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Creators (Definite): John William Scott Macfie; Warrington YorkeDate: 1924
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CitesW. Rees Wright
Description:On adoption of mosquitoes as transmitters (NB: blood transfusion ruled out due to familial objections) between patients at Whittingham Mental Hospital: ‘For a number of reasons, [note: ‘The relatives of a number of cases objected to the inoculation of infective blood from G.P.I. patients.’] which we need not discuss here, it was considered desirable to infect certain patients by the bite of mosquitoes instead of by direct inoculation of infective blood. The mosquitoes used were mainly A. maculipennis, for a constant supply of which we are greatly indebted to Mr Rees Wright, B.Sc., of the Department of Zoology, University College, Bangor, who collected the hibernating females mainly in farm buildings in Carnarvonshire, and who has sent us, from 11th October, 1923, to the end of April, 1924, about 2,000 mosquitoes. During August, September, and the early part of October, 1923, before we began to receive a regular supply of A. maculipennis from Mr. Wright, we used A. maculipennis and A. bifurcatus reared from larvae collected in Cheshire.' (16)
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![S.P. James et. al., 'Discussion: Observations on malaria made during treatment of general paralysis [Yorke and Macfie],' Transactions of the Royal Society of Tropical Medicine and Hygiene 18 (1-2) (1924), pp. 33-44.](/cslide/img/icons/document.png)
Cited byS.P. James et. al., 'Discussion: Observations on malaria made during treatment of general paralysis [Yorke and Macfie],' Transactions of the Royal Society of Tropical Medicine and Hygiene 18 (1-2) (1924), pp. 33-44.
Description:'After some general remarks from the Chairman the discussion was opened by --
Colonel S.P. JAMES: In opening the discussion on this important paper, I think I should approach the subject rather from the point of view of the administrative authorities, who have to decide whether, and under what regulations, this method of treatment should be applied in mental hospitals in England, than from the point of view of the malariologist. Having this in mind, the first question to be answered in connection with the treatment is whether it is really efficacious in curing general paralysis. On this point it is very important that the results of the enquiries made by the Liverpool School of Tropical Medicine, with their high reputation for critical analysis and scientific caution, confirm those of previous observers in the conclusion that the results of the new treatment are most satisfactory. One could have wished that Professor YORKE had spoken in more detail on this subject, but, in any case, the opinion expressed is helpful in deciding to what extent facilities must be provided for carrying out the treatment. A second important matter in connection with these facilities is the decision whether the arrangements should be for inducing malaria in the natural way by mosquito bites, or whether the artificial method of blood inoculation will suffice. In Professor YORKE'S series of cases, forty-one patients were given benign tertian malaria by mosquito bites and seventy or more by blood inoculation, and we [33-34] might justifiably expect a considered opinion on the relative merits of the two entirely different methods. My own more limited experience leads me to think that the therapeutic results obtained from naturally-acquired malaria are more speedy and striking than they are from malaria contracted by blood inoculation, and that the former should be, whenever possible, the method of choice. A subsidiary problem of the same subject is the relative efficacy of mild and severe attacks of induced malaria, particularly with reference to the degree of fever registered in the paroxysmal attacks. From the experimental work done in Austria on the spirochceticidal influence of high temperatures it would seem necessary that temperatures between 105°F and 106°F should be reached in most of the paroxysms. These high temperatures, and the heavy parasite infections necessary to produce them, involve considerable risk to the patient, and necessitate great care and watchfulness during the course, but I feel sure that the risk must be taken if successful results are to be obtained. Finally, of course, all the arrangements for preventing the spread of the disease have to be considered. These and other reasons have led the Board of Control, in consultation with the Ministry of Health, to arrange for special classes of instruction in malaria for medical officers of mental hospitals where the treatment is to be carried out. I am glad to be able to say that, through the good offices of Colonel ALCOCK, it has been arranged that these courses will be carried out at the London School of Tropical Medicine, and it is hoped that the first course will commence almost at once.
Now, from the point of view of the malariologist, I should like to mention very briefly one or two of the particular points in malaria which are specifically dealt with in the paper before us. The first is that our experience in regard to the certainty of infection by the bites of infected mosquitoes differs from that of the authors of the paper. On page 17 they state that the feeding of a mosquito, which on dissection immediately after the meal was found to contain sporozoites in its salivary glands, never failed to result ininfection of the patient. In our experience of infections by mosquito bites, we have had two very clear instances in which the bites of mosquitoes known to be infected failed to cause malaria in the patients bitten. In this connection also I would like to ask Professor YORKE whether, in coming to the conclusion that the bites of infected mosquitoes always have a positive result, he has taken into account the twenty-three negative results printed in Table II, on page 19. The patients in this table were treated with quinine, but I do not know how it has been decided that the negative result was due to quinine and not to a failure to infect.
The next point to which I would like to refer has reference to the so-called "virulence" of different strains of the benign tertian parasite, and as to whether a given strain can undergo an increase or deterioration of its virulence. Professor YORKE's paper contains no details bearing on the different virulence of different strains, but, as regards one of the strains which he studied, the opinion is expressed that its virulence did not increase as a result of direct passage from man to man through twenty-three generations. As I have already spoken too long, I will merely say that on this point our experience differs from that recorded by the authors of the paper, and that [34-35] I think Dr. HENSCHELL, Dr. Low and others will bear me out in the opinion that the strain which we are using has become more "virulent" than the benign tertian strains commonly encountered in the tropics. It causes almost invariably a quotidian fever, the temperature rising to 105°F or higher. In several cases we have found it necessary to commence quinine treatment earlier than we had intended to do.
Finally, I must say a word about treatment, which is very fully considered in the paper under discussion. I quite agree with the authors that the susceptibility of induced malaria to quinine treatment has something to do with the fact that we are dealing with primary infections instead of with relapses, but I cannot follow them in the theoretical explanation of the mechanism by which cure is obtained. "Susceptibility," "immunity," "tolerance to the effects of the parasite invasion," and "individual resistance" are debatable subiects which cannot be dealt with in a rapid survey of the present nature, but I take the opportunity to refer to two observations made during the procedure of treating patients suffering from general paralysis, and other nervous diseases, by infecting them with malaria by the bites of mosquitoes. The first is that two of the patients, on whom I have successfully carried out this procedure, failed to develop malaria after being bitten by mosquitoes which were proved to be infective. The second is that one patient developed, after the usual incubation period, a moderate blood infection of parasites but showed no rise of temperature, and the parasites gradually disappeared without quinine treatment. The interest of these observations is that all three patients were already anaemic, undernourished, and in a feeble state of health, and that it would be out of the question to affirm either that they already possessed some degree of "immunity," or that their general health was so good that their "resisting power" prevented the development of the infection. Indeed, what has struck us most in connection with malaria infection in the course of this work has been that the patients who are best nourished and in the best "general health," and whose blood is the least anaemic at the time of infection, are those who develop the disease most surely and in most typical form. The experience is reminiscent of the common observation in the tropics that the young and vigorous newcomer from Europe is very "susceptible" to malaria, and that, when he contracts the disease, his attack is sharper and more typical than are attacks in local residents, even when it cannot be said of the latter that they have attained a relative "immunity" or "tolerance" to the parasites or to the disease. It seems to me quite possible that, as regards the two observations I have mentioned above, the failure of the parasites to develop in the particular patients concerned is a factor of their undernourishment and feeble state of health, rather than of any natural or acquired immunity to malaria infection. If this is true, I suppose it would be necessary for Professor YORKE and Dr. MACFIE to modify completely their theory of the mechanism by which a cure is brought about. I am not prepared to discuss why a condition of anaemia and undernourishment seems to be inhibitory to malaria, but, I suppose, one might conjecture that this condition is accompanied by some chemical or other change in the blood, which causes it to be a less favourable [35-36] medium for the growth of the parasite than is the blood of quite healthy persons. Whether or not this conjecture is worthy of attention, I think it will be agreed that serious research work on the biochemistry of the blood in relation to malarial infection is of pressing importance.' (33-36)
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Cited byS.P. James, ‘Some General Results of a Study of Induced Malaria in England,’ Transactions of the Royal Society of Tropical Medicine and Hygiene 24 (5) (1931), pp. 477-525.
Description:‘As long ago as 1901 it was found that, even under what seemed to be the most favourable conditions, certain individual mosquitoes in a successful batch either failed altogether to become infected or became infected very lightly. In 1908, Darling again called attention to the point, and in 1921, Wenyon laid stress on it in recording the results of his feeding experiments in Macedonia. In our first laboratory report we were inclined to attribute the differences to technical circumstances. Yorke and Macfie, in their paper read at a meeting [486-488] of this Society in 1924, attributed the differences to a state of the patient's blood rather than to varying receptivity of different individual mosquitoes of the batch.' (486-487)
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Cited byW. Yorke and W. Rees Wright, ‘The Mosquito Infectivity of P. Vivax After Prolonged Sojourn in the Human Host,‘ Annals of Tropical Medicine and Parasitology, 20 (3) (1926), pp. 327-328.
Description:‘In the now extensive literature relating to the malaria treatment of general paralysis, the statement is not infrequently encountered that maintenance in the human host for prolonged periods, by direct inoculation of infective blood from one individual to another, modifies the malaria parasite in certain important respects.
...
In previous papers (Yorke and Macfie, 1924, and Yorke, 1925) reference is made to the fact that a strain of Plasmodium vivax maintained by direct passage in the human host since September, 1922 -partly at Whittingham, and partly at Sheffield, mental hospitals - was still capable of infecting A. maculipennis at various passages up to the forty-first.’ (327)
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Related toWhittingham Mental Hospital
Description:On adoption of mosquitoes as transmitters (NB: blood transfusion ruled out due to familial objections) between patients at Whittingham Mental Hospital: ‘For a number of reasons, [note: ‘The relatives of a number of cases objected to the inoculation of infective blood from G.P.I. patients.’] which we need not discuss here, it was considered desirable to infect certain patients by the bite of mosquitoes instead of by direct inoculation of infective blood. The mosquitoes used were mainly A. maculipennis, for a constant supply of which we are greatly indebted to Mr Rees Wright, B.Sc., of the Department of Zoology, University College, Bangor, who collected the hibernating females mainly in farm buildings in Carnarvonshire, and who has sent us, from 11th October, 1923, to the end of April, 1924, about 2,000 mosquitoes. During August, September, and the early part of October, 1923, before we began to receive a regular supply of A. maculipennis from Mr. Wright, we used A. maculipennis and A. bifurcatus reared from larvae collected in Cheshire.
The first batches of mosquitoes were infected with P. vivax by feeding on patients in the twelfth and sixteenth passages of the direct inoculation strain. These mosquitoes were subsequently used to infect fresh cases, which in turn infected other batches of mosquitoes, and so the strain was carried on in the natural manner, passing alternately through the insect and vertebrate host.
It is to be noted that both A. maculipennis and A. bifurcatus were easily infected, a single meal of infective blood being frequently sufficient to produce a massive infection... The degree of infection observed varied enormously in the different batches, and occasionally, though to a much less degree, even among the individuals of the same batch. Sometimes only two or three oöcysts could be found, while on other occasions they were so numerous as almost entirely to cover the stomach wall. As a general rule, however, the intensity of infection among the mosquitoes of the same batch - fed at the same time on the same patient - was pretty constant, all the infected individuals of a batch being either heavily, or lightly, [16-17] infected. It appears to us that the explanation of these differences in intensity of infection is to be sought not in any variations in the mosquito, but rather in the state of the patient's blood at the time the insects fed.’ (16-17)
‘The feeding of a mosquito which on dissection immediately after the meal was found to contain sporozoites in its salivary glands, in our experience, never failed to result in infection of the patient. It is necessary, however, to point out that in our work the mosquitoes were always used for producing infection within a period of from twelve to thirty days (almost always twelve to twenty) after the infecting feed; we did not attempt to investigate the question, how long they remained infective or how many, persons it was possible by successive feeds to infect from one mosquito, but it was observed, on the few occasions where an infective mosquito was fed successively (within the periods mentioned) on three or four patients, infection always resulted.’ (17)
‘Reference has already been made in the previous section to the prophylactic action of quinine in inoculated malaria. It was decided to repeat these observations with the mosquito-borne strain, not only for the reasons given previously, but also because Anopheles capable of spreading malaria are known to exist in the grounds of many of the mental hospitals in this country, and we consequently felt it incumbent upon ourselves to ascertain whether, in the event of necessity, the inmates of the mental hospitals could be protected against accidental infection by quinine administered as a prophylactic. The possibility of such accidental infection is clearly recognised by our own and by various foreign health authorities, and measures are being taken already to safe-guard the patients in the mental hospitals, and the general public, from dangers of this nature.’ (19)
‘Even up to the present time a number of authors, more particularly the French, still adhere to the view that there is only a single species of malaria parasite found in man. The question was discussed in some detail quite recently by Vialatte (1922), and although it is not our intention to consider the matter at any length... observations made in the course of our work appear to us to render the unicity hypothesis untenable’ (19)
‘It is now well recognised that many trypanosomes pathogenic to man and stock undergo a marked increase in virulence to certain Species of [20-21] laboratory animals when maintained in them for long periods by direct inoculation from one host to another. In some cases, e.g., Trypanosoma brucei vel rhodesiense, this alteration of virulence is attended by certain morphological changes. It is important, however, to note that such changes do not occur in the early passages, but apparently take place only after the strain has undergone a certain number of direct passages through the vertebrate host. It is, therefore, of considerable interest and importance to enquire whether the prolonged sojourn of P. vivax in the human host, comprising twenty-three direct passages, from man to man without the intervention of the insect intermediary, during a period of nearly two years, has had any influence on the parasite, or on the type of infection which it produces.
...
Comparison of the temperature charts and clinical signs failed to show any definite evidence that the infections in the latest passages differed in any respect from those in the earliest.
Of the seventy patients comprising the chain of direct inoculations, only five failed to become infected at the first inoculation; one of these was inoculated with the strain at the seventh passage, two at the thirteenth, and two at the eighteenth: only one, however, failed to become infected on reinoculation. Again, of the twenty-eight other cases of simple tertian malaria inoculated from naturally infected patients, or from second passages, four failed to become infected at the first inoculation. Such data as we possess indicate therefore that the strain had undergone no increase in virulence during its direct passage from man to man through twenty-three generations.
We have carefully studied the morphology of the parasite as it appears in the blood of patients in the later passages, without being able to discover that the parasite differs in any way from that found in a naturally infected case.
... we have fed uninfected A. maculipennis on patients belonging to the twelfth to the eighteenth passages of our inoculation chain: in every instance a large proportion of those fed developed massive infection of oöcysts and sporozoites.’ (20-21)
‘one cannot explain the success obtained in the cure, of these induced infections by any special virtue of the particular mode of treatment adopted... the true explanation of the success of treatment in these induced infections is to be sought in the fact that we are here concerned with the early treatment of the disease, or, in other words, with the treatment of primary infections, and not as in the war, or as frequently in practice, with old-standing relapse cases.’ (24)
‘there is, in our opinion, a considerable mass of evidence indicating that man exhibits some degree of immunity to malaria. His natural immunity is but slight and in the vast majority of cases insufficient to prevent the development of the infection; in patients who have recovered either spontaneously, or after medication, from an acute attack of the infection the immunity may be increased to such an extent that it may be impossible to re-infect for various periods which are probably much shorter in the European than in the Native; and, finally, in cases where the symptoms have subsided spontaneously, without the complete disappearance of parasites from the blood, re-infection by the feeding of infective mosquitoes does not result in an exacerbation of fever. The immunity is, however, [27-28] relatively slight, and there is evidence that the malaria parasites readily develop an immune-body resistance. It is important to note that immunity developed against one species of Plasmodium does not confer a similar protection against the other species.
... the essential factor for the production of cures in malaria is the capacity of the host to produce immune-body), in response to the antigen formation resulting from the destruction of a considerable number of parasites by a medicament. When, for any reason, the host is unable to produce immune-body in sufficient amount, sterilisation does not take place and a relapse occurs. We surmise that certain individuals are unable to produce a sufficiency of immune-body to sterilise the malaria infection owing to ill-health at the time of infection and treatment, or possibly owing to a personal idiosyncrasy, and that these are the patients who develop eventually into chronic relapse cases.’ (27-28)
