result of quinin (or, as we will see further on, even without the administration of quinin) in people who have frequently suffered from malaria , but are, for the time being, free from infection-in these two categories the mechanism of the hemoglobinuria, is clear. For in category (1) we may make the parasites or their toxin, in category (2) the quinin, responsible for the destruction of the red blood corpuscles, with subsequent solution of the hemoglobin.

The cases of the third category-attacks of hemoglobinuria during acute malarial infection, after the administration of quinin-are difficult to diagnose, for in these we cannot say whether it was the quinin that produced the destruction of the blood corpuscles, or whether this would have taken place without its administration.

If we find, in a series of cases following the administration of quinin, that an interval occurs when the quinin is removed, this would evidently pronounce for the toxicity of the drug, but such series of hemoglobinuric paroxysms are very uncommon. What usually happens is that when a blackwater paroxysm occurs as the apparent result of quinin, further fever paroxysms either do not occur, or, if they do, may be successfully combated by quinin, without hemoglobinuria appearing a second time. This is a difficulty in the way of the quinin theory, for it is difficult to imagine that a medicament could be very toxic one day and a few days later be entirely indifferent. [The difficulty is perhaps only an apparent one, for if we assume that only a certain number of corpuscles are of such a kind that they are capable of being destroyed by the quinin, then when these (weak) corpuscles are dissolved by the quinin, it is evident that a second dose of quinin may produce no hemoglobinuria, simply because there are no suitable corpuscles to be attacked.-Ed.] In the case of paroxysmal hemoglobinuria ex frigore, as well as in the case of pure quinin hemoglobinuria, we can produce an attack at any time by means of cold or quinin respectively. Among the 35 histories published by A. Plehn, it is expressly remarked in 13 that the later fever paroxysms were cured by quinin without hemoglobinuria appearing [yet on the above hypothesis this is intelligible, and, indeed, there are facts, such as the increased tonicity of the blood in blackwater fever, which support this view, the corpuscles of lessened tonicity having presumably been the first to disappear. -Ed.]. According to the report of Dupuy, a close of quinin is regularly administered to the blackwater fever convalescents coming to the sanatorium at Kita (Senegal), in order to prevent further paroxysms, and it always has had this result. [Marchouse has recently made the very important observation that during the hemoglobinuria quinin cannot be detected in the urine, but that it is present later. It is perhaps justifiable to conclude that it is lack of excretion that is responsible for the hemoglobinuria.-Ed.]