Related to W. Yorke and J.W.S. Macfie, 'Observations on Malaria made During Treatment of General Paralysis,' Transactions of the Royal Society of Tropical Medicine and Hygiene 18 (1-2) (1924), pp. 13-33.
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)