Popular Science Monthly/Volume 59/July 1901/The Transmission of Yellow Fever by Mosquitoes

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JULY, 1901.




THE discoveries which have been made during the past twenty-five years with reference to the etiology of infectious diseases constitute the greatest achievement of scientific medicine and afford a substantial basis for the application of intelligent measures of prophylaxis. We now know the specific cause ('germ') of typhoid fever, of pulmonary consumption, of cholera, of diphtheria, of erysipelas, of croupous pneumonia, of the malarial fevers and of various other infectious diseases of man and of the domestic animals, but, up to the present time, all efforts to discover the germ of yellow fever have been without success. The present writer, as a member of the Havana Yellow Fever Commission, in 1879, made the first systematic attempt to solve the unsettled questions relating to yellow fever etiology by modern methods of research. Naturally the first and most important question to engage my attention was that relating to the specific infectious agent, or 'germ,' which there was every reason to believe must be found in the bodies of infected individuals. Was this germ present in the blood, as in the case of relapsing fever; or was it to be found in the organs and tissues which upon post mortem examination give evidence of pathological changes, as in typhoid fever, pneumonia and diphtheria; or was it to be found in the alimentary canal, as in cholera and dysentery. The clinical history of the disease indicated a general blood infection. As my equipment included the best microscopical apparatus made, I had strong hopes that in properly stained preparations of blood taken from the circulation of yellow fever patients my Zeiss 1-18 oil immersion objective would reveal to me the germ I was in search of. But I was doomed to pointment. Repeated examinations of blood from patients in every stage of the disease failed to demonstrate the presence of microorganisms of any kind. My subsequent investigations in Havana, Vera Cruz and Rio de Janeiro, made in 1887, 1888 and 1889, were equally unsuccessful. And numerous competent microscopists of various nations have since searched in vain for this elusive germ. Another method of attacking this problem consists in introducing blood from yellow fever patients or recent cadavers into various culture media' for the purpose of cultivating any germ that might be present. Extended researches of this kind also gave a negative result, which in my final report I stated as follows:

The specific cause of yellow fever has not yet been demonstrated.

It is demonstrated that micro-organisms, capable of development in the culture-media usually employed by bacteriologists, are only found in the blood and tissues of yellow fever cadavers in exceptional cases, when cultures are made very soon after death.

Since this report was made various investigators have attacked the question of yellow fever etiology, and one of them has made very positive claims to the discovery of the specific germ, I refer to the Italian bacteriologist, Sanarelli. His researches were made in Brazil, and, singularly enough, he found in the blood of the first case examined by him a bacillus. It was present in large numbers, but this case proved to be unique, for neither Sanarelli nor any one else has since found it in such abundance. It has been found in small numbers in the blood and tissues of yellow fever cadavers in a certain number of the cases examined. But carefully conducted researches by competent bacteriologists have failed to demonstrate its presence in a considerable proportion of the cases, and the recent researches of Eeed, Carroll and Agramonte, to which I shall shortly refer, demonstrate conclusively that the bacillus of Sanarelli has nothing to do with the etiology of yellow fever.

So far as I am aware. Dr. Carlos Finlay, of Havana, Cuba, was the first to suggest the transmission of yellow fever by mosquitoes. In a communication made to the Academy of Sciences of Havana, in October, 1881, he gave an account of his first attempts to demonstrate the truth of his theory. In a paper contributed to the 'Edinburgh Medical Journal' in 1894 Dr. Finlay gives a summary of his experimental inoculations up to that date as follows:

A summary account of the experiments performed by myself (and some also by my friend. Dr. Delgado), during the last twelve years, will enable the reader to judge for himself. The experiment has consisted in first applying a captive mosquito to a yellow fever patient, allowing it to introduce its lance and to fill itself with blood; next, after the lapse of two or more days, applying the same mosquito to the skin of a person who is considered susceptible to yellow fever; and, finally, observing the effects, not only during the first few weeks, but during periods of several years, so as to appreciate the amount of immunity that should follow.

Between the 30th of June, 1881, and the 2d of December, 1893, eighty-eight persons have been so inoculated. All were white adults, uniting the conditions which justify the assumption that they were susceptible to yellow fever. Only three were women. The chronological distribution of the inoculations was as follows: Seven in 1881, ten in 1883, nine in 1885, three in 1886, twelve in 1887, nine in 1888, seven in 1889, ten in 1890, eight in 1891, three in 1892, and ten in 1893.

The yellow fever patients upon whom the mosquitoes were contaminated were, almost in every instance, well-marked cases of the albuminuric or melanoalbuminuric forms, in the second, third, fourth, fifth, or sixth day of the disease. In some of the susceptible subjects, the inoculation was repeated when the source of the contamination appeared uncertain.

Among the eighty-seven who have been under observation, the following results have been recorded:

Within a term of days, varying between five and twenty-five after the inoculation, one presented a mild albuminuric attack, and thirteen only 'acclimation fevers.'

While Finlay's theory appeared to be plausible and to explain many of the facts relating to the etiology of yellow fever, his experimental inoculations not only failed to give it substantial support, but the negative results, as reported by himself, seemed to be opposed to the view that yellow fever is transmitted by the mosquito. It is true that he reports one case which presented a mild albuminuric attack' which we may accept as an attack of yellow fever. But in view of the fact that this case occurred in the city of Havana, where yellow fever is endemic, and of the eighty-six negative results from similar inoculations, the inference seemed justified that in this case the disease was contracted in some other way than as a result of the so-called 'mosquito inoculation.' The thirteen cases in which 'only acclimation fevers' occurred 'within a term of days varying between five and twenty-five after the inoculation' appeared to me to have no value as giving support to Finlay's theory; first, because these 'acclimation fevers' could not be identified as mild cases of yellow fever; second, because the ordinary period of incubation in yellow fever, is less than five days; and, third, because these individuals, having recently arrived in Havana, were liable to attacks of yellow fever, or of 'acclimation fever' as a result of their residence in this city and quite independently of Dr. Finlay's mosquito inoculations. For these reasons Dr. Finlay's experiments failed to convince the medical profession generally of the truth of his theory relating to the transmission of yellow fever, and this important question remained in doubt and a subject of controversy. One party regarded the disease as personally contagious and supposed it to be communicated directly from the sick to the well, as in the case of other contagious diseases, such as smallpox, scarlet fever, etc. Opposed to this theory was the fact that in innumerable instances non-immune persons had been known to care for yellow fever patients as nurses, or physicians, without contracting the disease; also the fact that the epidemic extension of the disease depends upon external conditions relating to temperature, altitude, rainfall, etc. It was a well-establislied fact that the disease is arrested by cold weather and does not prevail in northern latitudes or at considerable altitudes. But diseases which are directly transmitted from man to man by personal contact have no such limitations. The alternate theory took account of the above-mentioned facts and assumed that the disease was indirectly transmitted from the sick to the well, as is the case in typhoid fever and cholera, and that its germ was capable of development external to the human body when conditions were favorable. These conditions were believed to be a certain elevation of temperature, the presence of moisture and suitable organic pabulum (filth) for the development of the germ. The two first-mentioned conditions were known to be essential, the third was a subject of controversy.

Yellow fever epidemics do not occur in the winter months in the temperate zone and they do not occur in arid regions. As epidemics have frequently prevailed in sea-coast cities known to be in an insanitary condition, it has been generally assumed that the presence of decomposing organic material is favorable for the development of an epidemic and that, like typhoid fever and cholera, yellow fever is a 'filth disease.' Opposed to this view, however, is the fact that epidemics have frequently occurred in localities (e. g., at military posts) where no local insanitary conditions were to be found. Moreover, there are marked differences in regard to the transmission of the recognized filth diseases—typhoid fever and cholera—and yellow fever. The first-mentioned diseases are largely propagated by means of a contaminated water supply, whereas there is no evidence that yellow fever is ever communicated in this way. Typhoid fever and cholera prevail in all parts of the world and may prevail at any season of the year, although cholera, as a rule, is a disease of the summer months. On the other hand, yellow fever has a very restricted area of prevalence and is essentially a disease of seaboard cities and of warm climates. Evidently neither of the theories referred to accounts for all of the observed facts with reference to the endemic prevalence and epidemic extension of the disease under consideration.

Having for years given much thought to this subject, I became some time since impressed with the view that probably in yellow fever, as in the malarial fevers, there is an 'intermediate host.' I therefore suggested to Dr. Reed, president of the board[1] appointed upon my recommendation for the study of this disease in the Island of Cuba, that he should give special attention to the possibility of transmission by some insect, although the experiments of Finlay seemed to show that this insect was not a mosquito of the genus Culex, such as he had used in his inoculation experiments. I also urged that efforts should be made to ascertain definitely whether the disease can be communicated from man to man by blood inoculations. Evidently if this is the case the blood must contain the living infectious agent upon which the propagation of the disease depends, notwithstanding the fact that all attempts to demonstrate the presence of such a germ in the blood, by means of the microscope and culture methods, had proved unavailing. I had previously demonstrated by repeated experiments that inoculations of yellow fever blood into lower animals—dogs, rabbits, guinea-pigs—give a negative result, but this negative result might well be because these animals were not susceptible to the disease and could not be accepted as showing that the germ of yellow fever was not present in the blood. A single inoculation experiment on man had been made in my presence in the city of Vera Cruz, in 1887, by Dr. Daniel Ruiz, who was in charge of the civil hospital in that city. But this experiment was inconclusive for the reason that the patient from whom the blood was obtained was in the eighth day of the disease, and it was quite possible that the specific germ might have been present at an earlier period and that after a certain number of days the natural resources of the body are sufficient to effect its destruction, or in some way to cause its disappearance from the circulation.

This was the status of the question of yellow fever etiology when Dr. Reed and his associates commenced their investigations in Cuba during the summer of 1900. In a 'Preliminary Note,' read at the meeting of the American Public Health Association, October 22, 1900, the board gave a report of three cases of yellow fever which they believed to be the direct result of mosquito inoculations. Two of these were members of the board, viz.: Dr. Jesse W. Lazear and Dr. James Carroll, who voluntarily submitted themselves to the experiment. Dr. Carroll suffered a severe attack of the disease and recovered, but Dr. Lazear fell a victim to his enthusiasm in the cause of science and humanity. His death occurred on September 25th, after an illness of six days' duration. About the same time nine other individuals who volunteered for the experiment were bitten by infected mosquitoes—i. e., by mosquitoes which had previously been allowed to fill themselves with blood from yellow fever cases—and in these cases the result was negative. In considering the experimental evidence thus far obtained the attention of the members of the board was attracted by the fact that in the nine inoculations with a negative result "the time elapsing between the biting of the mosquito and the inoculation of the healthy subject varied in seven cases from two to eight days and in the remaining two from ten to thirteen days, whereas in two of the three successful cases the mosquito had been kept for twelve days or longer." In the third ease, that of Dr. Lazear, the facts are stated in the report of the board as follows:

Case 3. Dr. Jesse W. Lazear, Acting Assistant Surgeon U. S. Army, a member of this board, was bitten on August 16, 1900 (Case 3, Table III) by a mosquito (Culex fasciatus) which ten days previously had been contaminated by biting a very mild case of yellow fever (fifth day). No appreciable disturbance of health followed this inoculation.

On September 13, 1900 (forenoon). Dr. Lazear, while on a visit to Las Animas Hospital, and while collecting blood from yellow fever patients for study, was bitten by a Culex mosquito (variety undetermined). As Dr. Lazear had been previously bitten by a contaminated insect without after effects, he deliberately allowed this particular mosquito, which had settled on the back of his hand, to remain until it had satisfied its hunger.

On the evening of September 18, 5 days after the bite. Dr. Lazear complained of feeling 'out of sorts,' and had a chill at 8 p. m.

On September 19, 12 o'clock noon, his temperature was 102.4°, pulse 112; his eyes were injected and his face suffused; at 3 p. m. temperature was 103.4°, pulse 104; 6 p. m., temperature 103.8° and pulse 106; albumin appeared in the urine. Jaundice appeared on the third day. The subsequent history of this case was one of progressive and fatal yellow fever, the death of our much-lamented colleague having occurred on the evening of September 25, 1900.

Evidently in this case the evidence is not satisfactory as to the fatal attack being a result of the bite by a mosquito 'while on a visit to Las Animas Hospital' although Dr. Lazear himself was thoroughly convinced that this was the direct cause of his attack.

The inference drawn by Dr. Reed and his associates, from the experiments thus far made, was that yellow fever may be transmitted by mosquitoes of the genus Culex, but that in order to convey the infection to a non-immune individual the insect must be kept for 12 days or longer after it has filled itself with blood from a yellow fever patient in the earlier stages of the disease. In other words, that a certain period of incubation is required in the body of the insect before the germ reaches its salivary glands and consequently before it is able to inoculate an individual with the germs of yellow fever. This inference, based upon experimental data, received support from other observations, which have been repeatedly made, with reference to the introduction and spread of yellow fever in localities favorable to its propagation. When a case is imported to one of our southern seaport cities, from Havana, Vera Cruz or some other endemic focus of the disease, an interval of two weeks or more occurs before secondary cases are developed as a result of such importation. In the light of our present knowledge this is readily understood. A certain number of mosquitoes having filled themselves with blood from this first case after an interval of twelve days or more bite non-immune individuals living in the vicinity, and these individuals after a brief period of incubation fall sick with the disease; being bitten by other mosquitoes they serve to transmit the disease through the 'intermediate host' to still others. Thus the epidemic extends, at first slowly as from house to house, then more rapidly, as by geometrical progression.

It will be seen that the essential difference between the successful experiments of the board of which Dr. Reed is president and the unsuccessful experiments of Finlay consists of the length of time during which the mosquitoes were kept after filling themselves with blood from a yellow-fever patient. In Finlay's experiments the interval was usually short—from two to five or six days, and it will be noted that in the experiments of Reed and his associates the result was invariably negative when the insect had been kept for less than eight days (7 cases).

Having obtained what they considered satisfactory evidence that yellow fever is transmitted by mosquitoes, Dr. Reed and his associates proceeded to extend their experiments for the purpose of establishing the fact in such a positive manner that the medical profession and the scientific world generally might be convinced of the reliability of the experimental evidence upon which their conclusions were based. These conclusions, which have been fully justified by their subsequent experiments were stated in their 'Preliminary Note' as follows:

1. Bacillus icteroides (Sanarelli) stands in no causative relation to yellow fever, but, when present, should be considered as a secondary invader in this disease. 2. The mosquito serves as the intermediate host for the parasite of yellow fever.

In 'An Additional Note' read at the Pan-American Medical Congress held in Havana, Cuba, February 4-7, 1901, a report is made of the further experiments made up to that date. In order that the absolute scientific value of these experiments may be fully appreciated I shall quote quite freely from this report with reference to the methods adopted for the purpose of excluding all sources of infection other than the mosquito inoculation:

In order to exercise perfect control over the movements of those individuals who were to be subjected to experimentation, and to avoid any other possible source of infection, a location was selected in an open and uncultivated field, about one mile from the town of Quemados, Cuba. Here an experimental sanitary station was established under the complete control of the senior member of this Board. This station was named Camp Lazear, in honor of our late colleague. Dr. Jesse W. Lazear, Acting Assistant Surgeon U. S. A., who died of yellow fever, while courageously investigating the causation of this disease. The site selected was well drained, freely exposed to sunlight and winds, and from every point of view satisfactory for the purposes intended.

The personnel of this camp consisted of two medical officers. Dr. Roger P. Ames, Acting Assistant Surgeon U. S. A., an immune,' in immediate charge; Dr. R. P. Cooke, Acting Assistant Surgeon U. S. A., non-immune; one acting hospital steward, an immune; nine privates of the hospital corps, one of whom was immune, and one immune ambulance driver.

For the quartering of this detachment, and of such non-immune individuals as should be received for experimentation, hospital tents, properly floored, were provided. These were placed at a distance of about twenty feet from each other, and were numbered 1 to 7 respectively.

Camp Lazear was established Nov. 20, 1900, and from this date was strictly quarantined, no one being permitted to leave or enter camp except the three immune members of the detachment and the members of the board. Supplies were drawn chiefly from Columbia Barracks, and for this purpose a conveyance under the control of an immune acting hospital steward, and having an immune driver, was used.

A few Spanish immigrants recently arrived at the port of Havana were received at Camp Lazear, from time to time, while these observations were being carried out. A non-immune person, having once left this camp, was not permitted to return to it under any circumstances whatever.

The temperature and pulse of all non-immune residents were carefully recorded three time a day. Under these circumstances any infected individual entering the camp could be promptly detected and removed. As a matter of fact, only two persons, not the subject of experimentation, developed any rise of temperature; one, a Spanish immigrant, with probable commencing pulmonary tuberculosis, who was discharged at the end of three days; and the other, a Spanish immigrant, who developed a temperature of 102.6° F. on the afternoon of his fourth day in camp. He was at once removed with his entire bedding and baggage and placed in the receiving ward at Columbia Barracks. His fever, which was marked by daily intermissions for three days, subsided upon the administration of cathartics and enemata. His attack was considered to be due to intestinal irritation. He was not permitted, however, to return to the camp.

No non-immune resident was subjected to inoculation who had not passed in this camp the full period of incubation of yellow fever, with one exception, to be hereinafter mentioned.

For the purpose of experimentation subjects were selected as follows: From Tent No. 2, 2 non-immunes, and from Tent No. 5, 3 non-immunes. Later, 1 nonimmune in Tent No. 6 was also designated for inoculation.

It should be borne in mind that at the time when these inoculations were begun, there were only 12 non-immune residents at Camp Lazear, and that 5 of these were selected for experiment, viz., 2 in Tent No. 2, and 3 in Tent No. 5. Of these we succeeded in infecting 4, viz., 1 in Tent No. 2 and 3 in Tent No. 5, each of whom developed an attack of yellow fever within the period of incubation of this disease. The one negative result, therefore, was in Case 2—Moran—inoculated with a mosquito on the fifteenth day after the insect had bitten a case of yellow fever on the third day. Since this mosquito failed to infect Case 4, three days after it had bitten Moran, it follows that the result could not have been otherwise than negative in the latter case. We now know, as the result of our observations, that in the case of an insect kept at room temperature during the cool weather of November, fifteen or even eighteen days would, in all probability, be too short a time to render it capable of producing the disease.

As bearing upon the source of infection, we invite attention to the period of time during which the subjects had been kept under rigid quarantine, prior to successful inoculation, which was as follows: Case 1, fifteen days; Case 3, nine days; Case 4, nineteen days; Case 5, twenty-one days. We further desire to emphasize the fact that this epidemic of yellow fever, which affected 33.33 per cent, of the non-immune residents of Camp Lazear, did not concern the 7 nonimmunes occupying Tents Nos. 1, 4, 6 and 7, hut was strictly limited to those individuals who had been bitten by contaminated mosquitoes.

Nothing could point more forcibly to the source of this infection than the order of the occurrence of events at this camp. The precision with which the infection of the individual followed the bite of the mosquito left nothing to be desired in order to fulfill the requirements of a scientific experiment.

In summing up their results at the conclusion of this report the following statement is made:

Out of a total of 18 non-immunes whom we have inoculated with contaminated mosquitoes, since we began this line of investigation, 8, or 44.4 per cent., have contracted yellow fever. If we exclude those individuals bitten by mosquitoes that had been kept less than twelve days after contamination, and which were therefore probably incapable of conveying the disease, we have to record eight positive and two negative results—80 per cent. In a still later report (May, 1901) Dr. Reed says: "We have thus far succeeded in conveying yellow fever to twelve individuals by means of the bites of contaminated mosquitoes."

The non-immune individuals experimented upon were all fully informed as to the nature of the experiment and its probable results and all gave their full consent. Fortunately no one of these brave volunteers in the cause of science and humanity suffered a fatal attack of the disease, although several were very ill and gave great anxiety to the members of the board, who fully appreciated the grave responsibility which rested upon them. That these experiments were justifiable under the circumstances mentioned is, I believe, beyond question. In no other way could the fact established have been demonstrated and the knowledge gained is of inestimable value as a guide to reliable measures of prevention. Already it is being applied in Cuba and without doubt innumerable lives will be saved as a result of these experiments showing the precise method by which yellow fever is contracted by those exposed in an 'infected locality.' Some of these volunteers were enlisted men of the United States Army and some were Spanish immigrants who had recently arrived in Cuba. When taken sick they received the best possible care and after their recovery they had the advantage of being 'immunes' who had nothing further to fear from the disease which has caused the death of thousands and tens of thousands of Spanish soldiers and immigrants who have come to Cuba under the orders of their Government or to seek their fortunes.

The experiments already referred to show in the most conclusive manner that the blood of yellow-fever patients contains the infectious agent, or germ, to which the disease is due, and this has been further demonstrated by direct inoculations from man to man. This experiment was made by Dr. Reed at 'Camp Lazear' upon four individuals, who freely consented to it; and in three of the four a typical attack of yellow fever resulted from the blood injection. The blood was taken from a vein at the bend of the elbow on the first or second day of sickness and was injected subcutaneously into the four non-immune individuals, the amount being in one positive case 2 c. c, in one 1.5 c. c, and in one 0.5 c. e. In the case attended with a negative result, a Spanish immigrant, a mosquito inoculation also proved to be without effect, and Dr. Reed supposes that this individual 'probably possesses a natural immunity to yellow fever.' Dr. Reed says with reference to these experiments:

It is important to note that in the three cases in which the injection of the blood brought about an attack of yellow fever, careful culture from the same blood, taken immediately after injection, failed to show the presence of Sanarelli's bacillus.

Having demonstrated the fact that yellow fever is propagated by mosquitoes Dr. Reed and his associates have endeavored to ascertain whether it may also be propagated, as has been commonly supposed, by clothing, bedding and other articles which have been in use by those sick with this disease. With reference to the experiments made for the solution of this question I cannot do better than to quote in extenso from Dr. Reed's paper read at the Pan-American Medical Congress in Havana. He says:

We believe that the general consensus of opinion both of the medical profession and of the laity is strongly in favor of the conveyance of yellow fever by fomites. The origin of epidemics, devastating in their course, has been frequently attributed to the unpacking of trunks and boxes that contained supposedly infected clothing; and hence the efforts of health authorities, both state and national, are being constantly directed to the thorough disinfection of all clothing and bedding shipped from ports where yellow fever prevails. To such extremes have efforts at disinfection been carried, in order to prevent the importation of this disease into the United States, that, during the epidemic season, all articles of personal apparel and bedding have been subjected to disinfection, sometimes both at the port of departure and at the port of arrival; and this has been done whether the articles have previously been contaminated by contact with yellow-fever patients or not. The mere fact that the individual has resided, even for a day, in a city where yellow fever is present, has been sufficient cause to subject his baggage to rigid disinfection by the sanitary authorities.

To determine, therefore, whether clothing and bedding which have been contaminated by contact with yellow fever patients and their discharges can convey this disease is a matter of the utmost importance. Although the literature contains many references to the failure of such contaminated articles to cause the disease, we have considered it advisable to test, by actual experiment on non-immune human beings, the theory of the conveyance of yellow fever by fomites, since we know of no other way in which this question can ever be finally determined.

For this purpose there was erected at Camp Lazear a small frame house consisting of one room 14 x 20 feet and known as 'Building No. 1,' or the 'Infected Clothing and Bedding Building.' The cubic capacity of this house was 2,800 feet. It was tightly ceiled within with 'tongue-and-grooved' boards, and was well battened on the outside. It faced to the south and was provided with two small windows, each 26 x 34 inches in size. These windows were both placed on the south side of the building, the purpose being to prevent, as much as possible, any thorough circulation of the air within the house. They were closed by permanent wire screens of.5 mm. mesh. In addition sliding glass sash were provided within and heavy wooden shutters without; the latter intended to prevent the entrance of sunlight into the building, as it was not deemed desirable that the disinfecting qualities of sunlight, direct or diffused, should at any time be exerted on the articles of clothing contained within this room. Entrance was effected through a small vestibule, 3 x 5 feet, also placed on the southern side of the house. This vestibule was protected without by a solid door and was divided in its middle by a wire screen door, swung on spring hinges. The inner entrance was also closed by a second wire screen door. In this way the passage of mosquitoes into this room was effectually excluded. During the day, and until after sunset, the house was kept securely closed, while by means of a suitable heating apparatus the temperature was raised to 92° to 95° F. Precaution was taken at the same time to maintain a sufficient humidity of the atmosphere. The average temperature of this house was thus kept at 76.2° F. for a period of sixty-three days.

Nov. 30, 1900, the building now being ready for occupancy, three large boxes filled with sheets, pillow-slips, blankets, etc., contaminated by contact with cases of yellow fever and their discharges were received and placed therein. The majority of the articles had been taken from the beds of patients sick with yellow fever at Las Animas Hospital, Havana, or at Columbia Barracks. Many of them had been purposely soiled with a liberal quantity of black vomit, urine, and fecal matter. A dirty 'comfortable' and a much-soiled pair of blankets, removed from the bed of a patient sick with yellow fever in the town of Quemados, were contained in one of these boxes. The same day, at 6 p. m., Dr. R. P. Cooke, Acting Assistant-Surgeon U. S. A., and two privates of the hospital corps, all non-immune young Americans, entered this building and deliberately unpacked these boxes, which had been tightly closed and locked for a period of two weeks. They were careful at the same time to give each article a thorough handling and shaking, in order to disseminate through the air of the room the specific agent of yellow fever, if contained in these fomites. These soiled sheets, pillow-cases, and blankets were used in preparing the beds in which the members of the hospital corps slept. Various soiled articles were hung around the room and placed about the bed occupied by Dr. Cooke.

From this date until Dec. 19, 1900, a period of twenty days, this room was occupied each night by these three non-immunes. Each morning the various soiled articles were carefully packed in the aforesaid boxes, and at night again unpacked and distributed about the room. During the day the residents of this house were permitted to occupy a tent pitched in the immediate vicinity, but were kept in strict quarantine.

December 12, a fourth box of clothing and bedding was received from Las Animas Hospital. These articles had been used on the beds of yellow-fever patients, but in addition had been purposely soiled with the bloody stools of a fatal case of this disease. As this box had been packed for a number of days, when opened and impacked by Dr. Cooke and his assistants, on December 12th, the odor was so offensive as to compel them to retreat from the house. They pluckily returned, however, within a short time and spent the night as usual.

December 19 these three non-immimes were placed in quarantine for five days and then given the liberty of the camp. All had remained in perfect health, notwithstanding their stay of twenty nights amid such unwholesome surroundings.

During the week, December 20-27, the following articles were also placed in this house, viz.: pajamas suits, 1; undershirts, 2; night-shirts, 4; pillow-slips, 4; sheets, 6; blankets, 5; pillows, 2; mattresses, 1. These articles had been removed from the persons and beds of four patients sick with yellow fever and were very much soiled, as any change of clothing or bed-linen during their attacks had been purposely avoided, the object being to obtain articles as thoroughly contaminated as possible.

From Dec. 21, 1900, till Jan. 10, 1901, this building was again occupied by two non-immune young Americans, under the same conditions as the preceding occupants, except that these men slept every night in the very garments worn by yellow fever patients throughout their entire attacks, besides making use exclusively of their much-soiled pillow-slips, sheets, and blankets. At the end of twenty-one nights of such intimate contact with these fomites, they also went into quarantine, from which they were released five days later in perfect health.

From January 11 till January 31, a period of twenty days, 'Building No. 1' continued to be occupied by two other non-immune Americans, who, like those who preceded them, have slept every night in the beds formerly occupied by yellow fever patients and in the night-shirts used by these patients throughout the attack, without change. In addition, during the last fourteen nights of their occupancy of this house they have slept, each night, with their pillows covered with towels that had been thoroughly soiled with the blood drawn from both the general and capillary circulation, on the first day of the disease, in the case of a well-marked attack of yellow fever. Notwithstanding this trying ordeal, these men have continued to remain in perfect health.

The attempt which we have therefore made to infect 'Building No. 1,' and its seven non-immune occupants, during a period of sixty-three days, has proved an absolute failure. We think we cannot do better here than to quote from the classic work of La Roche.[2] This author says: "In relation to the yellow fever, we find so many instances establishing the fact of the non-transmissibility of the disease through the agency of articles of the kind mentioned, and of merchandise generally, that we cannot but discredit the accounts of a contrary character assigned in medical writings, and still more to those presented on the strength of popular report solely. For if, in a large number of well-authenticated cases, such articles have been handled and used with perfect impunity—and that, too, often under circumstances best calculated to insure the effect in question—we have every reason to conclude that a contrary result will not be obtained in other instances of a similar kind; and that consequently the effect said to have been produced by exposure to those articles, must—unless established beyond the possibility of doubt—be referred to some other agency."

The question here naturally arises: How does a house become infected with yellow fever? This we have attempted to solve by the erection at Camp Lazear of a second house, known as 'Building No. 2,' or the 'Infected Mosquito Building.' This was in all respects similar to 'Building No. 1,' except that the door and windows were placed on opposite sides of the building so as to give through-and through ventilation. It was divided, also, by a wire-screen partition, extending from floor to ceiling, into two rooms, 12 x 14 feet and 8 x 14 feet respectively. Whereas, all articles admitted to 'Building No. 1' had been soiled by contact with yellow fever patients, all articles admitted to 'Building No. 2' were first carefully disinfected by steam before being placed therein.

On Dec. 21, 1900, at 11.45 a. m., there were set free in the larger room of this building fifteen mosquitoes—C. fasciatus—which had previously been contaminated by biting yellow fever patients, as follows: 1, a severe case, on the second day, Nov. 27, 1900, twenty-four days; 3, a well-marked case, on the first day, Dec. 9, 1900, twelve days; 4, a mild ease, on the first day, Dec. 13, 1900, eight days; 7, a well-marked case, on the first day, Dec. 16, 1900, five days—total, 15.

Only one of these insects was considered capable of conveying the infection, viz., the mosquito that had bitten a severe case twenty-four days before; while three others—the twelve-day insects—had possibly reached the dangerous stage, as they had been kept at an average temperature of 82° F.

At 12, noon, of the same day, John J. Moran—already referred to as Case 2 in this report—a non-immune American, entered the room where the mosquitoes had been freed, and remained thirty minutes. During this time he was bitten about the face and hands by several insects. At 4.30 p. m., the same day, he again entered and remained twenty minutes, and was again bitten. The following day, at 4.30 p. m., he, for the third time, entered the room, and was again bitten.

Case 7.—On Dec. 25, 1900, at 6 a. m., the fourth day, Moran complained of slight dizziness and frontal headache. At 11 a. m. he went to bed, complaining of increased headache and malaise, with a temperature of 99.6° F., pulse 88; at noon the temperature was 100.4° F., the pulse 98; at 1 p. m., 101.2° F., the pulse 90, and his eyes were much injected and face suffused. He was removed to the yellow fever wards. He was seen on several occasions by the board of experts and the diagnosis of yellow fever confirmed.

The period of incubation in this case, dating from the first visit to 'Building No. 2,' was three days and twenty-three hours. If reckoned from his last visit it was two days and eighteen hours. There was no other possible source for his infection, as he had been strictly quarantined at Camp Lazear for a period of thirty-two days prior to his exposure in the mosquito building.

During each of Moran's visits, two non-immunes remained in this same building, only protected by the wire-screen partition. From Dec. 21, 1900, till Jan. 8, 1901, inclusive—eighteen nights—these non-immunes have slept in this house, only protected by the wire-screen partition. These men have remained in perfect health to the present time.

Thus at Camp Lazear, of 7 non-immunes whom we attempted to infect by means of the bites of contaminated mosquitoes, we have succeeded in conveying the disease to 6, or 85.71 per cent. On the other hand, of 7 non-immunes whom we tried to infect by means of fomites, under particularly favorable circumstances, we did not succeed in a single instance.

It is evident that in view of our present knowledge relating to the mode of transmission of yellow fever, the preventive measures which have heretofore been considered most important, i. e., isolation of the sick, disinfection of clothing and bedding, and municipal sanitation—are either of no avail or of comparatively little value. It is true that yellow fever epidemics have resulted, as a rule, from the introduction to a previously healthy locality of one or more persons suffering from the disease. But we now know that its extension did not depend upon the direct contact of the sick with the non-immune individuals and that isolation of the sick from such contact is unnecessary and without avail. On the other hand complete isolation from the agent which is responsible for the propagation of the disease is all-important. In the absence of a yellow-fever patient from which to draw blood the mosquito is harmless, and in the absence of the mosquito the yellow-fever patient is harmless—as the experimental evidence now stands. Yellow fever epidemics are terminated by cold weather because then the mosquitoes die or become torpid. The sanitary condition of our southern seaport cities is no better in winter than in summer and if the infection attached to clothing and bedding it is difficult to understand why the first frosts of autumn should arrest the progress of an epidemic. But all this is explained now that the mode of transmission has been demonstrated.

Insanitary local conditions may, however, have a certain influence in the propagation of the disease, for it has been ascertained that the species of mosquito which serves as an intermediate host for the yellow fever germ may breed in cesspools and sewers, as well as in stagnant pools of water. If, therefore, the streets of a city are unpaved and ungraded and there are open spaces where water may accumulate in pools, as well as open cesspools to serve as breeding places for Culex fasciatus, that city will present conditions more favorable for the propagation of yellow fever than it would if well paved and drained and sewered.

The question whether yellow fever may be transmitted by any other species of mosquito than Culex fasciatus has not been determined. Facts relating to the propagation of the disease indicate that the mosquito which serves as an intermediate host for the yellow-fever germ has a somewhat restricted geographical range and is to be found especially upon the sea-coast and the margins of rivers in the so-called yellow fever zone.' While occasional epidemics have occurred upon the southwest coast of the Iberian peninsula, the disease, as an epidemic, is unknown elsewhere in Europe, and there is no evidence that it has ever invaded the great and populous continent of Asia. In Africa it is limited to the west coast. In North America, although it has occasionally prevailed as an epidemic in every one of our seaport cities as far north as Boston, and in the Mississippi Valley as far north as St. Louis, it has never established itself as an endemic disease within the limits of the United States. Vera Cruz, and probably other points on the Gulf coast of Mexico, are, however, at the present time endemic foci of the disease. In South America it has prevailed as an epidemic at all of the seaports on the Gulf and Atlantic Coasts, as far south as Montevideo and Buenos Ayres, and on the Pacific along the coast of Peru.

The region in which the disease has had the greatest and most frequent prevalence is bounded by the shores of the Gulf of Mexico, and includes the West India islands. Within the past few years yellow fever has been carried to the west coast of North American, and has prevailed as an epidemic as far north as the Mexican port of Guaymas, on the Gulf of California.

It must not be supposed that Culex fasciatus is only found where yellow fever prevails. The propagation of the disease depends upon the introduction of an infected individual to a locality where this mosquito is found, at a season of the year when it is active. Owing to the short period of incubation (five days or less), the brief duration of the disease and especially of the period during which the infectious agent (germ) is found in the blood, it is evident that ships sailing from infected ports, upon which cases of yellow fever develop, are not likely to introduce the disease to distant seaports. The continuance of an epidemic on ship-board, as on the land, must depend upon the presence of infected mosquitoes and of non-immune individuals. Under these conditions we can readily understand why the disease should not be carried from the West Indies or from South America to the Mediterranean, to the east coast of Africa or to Asiatic seaport cities. On the other hand, if the disease could be transmitted by infected clothing, bedding, etc., there seems no good reason why it should not have been carried to these distant localities long ago.

The restriction as regards altitude, however, probably depends upon the fact that the mosquito which serves as an intermediate host is a coast species, which does not live in elevated regions. It is a well-established fact that yellow fever has never prevailed in the City of Mexico, although this city has constant and unrestricted intercourse with the infected seaport. Vera Cruz. Persons who have been exposed in Vera Cruz during the epidemic season frequently fall sick after their arrival in the City of Mexico, but they do not communicate the disease to those in attendance upon them or to others in the vicinity. Evidently some factor essential for the propagation of the disease is absent, although we have the sick man, his clothing and bedding and the insanitary local conditions which have been supposed to constitute an essential factor. I am not aware that any observations have been made with reference to the presence or absence of Culex fasciatus in high altitudes, but the inference that it is not to be found in such localities as the City of Mexico seems justified by the established facts already referred to.

As pointed out by Hirsch, "the disease stops short at many points in the West Indies where the climate is still in the highest degree tropical." In the Antilles it has rarely appeared at a height of more than 700 feet. In the United States the most elevated locality in which the disease has prevailed as an epidemic is Chattanooga, Tenn., which is 745 feet above sea level.

It will be remembered that the malarial fevers are contracted as a result of inoculation by mosquitoes of the genus Anopheles, and that the malarial parasite has been demonstrated not only in the blood of those suffering from malarial infection, but also in the stomach and salivary glands of the mosquito. If the yellow fever parasite resembled that of the malarial fevers it would no doubt have been discovered long ago. But, as a matter of fact, this parasite, which we now know is present in the blood of those sick with the disease, has thus far eluded all researches. Possibly it is ultra-microscopic. However this may be, it is not the only infectious disease germ which remains to be discovered. There is without doubt a living germ in vaccine lymph and in the virus from smallpox pustules, but it has not been demonstrated by the microscope. The same is true of foot and mouth disease and of infectious pleuro-pneumonia of cattle, although we know that a living element of some kind is present in the infectious material by which these diseases are propagated. In Texas fever, of cattle, which is transmitted by infected ticks, the parasite is very-minute, but by proper staining methods and a good microscope it may be detected in the interior of the red blood corpuscles. Drs. Reed and Carroll are at present engaged in a search for the yellow fever germ in the blood and in the bodies of infected mosquitoes. What success may attend their efforts remains to be seen, but at all events the fundamental facts have been demonstrated that this germ is present in the blood and that the disease is transmitted by a certain species of mosquito—C. fasciatus.

The proper measures of prophylaxis in view of this demonstration are given in the following circular, which was submitted for my approval by the Chief Surgeon, Department of Cuba, and has recently been published by the Commanding General of that Department, who, until quite recently, was a member of the Medical Corps of the Army:

Circular, Headquarters Department of Cuba,
No. 5. Havana, April 21, 1901.
Upon the recommendation of the Chief Surgeon of the Department, the following instructions are published and will be strictly enforced at all military posts in this Department:

The recent experiments made in Havana by the Medical Department of the Army having proved that yellow fever, like malarial fever, is conveyed chiefly, and probably exclusively, by the bite of infected mosquitoes, important changes in the measures used for the prevention and treatment of this disease have become necessary.

1. In order to prevent the breeding of mosquitoes and protect officers and men against their bites, the provisions of General Orders No. 6, Department of Cuba, December 21, 1900, shall be carefully carried out, especially during the summer and fall.

2. So far as yellow fever is concerned, infection of a room or building simply means that it contains infected mosquitoes, that is, mosquitoes which have fed on yellow-fever patients. Disinfection, therefore, means the employment of measures aimed at the destruction of these mosquitoes. The most effective of these measures is fumigation, either with sulphur, formaldehyde or insect powder. The fumes of sulphur are the quickest and most effective insecticide but are otherwise objectionable. Formaldehyde gas is quite effective if the infected rooms are kept closed and sealed for two or three hours. The smoke of insect powder has also been proved very useful; it readily stupefies mosquitoes, which drop to the floor and can then be easily destroyed.

The washing of walls, floors, ceilings and furniture with disinfectants is unnecessary.

3. As it has been demonstrated that yellow fever cannot be conveyed by fomites, such as bedding, clothing, effects and baggage, they need not be subjected to any special disinfection. Care should be taken, however, not to remove them from the infected rooms until after formaldehyde fumigation, so that they may not harbor infected mosquitoes.

Medical officers taking care of yellow-fever patients need not be isolated; they can attend other patients and associate with non-immunes with perfect safety to the garrison. Nurses and attendants taking care of yellow fever patients shall remain isolated, so as to avoid any possible danger of their conveying mosquitoes from patients to non-immunes.

4. The infection of mosquitoes is most likely to occur during the first two or three days of the disease. Ambulant cases, that is, patients not ill enough to take to their beds and remaining unsuspected and unprotected, are probably those most responsible for the spread of the disease. It is therefore essential that all fever cases should be at once isolated and so protected that no mosquitoes can possibly get access to them until the nature of the fever is positively determined.

Each post shall have a 'reception ward' for the admission of all fever cases and an 'isolation ward' for the treatment of cases which prove to be yellow fever. Each ward shall be made mosquito-proof by ware netting over doors and windows, a ceiling of wire netting at a height of seven feet above the floor, and mosquito bars over the beds. There should be no place in it where mosquitoes can seek refuge, not readily accessible to the nurse. Both wards can be in the same building, provided they are separated by a mosquito-tight partition.

5. All persons coming from an infected locality to a post shall be kept under careful observation until the completion of five days from the time of possible infection, either in a special detention camp or in their own quarters; in either case, their temperature should be taken twice a day during this period of observation so that those who develop yellow-fever may be placed under treatment at the very inception of the disease.

6. Malarial fever, like yellow fever, is communicated by mosquito bites and therefore is just as much of an infectious disease and requires the same measures of protection against mosquitoes. On the assumption that mosquitoes remain in the vicinity of their breeding places, or never travel far, the prevalence of malarial fever at a post would indicate want of proper care and diligence on the part of the Surgeon and Commanding Officer in complying with General Orders No. 6, Department of Cuba, 1900.

7. Surgeons are again reminded of the absolute necessity, in all fever cases, to keep, from the very beginning, a complete chart of pulse and temperature, since such a chart is their best guide to a correct diagnosis and the proper treatment.

By Command of Major General Wood:
Adjutant General.

  1. The members of the board were: Major Walter Reed, Surgeon U. S. A.; Dr. James Carroll, Contract Surgeon U. S. A.; Dr. A. Agramonte, Contract Surgeon U. S. A., and Dr. Jesse W. Lazear, Contract Surgeon U. S. A.
  2. R. La Roche: Yellow Fever, Vol. II, p. 516, Philadelphia.