CHAPTER V

YELLOW FEVER

DEFINITION AND SYNONYMS

=Definition.=—Yellow fever is an important epidemic disease of the West Coast of Africa and tropical America caused by a spirochaetal organism, _Leptospira icteroides_. The spirochaete is contained in the peripheral blood only during the first three days of the disease. A mosquito, _Stegomyia calopus_ (_Aedes calopus_), biting a patient during this period of his illness, takes in the organism which undergoes some developmental cycle of the nature of which we are ignorant, but we do know experimentally that a minimum period of twelve days is requisite for the completion of the cycle which makes the mosquito infectious for man.

When a susceptible individual is bitten by an infected mosquito there develops, after a period of incubation of from two to five days, a rapid rise of fever, with markedly congested face and severe pains of back and head. About the end of the third day the sthenic manifestations are succeeded by asthenic ones in which jaundice, haemorrhages, particularly black vomit, and anuria are the important features.

Faget’s sign of a lack of accordance between pulse and temperature is of great diagnostic importance.

=Synonyms.=—Febris Flava, Typhus Icteroides. Spanish: Fiebre Amarilla, German: Gelbfieber, French: Fièvre Jaune.

History and Geographical Distribution

=History.=—It would seem probable that yellow fever was the disease from which those of Columbus’ second expedition suffered in San Domingo, in 1495. At the same time the first definite description of the disease was that of Dutertre, in Guadaloupe, in 1635. There has been much discussion as to whether the West Coast of Africa may not have been the original endemic centre and the importation to the West Indies the result of the slave traffic. While there is very little support given this view the recent recognition of the extent and importance of the African endemic area, as brought out by Boyce, is somewhat suggestive. Spinden advances evidence to show that a devastating epidemic disease, attended with bleeding from the mouth and nose, raged among the Mayas and Aztecs in pre-Columbian periods. One such epidemic is recorded as of 1454. There have been numerous severe outbreaks in the United States, that occurring in Philadelphia, in 1793, being the most celebrated and that centering in Memphis, in 1878, probably the most terrible. Yellow fever has been a scourge in Brazil since its introduction in 1849, until quite recently. Lisbon experienced severe outbreaks of the disease in 1723 and in the next century in 1850 and 1856. Many of the Spanish cities have also suffered from time to time.

The history of the connection between yellow fever and the mosquito is discussed under etiology.

[Illustration: FIG. 40.—Geographical distribution of yellow fever.]

=Geographical Distribution.=—As will be seen from the chart the chief epidemic centers are the islands and coasts of the Gulf of Mexico and the West Coast of Africa. The disease has at times extended down the West Coast of South America and is now rather prevalent in Ecuador. The last epidemic in the United States was that in New Orleans.

The disease has never invaded Asia or Australia and there is fear that the opening of the Panama canal may bring this about.

Guiteras, who has recently returned from an investigation of the problem of yellow fever on the West Coast of Africa, was unable to find evidence of its existence there at the present time. He notes an absence of the extreme heat and abundance of mosquitoes which are features of yellow fever ports of South America.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—It is now generally accepted that the cause of yellow fever is a spirochaete, _Leptospira icteroides_, which is very similar to but slightly smaller than _L. icterohaemorrhagiae_ of infectious jaundice. Noguchi injected 74 guinea pigs with about 5 cc. of blood from 27 cases of yellow fever. The blood from 6 of these cases proved infectious, producing in 8 guinea pigs fever, conjunctival injection, albuminuria, a leucocytosis followed by leucopenia and, after a few days, a subsidence of the fever to normal or subnormal. At this time jaundice and haemorrhages occurred.

[Illustration: FIG. 41.—Dark-field view of _Leptospira icteroides_ in a culture 16 days old. × 1000. (After Noguchi.)]

Autopsies of the guinea pigs showed a fatty and yellow liver with nephritis. Some of the injected guinea pigs showed only fever but seemed to have acquired an immunity to subsequent injections of a virulent virus. In the blood, liver and kidneys of the animals showing the jaundice and albuminuria Noguchi was able to demonstrate spirochaetes by dark-field illumination. He also obtained cultures from such animals. Leptospiras were demonstrated in the blood of 3 out of 27 human cases but only after prolonged search. Cultures have been obtained from human yellow fever blood. For culturing, a medium is used consisting of 1 part of serum and 3 parts of Ringer’s solution made semisolid with 0.3% agar and contained in tall tubes. One cc. citrated yellow fever blood is introduced into the lower part of the medium. A thin layer of liquid petrolatum is poured on the top of the medium. We need partial oxygen tension but not anaerobiasis. Optimum growth temperature is 33°C. _L. icteroides_ is from 4 to 9 microns long by 0.2 wide and tapers gradually to extremely thin sharp points. These organisms will pass the pores of V and N Berkefeld filters thus placing them in the group of filterable viruses. The virulence of different strains varies, with some strains as little as 0.00001 cc. of culture proving fatal for guinea pigs. Monkeys, rabbits and birds were not susceptible to infection but the marmoset and puppy seemed to respond as did the guinea pig.

By having _Stegomyia_ (_Aedes calopus_) feed on infected guinea pigs as well as the human case of yellow fever, and subsequently allowing these mosquitoes to bite normal guinea pigs, the disease was transmitted in a few cases. In certain infected mosquitoes Noguchi found leptospiral organisms with dark-field illumination. Mosquitoes fed on infected guinea pigs became infectious in 8 days, this shorter period over human feedings being due, probably, to the greater abundance of organisms in the blood of the infected guinea pigs over human yellow fever blood.

Guiteras doubts the etiological relation of Noguchi’s leptospira to yellow fever on the ground that in view of the susceptibility of animals to this organism the disease should exist as an epizootic, which is improbable in view of the ease with which yellow fever is eradicated when measures applied solely to man and the mosquito are practiced. Among other points of objection he notes the recovery of the spirochaete from the blood later than the third day of the disease.

[Illustration: FIG. 42.—_Leptospira icteroides_ in blood of a guinea pig inoculated with a culture × 1000. (After Noguchi.)]

_Infection by Injection of Blood._—The subcutaneous injection of as little as 0.1 cc. of the blood of a yellow fever patient in the first three or four days of the disease, or the serum of this blood, which has passed through the pores of a Chamberland filter (F but not B according to the French Commission), will bring about the infection of a susceptible person after an incubation period of from one day and fifteen hours to twelve days and eighteen hours.

In the natural method of transmission the mosquito, _Stegomyia calopus_, is the intermediary. In order that the female of this culicine species may transmit the disease it is necessary that she bite a yellow fever patient in the first three days of his illness, after which a period of approximately twelve days must elapse before the mosquito can transmit the disease. In such case the period of incubation varies from two days one hour to six days two hours. Carroll was bitten by a mosquito which had fed on a yellow fever patient twelve days previously, and four days later experienced a very severe attack, this fact being against the views of the French Commission that the disease shows a less severe form in those who may be bitten in the first period of the infectivity of the mosquito. A second case bitten five days later by the same mosquito that infected Doctor Carroll had a mild attack. Persons bitten by experimentally contaminated mosquitoes before an interval of twelve days had elapsed escaped infection.

Prior to the investigations of the American Commission our views as to the incidence and spread of yellow fever were chaotic.

Rush, in 1793, thought that the Philadelphia epidemic originated from “damaged coffee which putrefied on a wharf near Arch Street.”

In 1883, Doctor Friere reported that yellow fever was caused by a coccus, _Cryptococcus xanthogenicus_ and claimed that he could confer immunity by vaccination with attenuated cultures. Carmona y Valle of Mexico and Carlos Finlay of Havana considered that the _Micrococcus tetragenus_ was the cause but Sternberg, investigating these claims, showed that these cocci had nothing to do with yellow fever. In his work Sternberg isolated an organism which he designated “X.”

=Bacillus Icteroides.=—In 1897, Sanarelli isolated an organism which he named _Bacillus icteroides_. In investigating this organism Reed and Carroll found that it was closely related to the hog cholera bacillus. Certain American investigators substantiated the claims of Sanarelli. Sternberg, however, doubted these findings.

To further investigate the relation of _B. icteroides_ to yellow fever Army surgeons were sent to Cuba in 1900.

=American Commission.=—In addition to Reed and Carroll, Lazear and Agramonte were also members of the Commission.

The Commission first cultured the blood of 18 yellow fever patients with negative results for _B. icteroides_ in every case.

_B. icteroides_ grows as readily on culture media as does the typhoid organism.

It was also shown that yellow fever blood, which was negative for _B. icteroides_, could produce yellow fever when injected subcutaneously. In 11 autopsies made shortly after death cultures from various viscera were negative for _B. icteroides_. It was then decided to abandon, as fruitless, further investigations as to Sanarelli’s organism, and to take up the mosquito transmission theory.

=Mosquito Transmission.=—In 1848, Doctor Nott, of Mobile, strongly advocated the insect transmission of yellow fever but not specifically incriminating the mosquito.

Riley from a study of Nott’s original paper, thinks that the author had in mind invisible forms of insect life, which could act as disease producers, and simply cited the mosquito to illustrate his views. In 1853, Dr. Beauperthuis, in Guadeloupe, noted that malaria and yellow fever ceased to exist in regions which from their altitude fail to nourish “insectes tipulaires.”

He also thought that the virus of these diseases was introduced by the channel of insect inoculation. Furthermore he stated that the variety, zancudo bobo (_Stegomyia_), had white stripes on the legs and was in a way the domestic species. However, there is a question whether his zancudo bobo was _Stegomyia_ and furthermore if we translate the expression _inoffensif_ as without result it would negate the connection between this mosquito and disease production.

From 1881 Doctor Carlos Finlay had been advocating the transmission of yellow fever by _Culex fasciatus_ (Synonym for _Stegomyia calopus_).

In 100 experiments made by Finlay 13 cases of yellow fever developed.

In no instance had these experimental mosquitoes fed on a yellow fever patient more than six days previous to their biting and, knowing that a period of at least twelve days must elapse, the infections in the 13 cases could not have been brought about by these experimental mosquitoes.

=Extrinsic Incubation.=—An observation by Carter influenced the Commission in their investigations. Carter, in 1898, noted that a period of about two weeks generally elapsed between the appearance of the first case and the group of cases resulting from this first case. He termed this period the “extrinsic incubation” and we now know this as synonymous with the twelve-day period of incubation in the mosquitoes infected by the first case plus the two to five days of the period of incubation in man.

The American Commission obtained ova from Doctor Finlay and from these ova mosquitoes were hatched for the experimental work. Of 11 susceptible persons, bitten by contaminated mosquitoes, the first 9 remained uninfected while the two volunteers, bitten subsequently (Aug. 27 and 31), developed the disease. One of these cases was that of Doctor Carroll, whose infection was brought about by one of these laboratory reared mosquitoes which had fed on 4 cases of yellow fever, two of which were severe cases and two mild. This mosquito had fed on one of the severe cases just twelve days previously. The other case was bitten by 4 contaminated mosquitoes, one of which was the one that had infected Doctor Carroll.

Of the 9 negative cases 6 were bitten by mosquitoes which had fed on yellow fever patients from the fifth to the seventh day of the disease and the remaining 3 failures were where the interval between contamination and biting the volunteer was from two to six days only.

At this time the medical mind was obsessed with the idea that yellow fever was transmitted by fomites.

It had been forgotten that Cathrall, in 1800, had failed to infect himself with black vomit and that Ffirth, in 1804, in order to obtain material for a graduation thesis, swallowed black vomit and smeared it, as well as blood, upon wounds he had made on his skin with negative result. (It will be remembered that the fourth proposition of the French Commission was that application of infectious serum to the abraded skin would not produce the disease—the hypodermic injection being required.)

=Fomites.=—To settle the question of the relative importance of fomites and infected mosquitoes the Commission caused two houses, 14 × 20 feet, to be erected, one well ventilated for the infected mosquitoes and the other poorly lighted and ill ventilated for the black vomit contaminated clothes, sheets and blankets (fomites). A medical officer and two privates of the Hospital Corps slept in this room for twenty days in most intimate contact with the infected material. No infections resulted.

There were other experiments with similar results.

One of the occupants of the fomites building was afterward inoculated subcutaneously with 2 cc. of blood taken from a patient in the first day of the disease and developed yellow fever after four days of incubation. This proved that he was susceptible to yellow fever.

Blood from this patient, taken in the first three days of his attack, was injected into a third man who also developed yellow fever. This experiment was to prove that the production of the disease was due to a virus capable of multiplying rather than to a toxin. Of course, it would be impossible to conceive of a toxin so potent that it could produce symptoms in a third man when diluted in the circulation of the second man.

In the other building there was a screen partition dividing the space into two compartments, one containing 15 contaminated mosquitoes, the other with the same air but without mosquitoes. Controls occupying the mosquito free section remained free from yellow fever, while those exposing themselves in the mosquito-containing compartment developed yellow fever. One of these cases was bitten by mosquitoes contaminated thirty-nine days previously, a second one with fifty-one day insects and a third, who developed a severe case, was bitten by mosquitoes contaminated fifty-seven days previously.

As above stated the Commission inoculated men subcutaneously with blood, taken from yellow fever patients in the first three days of the disease, with positive results. It was also found that if the blood was heated to 55°C., for ten minutes the virus was destroyed and, finally, it was found that the filtrate from a Berkefeld filter was infectious, thus showing that the virus was so minute as to pass through the pores of a filter which would hold back the smallest known bacterium (_filterable virus_).

_Experiments of Guiteras._—During the summer of 1901 Doctor Guiteras, with a view to immunity production, repeated the experiments of the Army Commission and infected 8 persons, 3 of whom died. Gorgas thinks the greater severity of these infections may be explained by greater virulence of the virus developing in the mosquito during the hot season. It is known that the development of this virus requires fifteen to twenty days in winter as against the twelve days for summer.

_Note._—Doctor Lazear, who had charge of the mosquito work of the Commission, tried to infect himself with experimental insects prior to his applying a twelve-day mosquito to Doctor Carroll. About three weeks later he was bitten by a mosquito which he did not at the time consider a _Stegomyia_. The attack of yellow fever which resulted from this bite ended fatally.

_To summarize, the American Commission found:_

1. That _B. icteroides_ had nothing to do with yellow fever.

2. That fomites was a negligible factor.

3. That _Stegomyia calopus_, when fed on the blood of a yellow fever patient, in the first three days of the disease, became contaminated and, after a period of twelve days, but not before, was capable of transmitting the disease to a susceptible person. Once infectious the mosquito so remained for the rest of life.

[Illustration: FIG. 43.—_Aedes calopus_ (_Stegomyia calopus_), female. From P. H. Reports.

FIG. 44.—_Aedes calopus_ (_Stegomyia calopus_), male. From P. H. Reports.]

4. The blood of a yellow fever patient in the first three days, which was sterile for _B. icteroides_, was capable of producing the disease when injected subcutaneously. If heated to 55°C. for ten minutes the virus was destroyed however. Furthermore, infectious blood when passed through a Berkefeld filter remained infectious, thus showing that the virus is a filterable virus.

The French Commission verified these findings and in addition brought out the following points.

1. Cutaneous vaccination with infective serum is without result.

2. Infectious serum loses its yellow fever-producing power in forty-eight hours unless preserved under liquid petrolatum when it remains virulent for five days.

3. Infectious serum if heated for five minutes at 55°C. loses its virulence but has prophylactic and curative power.

4. Besides the method of hypodermic inoculation yellow fever can only be transmitted by the bite of a mosquito in which the virus has remained for at least twelve days.

5. In one instance it was thought that the progeny of infected mosquitoes transmitted the disease. Rosenau and Goldberger, in 38 experiments, failed to obtain such result.

_Paraplasma flavigenum._—In 1909, Seidelin reported certain minute protozoa as existing in the red cells of yellow fever patients. He considered them as related to the piroplasms and gave the name _Paraplasma flavigenum_. It is stated that the parasite has been found as late as the fourteenth day from the onset of the attack. The idea is advanced that there may be carriers of yellow fever. These claims are generally denied.

=Epidemiology.=—There are numerous records which attest the almost universal susceptibility to yellow fever. In the Orwood epidemic, Carter has reported that of 46 persons entering an infected house, “Gray Mansion,” 45 contracted yellow fever.

On the “Lombardia,” with a complement of 249, there were 242 cases and 134 deaths. The 7, who escaped, were immunes.

The idea that the colored race possesses immunity is now thought to be connected with the contraction of the disease in infancy or childhood, attacks at this period of life being very mild and difficult of diagnosis.

_Immunity._—As proof that such immunity is not racial we may note that in Ecuador the natives of the endemic area about Guayaquil possess an immunity due to mild attacks in childhood, but the natives of Quito, 300 miles distant, where there is no yellow fever, do not possess it, and many residents of Quito have contracted the disease when passing through Guayaquil to take steamer to Europe.

There has been some inclination to question the immunity conferred by an attack of yellow fever but Carter has shown that in quarantine practice we can admit such immunes with perfect safety. Thirty thousand such immunes were allowed to enter Key West and Tampa from Havana between 1888 and 1898 and no case of yellow fever developed from them. During the same period 450 non-immunes from Havana gave 13 cases in the quarantine stations.

_The Yellow Fever Mosquito._—A knowledge of the life history of _Stegomyia calopus_ explains the epidemiology of yellow fever. This culicine species is widely distributed in the tropical and subtropical world, extending from 38° north to 38° south latitude. It is rarely found at a greater altitude than 3000 feet. Petropolis, a railway-connected suburb of Rio, has an altitude of 2300 feet, with cool nights, at times about 9°C, and a freedom from _Stegomyia_. Persons having occupation in Rio during the day but returning to Petropolis in the afternoon escape yellow fever. In this connection it is generally accepted that the female _Stegomyia_ only bites between 5 o’clock P.M. and midnight. While the first feeding may occur earlier in the day, all subsequent feedings, which alone could be infectious, occur late in the afternoon or at night. (Recent observations show _Stegomyia_ to bite in daytime,—not at night.)

These views, which were advanced by Marchoux, would explain the apparent freedom from infection of those leaving infected areas by the early afternoon. Seidelin, however, claims that these mosquitoes will continue to bite in the day after numerous feedings of blood.

It is recognized that railways are unimportant factors in transporting these mosquitoes, differing in this respect from ships which offer better conditions.

The _Stegomyia_ is preëminently a house mosquito and a town mosquito. It is the domesticated one, while the malaria-transmitting ones are rural and feed in natural plant-containing bodies of water instead of the water in old tin cans, roof gutters, cisterns or other utensils surrounding the house which are preferred by the yellow fever mosquitoes.

_Stegomyia_ seem to prefer water for breeding that is slightly tainted with sewage, although developing equally well in fresh water. They will also develop in brackish water.

When once this mosquito takes up its residence in a certain room of a house it rarely leaves it and thus is explained the danger of occupying a room which has been occupied by a yellow fever patient. Then too, the warning sound, so characteristic of the approach of most mosquitoes, is not given by _Stegomyia_.

The female lays about 70 eggs in small groups and not in a compact egg raft as with _Culex_. The eggs are therefore difficult of detection. The eggs do not suffer after rather prolonged drying. Even temperatures approximately 0°C. do not seem to destroy the viability. It would seem probable that it is this stage in the metamorphosis of _Stegomyia_ which is responsible for the survival of the species under unfavorable conditions.

The eggs the American Commission received from Finley had been deposited thirty days previously on the edge of some water in a basin. The water had meanwhile evaporated and the eggs were dry. Notwithstanding this the eggs promptly hatched out when water was poured in the basin.

The most favorable temperatures for these mosquitoes range from 29° to 31°C. Under 20°C. the eggs do not hatch out.

The larvae, which hatch out in about two days, develop into pupae in approximately one week. In about two days the fully developed insect breaks out of the pupal case. It will thus be seen that a period of ten to fourteen days suffices for a generation. The insect is almost black and has a silvery lyre or Jew’s harp pattern marking on the thorax. The legs and abdomen also have silvery bands. The female lays several batches of eggs and has been observed in one instance to live 154 days. The French Commission kept a female alive 106 days. They consider that life under normal conditions is much shorter in duration than in captivity. If deprived of water the adult insect only lives about five days. In a refrigerator, Guiteras was able to keep mosquitoes alive, without food or water, for eighty-seven days.

On fruit and sugar vessels the conditions for the development of _Stegomyia_ are exceptionally favorable.

These mosquitoes are prone to remain in the same house where they have been feeding. Carter has pointed out that yellow fever rarely spreads more than 75 yards from an infected house so that it is improbable that infected mosquitoes fly, or are carried by the wind, any great distance.

The same authority has also noted that ships in Havana harbor lying about 400 yards from shore never become infected when the crew have not been ashore or where infected ships have not been anchored near by.

It is probable that they are carried aboard ships in connection with coaling or provisioning rather than blown aboard by prevailing winds.

[Illustration: FIG. 45.—Temperature chart of Yellow Fever. A, Mild case with recovery. B, Severe case showing the saddle-back temperature curve similar to that of dengue. C, Chart of fatal case of yellow fever.]

PATHOLOGY AND MORBID ANATOMY

The toxic effects are chiefly borne by the liver and endothelial linings of the capillaries. The cloudy swelling of the liver cells obstructs the bile canaliculi, causing jaundice, and the more advanced fatty degeneration of these cells brings about disturbances caused by interference with the important liver functions. The degenerative changes in the endothelial cells lining the capillaries bring about the haemorrhages so much a feature of yellow fever.

The icterus is apt to be more marked after death, and is especially prominent about the neck and eyelids. Dutroulau considers the absence of icterus in a cadaver as negativing yellow fever.

The liver is of a boxwood or chamois skin color and on section is very oily. Haemorrhagic patches may be seen dotting the yellow cut surface.

A midzonal fatty degeneration of the liver cells may be noted in cases dying by the 4th and 5th day but later there is degeneration of the entire lobule.

The stomach and intestines contain disintegrated blood. Petechiae and erosions are common in the cardiac end of the stomach. The upper part of the duodenum shows changes similar to those seen in the stomach but the other portions of the intestines are essentially negative.

The spleen does not show any particular change. The kidneys are enlarged, congested and on microscopical examination show fatty degeneration of the renal epithelium.

The adrenals often show fatty degeneration, especially of the cortex.

Haemorrhagic infiltrations are marked features in skin and mucous and serous membranes.

SYMPTOMATOLOGY

=A Typical Case.= _Sthenic Stage._—With very slight or absent prodromata, often during the night, the disease sets in rather abruptly with chilly sensations and the temperature rapidly rises to about 104°F. The face is flushed, dusky and swollen, the eyes injected. Very severe frontal and orbital headaches with marked rachialgia of the lumbo-dorsal region are peculiarly characteristic. The pulse is of high tension and the rate from 90 to 110. The systolic pressure is increased—at times as high as 175. These are the early manifestations of the _first or sthenic period_ of the disease.

Vomiting, first of mucus and bile, comes on very early. About the second day albumin appears in the urine and by the 3d or 4th day this is present in large amount and is associated with the presence of hyaline and granular casts. The temperature remains fairly high for three or four days, with morning remissions and evening exacerbations. Of great diagnostic value is _Faget’s law_ as to lack of correlation of temperature and pulse, in that by the 2d day, notwithstanding the high temperature, the pulse rate becomes less and by the 3d or 4th day it has probably decreased 20 to 40 beats from its initial rate.

_Stage of Remission._—About the close of the 3rd day or upon the 4th day there may occur a fall in the temperature and a decided amelioration of the symptoms. This however is frequently not noted and even when present may last only for a few hours. It is often called the _stage of remission or calm_. By the 3d day the congestion of the facies and other sthenic manifestations have disappeared and, possibly preceded by the short period of remission, there is ushered in the _second or asthenic stage_.

_Asthenic Stage._—It is at this time that we have the appearance of the most characteristic features of yellow fever—the jaundice and the haemorrhages. The jaundice is first noted in the sclerotics and rapidly spreads over the body as a lemon to orange yellow tinging. Swelling and bleeding of the gums are the earliest signs of the damage to the capillaries. This may go on to bleeding from the nasal mucosa, the intestines and, best known and most dreaded, the coffee ground vomiting or black vomit of gastric haemorrhage. Epigastric tenderness is often marked. In very severe cases haemorrhagic extravasation into the skin may appear. The mind is peculiarly clear, the patient alert and suspicious. At times patients may be delirious even to the extent of wild struggling to throw themselves out of bed.

In favorable cases the temperature rapidly falls to normal, associated with an unusually slow pulse rate, even below 45.

In the first few days there is a normal white count, with an increase in the percentage of the polymorphonuclears and later on an increase in the large mononuclears.

[Illustration: FIG. 46.—Temperature chart from one of the experimental yellow fever cases reported by the U. S. Army Yellow Fever Commission. A severe case with recovery.]

Besides the typical course we may have cases so mild that the albuminuria is insignificant and the jaundice and haemorrhages entirely absent. On the other hand we may have fulminating cases with jaundice and black vomit setting in by the end of the 3rd day and rapidly going on to a fatal termination.

=Symptoms in Detail=

_The Temperature._—This rises abruptly, reaching its maximum by the 1st day. Very high temperatures are not a feature of yellow fever. There is nothing characteristic in the further course of the fever chart and it should be borne in mind that the so-called intermission is transient and deceitful.

_General Appearance._—On the 1st day the face is swollen and congested. This florid congestion, which may extend down the neck to the upper part of the chest, is more marked in yellow fever than in any other disease. The eyes are shining, the conjunctivae injected and there is photophobia.

About the end of the 2d day the facial congestion disappears to be succeeded by an earthy tinging and subicteroid tinting of the conjunctivae. The jaundice does not appear until about the fourth day. This may be noted somewhat earlier if one blanches the skin by pressure with a glass slide. Petechial eruptions may be prominent in the later stages. The jaundice is best seen at a distance of 5 to 6 feet.

_The Circulatory System._—Of peculiar value in diagnosis is _Faget’s law_—a falling pulse rate with constant temperature or a constant pulse rate with a rising temperature.

A markedly slow pulse, between 40 and 50, is often recorded about the time of the period of remission.

It is interesting to note that the pulse of yellow fever made a great impression upon Benjamin Rush, who called it the indescribable or sulky pulse. The systolic blood pressure is high at first, but by the 2d day begins to fall, becoming quite low in the asthenic stage (even below 70 mm.) due probably to supra-renal involvement rather than to cardiac weakness.

Haemorrhages, especially from gums, nose and intestines, are common. Black vomit is the best known of these haemorrhages.

_Blood Examination._—This has generally been considered as varying but slightly from normal findings.

Noc states that in the first stages of the disease there is an increase of the polymorphonuclear percentage with a marked diminution or disappearance of eosinophiles while later on, from the 3d to the 6th day, there is an increase in the large mononuclears.

_The Alimentary Tract._—The tongue may be coated in the center. Vomiting often appears early and consists of whitish or bile-stained mucus. It must be remembered that if black vomit should appear it almost never comes on before the 4th day. There is usually marked epigastric tenderness. Bleeding from the gums and intestinal canal are not rare.

_The Nervous System._—The mind is unusually clear, the patient often mentally alert and suspicious. There is often insomnia. The severe cephalalgia, often frontal or supraorbital, as well as the severe loin pains (_coup de barre_) are striking features. There may be a marked hyperaesthesia. A delirious state may be present.

_The Liver and Spleen._—There is no special alteration in the size of either liver or spleen. There may be tenderness about the liver region. The jaundice of the asthenic stage is incident to the pressure of the swollen degenerating liver cells on the bile capillaries while the fatal issue is connected with the loss of the urea formation function. It has been claimed that an acidosis may occur. The spleen is not affected.

_The Genito-urinary System._—Albuminuria begins to appear about the second day and tends steadily to increase in amount. Various types of tube casts, often bile-stained, are abundant. The urine shows neither bile nor blood cells except in the later stages of the disease. The reaction is very acid. It is of the utmost importance to note the quantity of urine voided, as scanty secretion, leading to anuria, makes for a very grave prognosis.

DIAGNOSIS

The main points to consider in the diagnosis are: (1) the facies, (2) the severe cephalalgia and rachialgia, (3) the early albuminuria, (4) the epigastric tenderness, (5) Faget’s law of lack of correlation between pulse and temperature, (6) the absence of clouding of the consciousness, and finally the late appearance of the jaundice and haemorrhages.

Of the greatest importance is the history of the case as to recent whereabouts and associates. Also careful questioning as to prior attacks of jaundice or albuminuria related to hepatic or renal diseases. Influenza in its sudden onset and fever and pains has much in common with yellow fever. Weil’s disease is much like yellow fever.

The diseases with which yellow fever is most apt to be confused are:

_Aestivo-autumnal Malaria._—In ordinary aestivo-autumnal malarial paroxysms the search for the malarial parasite is of great importance, although the finding of a malarial infection does not exclude yellow fever. Albuminuria is not a feature of tropical malaria.

In that type of tropical malaria known as bilious remittent fever the clinical picture is rather asthenic and bile pigment in the urine is an early feature. Again jaundice comes on fairly early and the slow pulse is absent. The spleen is enlarged and tender.

_Blackwater Fever._—This is an asthenic disease with marked and very early jaundice. The haemoglobinuria (Blackwater) is pathognomonic. Splenic tenderness is marked.

_Smallpox._—The early headache, backache and vomiting of smallpox may well confuse one before the eruption of variola appears.

_Dengue._—This is probably the most difficult disease to diagnose from yellow fever. The facies, orbital pains and backache of yellow fever and dengue are similar. Dengue also shows a slowing of the pulse. The high blood pressure of the onset is not present in dengue. There is no albuminuria in dengue and there is a marked and early leukopenia with reduction of the polymorphonuclear percentage, which does not exist in yellow fever. The jaundice of yellow fever and the eruption of dengue do not show themselves until after the first three days.

Relapsing fever, typhus fever and plague have been considered by some authorities as possible of confusion with yellow fever.

_Bilious Typhoid of Egypt._—In 1851 Griesinger described a disease he called bilious typhoid of Egypt in which there was a sudden onset with marked chill and rise of temperature in four or five hours to 103° or 104°F. Rachialgia and bilious vomiting were marked. There was splenic enlargement. The temperature fell on the fourth or fifth day with at about this time the appearance of icterus. Relapses were the rule and the mortality was very high.

Bone pains, especially about the knee, were common and severe. This disease is now considered a relapsing fever. It is this disease which affected the troops of Napoleon in Egypt and which was thought by some authorities to have been yellow fever. Others think it may have been epidemic jaundice.

PROGNOSIS

This is bad with advancing years and possible lesions of liver or kidneys. It is difficult to make a statement as to the average mortality. Thus, in the epidemic of 1853, one of the most virulent that ever visited New Orleans, the mortality was estimated at 85%, while that of 1897, one of the mildest epidemics on record, only gave a mortality of ½%.

As a general rule the earlier in the year an epidemic starts the more virulent the disease; thus the 1853 epidemic, just referred to, started in May.

High temperatures and excessive albuminuria, as well as early appearance of jaundice, are bad signs. The mortality may be considered as averaging about 20%.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—By screening a patient during the first three days of the disease we prevent the infection of _Stegomyia_ (_Aedes_).

It must be remembered that this mosquito not only breeds near human habitations but that it tends to remain in the same room where it has been feeding. Consequently we should use sulphur fumigations or Giemsa’s spray or killing by hand to destroy insects. The larvae breed by preference in old tin cans near the house door. To kill these one should empty every old receptacle of water, and oil or cover other collections of water.

All receptacles used for collecting and storing water draining from roofs should be carefully screened with fine copper wire gauze. Of

## particular importance is it to treat every suspicious case as it if

were one of yellow fever and screen the patient as well as destroy any mosquitoes in the room or house occupied by such patient.

Noguchi reports success in prophylaxis by the injection of 2 cc. of a killed culture of _Leptospira icteroides_. Immunity is not conferred until after the tenth day. He notes that among 3607 persons vaccinated in Salvador there were no cases of yellow fever while among the unvaccinated 181 cases occurred. Killed cultures of _Leptospira icteroides_ were first used for protective inoculation in 1918 when 427 vaccinations were carried out.

=Treatment.=—At the onset one should give calomel in small doses, repeated every twenty minutes, until about 2 grains are taken, as 8 doses of ¼ grain calomel with soda. Magnesium citrate or sodium phosphate should follow the calomel. Some prefer castor oil in large doses (2 ounces). This treatment should not be repeated, it is only indicated at the onset of the disease, so that if the case is not seen until after the second day the laxative or purgative measures should be withheld.

During the first three days of the disease no nourishment whatever should be given. The patient should be allowed an abundance of fluid, of which the best is Vichy, of which may be given a couple of ounces every twenty minutes or so, iced or just cool, as the patient prefers. Water, to which 30 grains of bicarbonate of soda to the pint has been added, makes a good substitute. It is of vital importance to put the patient to bed and keep him quiet. When vomiting is severe cracked ice or iced champagne may be of value. Alkaline enemata are indicated when the patient cannot retain the Vichy. There would seem to be an acidosis in yellow fever.

A mustard foot bath is best given in bed, the feet and legs of the prone patient being immersed in a foot tub half full of warm water into which a pound of freshly ground mustard has been stirred. Every few minutes there should be added a quart of very hot water so that the bath may be very hot—just short of burning the feet. The blankets are kept over the patient and the foot tub, so that we also give a vapor bath which causes free sweating. This treatment relieves the headache and backache. This foot bath can be repeated 2 or 3 times in the first twenty-four hours. After the bath, the sweating patient must be thoroughly dried. Cold spongings are important means of keeping down fever. For anuria use dry cups to the loins or hot fomentations. Strychnine may be indicated in the asthenic stage and camphor in oil hypodermically for extreme cardiac weakness. The Sternberg treatment is 150 grains of sodium bicarbonate and ⅓ grain of bichloride of mercury in a quart of water. The dose is 1½ ounces every hour.

Any exertion causing a rise in blood pressure may be fatal. It is possible that the stimulation of the circulation incident to the taking of food may explain the dangers of allowing food to a patient. As before stated no food should be given for the first two or three days. Then commence with albumin water and thin barley gruel. Later on wine jelly and easily digestible broths. Even when convalescence sets in we should be very careful as to diet.

Noguchi has produced an immune serum to his spirochaete by injecting horses. He has records of 170 cases of yellow fever treated with this serum with a mortality of 13.6%, while untreated cases gave a death rate of 52%. He notes that the serum must be given before the third day of the disease to be of any value—best results in the first day. He believes also that though salvarsan and neosalvarsan have some leptospiricidal action they are both too damaging to the kidney to supplant serum in treatment.

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