Cites Horton Hospital Malaria Therapy Unit
Description:

'as some recent work for which I have been responsible in England in connection with the malaria treatment of general paralysis of the insane has produced interesting results, I communicated them to the Commission at its meeting in Paris on March 3rd last. The Commission having concluded that their submission to the Health Committee and publication was desirable, and the assent of the British Ministry of Health having been obtained, I have now the honour to submit the following report.’ (3)

 

‘Colonel J.R. Lord, C.B.E., Medical Superintendent of the Horton Mental Hospital, Epsom, arranged to set apart an isolated block of the hospital for the treatment of patients and to place a laboratory at my disposal in this block. I take the opportunity to thank him for these and other arrangements which greatly facilitated our task and also to thank Drs. Moodie and [3-4] Nicol, Medical Officers of the hospital, for much assistance in every respect of the work. Dr. Nicol was in medical charge of the patients who passed through the course of treatment at Horton during the two years with which this report is concerned and also collaborated with us in the laboratory and clinical studies.’ (3-4)

 

‘The length of life of mosquitoes is one of the most important factors in relation to their infection... a large supply of suitable mosquitoes was [therefore] the first condition necessary for obtaining mosquitoes with infection of the salivary glands (“infective mosquitoes”). It will be seen that batches of 80 or 100 mosquitoes sometimes became batches of only 2 to 12 by the time that the batch could be classed as “infective”’. (6)

 

'Having observed ‘the high mortality of mosquitoes in the [warm, humid] conditions necessary for infection... We find that even a small reduction of the temperature of the incubator lessens considerably the rate of mortality of the mosquitoes. For this reason, when our initial supply of insects is small, we make a rule to incubate the batch at 22°C instead of at 24°C.’ (6)

 

‘observations on the rate of mortality of mosquitoes kept at different temperatures under favourable conditions in the laboratory can be applied to problems of malarial epidemiology. For example, if our rate of mortality of maculipennis at 24°C is approximately correct, we must conclude that, when that temperature is continuous for ten days or more in nature, only one of every five individual mosquitoes which such blood from suitable cases of malaria will survive until it can infect another person. In other words, unless at least five mosquitoes bite a malaria carrier, the disease will not be carried from him to another person... rarity or absence of new cases of malaria during very hot seasons... may be due chiefly to the short life of mosquitoes during such periods.’ (7)

 

‘keeping the infected batch of mosquitoes in an ice-chest reproduces artificially what happens to maculipennis in nature during winter in northern climates.’ (8)

 

‘as regards P. vivax the oocysts in the stomach and the sporozoites in the glands are not killed when a mosquito lives continuously for three weeks at the low temperature of 4° to 5.5°C., nor even when the temperature during six days is below freezing point. Nor are they killed when a mosquito lives intermittently at a low and at a high temperature for a long period... we do not doubt that benign tertian malaria (P. vivax) can be carried through even a severe winter in hibernating mosquitoes.’ (11)

 

‘It is surprising what a small proportion of persons who suffer from malaria are infective to anopheles... no one who studies the literature of experiments relating to the infection of anopheles can fail to note the lack of success which in general attended those experiments. I am impressed, also, by our frequent failures to infect anopheles from seamen and others who (having contracted malaria abroad) suffer from relapses in England, as well as by some failures and some unexpectedly small infections during our work at mental hospitals. During this work it has been our experience that some patients with induced malaria are not at all infective to anopheles at any period of their malarial course, that others are only moderately so, and that rarely one comes across a patient who is quite strikingly infective.’ (13)

 

‘On blood examination the difference between the two classes of patients is usually indicated by finding that the patient who is a “good infector” carries a large number of gametocytes, while the patient who is a “poor infector” carries only a few, but my impression is that the quality of the gametocytes... is also different.’ (14)

 

‘I do not think that the English maculipennis becomes infected as readily as some tropical species of anopheles such as culicifacies, ludlowi, etc. might do if they were placed in the same favourable conditions as those in which our batches are kept. Infection of maculipennis after one feed upon a moderately infective case is quite uncertain, and we are tolerably sure that in some individuals of different batches, young zygotes which seem to have begun to grow well sometimes cease to develop and gradually become absorbed without coming to maturity... As a result of many trials we have come to believe that mosquitoes which at first seem refractory to infection can be [15-16] forced, so to speak, to become infected by repeated feeding on a suitable case. We think that this plan of repeated feeding added to the selection of suitable cases on which to feed have been the chief factors in our successful results.’ (15-16)

 

‘In our experience the best results in infecting A. maculipennis with P. vivax are obtained at temperatures between 22°C and 24°C. and in a saturated atmosphere. It is a mistake to try to hasten development of oöcysts by incubating the mosquitoes at temperatures above 23° or 24°C., as by doing so the life of the mosquito is endangered. Changes to different temperatures should also be gradual, not sudden. A batch which has been at a very low temperature in the ice-chest for some days may easily be killed if it is not given time to get accustomed to gradually increasing temperatures before being subjected to the high temperature of the incubator.’ (16)

 

‘Reference has already been made to the unfavourable effect of permitting mosquitoes which are being infected to have any other kind of food than fresh blood. It is possible that when a mosquito feeds on certain fruits the chemical reaction of the stomach is not entirely favourable to oöcyst development. After several feeds on human blood and omission of other kinds of food, the stomach becomes a more favourable medium.’ (17)

 

‘I do not suppose that observations made with regard to the induction of malaria among them [general paralysis patients] are in all respects applicable to the occurrence of the disease among healthier members of the general population. Perhaps this is particularly important in connection with the failure of certain of these patients to develop malaria after receiving a dose of sporozoites or of malarial blood which would cause an attack of malaria in a healthy person.’ (18)

 

‘our observations do not throw as much light [on questions of individual immunity and susceptibility] as I hoped they might do. One reason is that up to the present we have been occupied chiefly in overcoming various technical difficulties which arose during the endeavour to carry out a considerable series of infections by the natural method at all seasons of the year. During this work we have learned that when an inoculated patient fails to develop malaria, the cause must be sought first on technical rather than on biological grounds... What is happening to-day in connection with this subject is reminiscent of what happened fifteen or more years ago when many workers were engaged in experiments on the relative “infectibility” of different species of anopheles mosquitoes. At that time it was often found that, even under what seemed to be the most favourable conditions, certain infevidual mosquitoes in a successful batch failed to become infected; and the cause was at once stated to be that “these individuals no doubt possess an active immunity to the malarial parasite”. At present, because we know more about the technical circumstances relating to the infection of individual mosquitoes, we are more cautious in attributing failure to biological conditions. The same caution must be exercised in explaining apparent failures to infect or to re-infect human beings.’ (19)

 

‘I am not disposed to discuss in the present report the possible influence of the winter on the failure of malaria to develop within the usual incubation period... On the whole, it seems preferable to defer consideration of that subject until we have worked with a batch of mosquitoes whose infective rate as regards both number of individual mosquitoes infected and intensity of infection of each insect has been 100 per cent during the whole period of their use.’ (19)

 

‘there are patients for whom a malarial course of treatment of their mental disease is quite unsuitable, because it can be predicted with some assurance that the malarial infection in them will be manifested by only a few inconspicuous rises of temperature and a scanty parasite invasion of the blood. In my opinion it is quite incorrect to consider that these patients possess a relative “immunity” if we mean by that term to imply that their blood contains “immune bodies”. I am inclined to suggest that it would be worth ascertaining whether some of the differences of “susceptibility” and of “resistance” to malarial infection among different individuals may be due to a relatively simple cause, such as a slight modification of the normal alkalinity of the blood, or a change in its content of lecithin and other proteins, or perhaps of phosphorous, rather than that it may be due to the presence or absence of “immune bodies”.’ (22)

 

‘our observations... indicate how small is the chance that a particular brood of malaria-carrying mosquitoes in nature will ever be concerned in transmitting the disease. It is probable that at least 95 per cent of the potential malaria-carrying mosquitoes which emerge from the larval stage in nature will never play that role, which is reserved for a few individuals whose life will be passed in a manner very different from that of the remainder of the brood... I do not hesitate to affirm that in nature the only mosquitoes which succeed in transmitting malaria are those rare individuals who happen to pass their life in conditions which resemble very closely those which we have found to be essential for the successful transmission of the disease in experimental work. No one who fully appreciates the importance of this conclusion and accepts it as true can fail to regard anti-mosquito measures for dealing with malaria from a new point of view. He will at least realise what a great waste of effort is involved in measures directed against the breeding-places of mosquitoes as a whole, and even in similar measures directed against one species. He will begin to appreciate how the secret of a successful control of malaria lies not in the general knowledge [27-28] that the disease is spread by mosquitoes of a certain kind, but in the particular and exact knowledge of the life history of the few individual mosquitoes which succeed in becoming transmitters of the disease.’ (27-28)

 

‘the presence of oöcysts in a mosquitoes stomach does not inevitably mean that the salivary glands will become infected, for we believe that in some individual insects young oöcysts fail to come to maturity and disappear even when the insect lives long enough for their full development.’ (28)

 

‘we must certainly regard malaria as a disease which does not spread unless a large number of special conditions are fulfilled. Our observations on these conditions help to explain why it is the general rule to find only a low percentage of infected anopheles in nature and why malaria in nature is seldom or never contracted except in certain houses or shelters where the above circumstances and conditions pertain. They fortify the conclusion that malaria is essentially a household disease and particularly a disease of certain kinds of houses that fulfil the “laboratory conditions” which we have described. The reasonable inference is that malaria should be dealt with in the houses of the people rather than in the environment.’ (28)

 

‘a mosquito which has succeeded in becoming infective retains its infecting power for a long period and can infect many people... In nature, a mosquito which has made its home in a house containing several malarious children who are untreated has frequent opportunities of becoming freshly infected; the result is that its stomach carries oöcysts in many stages of growth and its salivary glands are restocked with sprozoites from time to time thoughout the remainder of its life. The tabular statement on page 12 [results of comparative study of sporozoite number in mosquitoes continuously fed infective material v’s those given a single meal of infective material] states how dangerous a mosquito may be when it is continuously infective in this manner.’ (29)