IV. THE TROPICAL RELAPSING FEVERS
DEFINITION AND SYNONYMS
=Definition.=—There is a group of tropical fevers more or less identical clinically with European relapsing fever and caused by spirochaetes closely allied to Spironema recurrentis (Spirillum obermeieri). It seems probable that the relapsing fevers of East and West Africa are caused by a single species, S. duttoni, which is transmitted by a tick, Ornithodoros moubata, while that of Northern Africa is caused by another species, S. berbera, which is transmitted by lice, either Pediculus vestimenti or Pediculus capitis. Another species of spirochaete, S. carteri, is supposed to cause the relapsing fever of India and it seems probable that its transmission is brought about by infected lice.
Besides the above species of spirochaetes others have been reported, as S. novyi for American and S. persica for Persian relapsing fever. The view taken by Nuttall, that these various names may be of convenience in the study of relapsing fevers but that there is no adequate morphological difference to justify them as species, seems worthy of acceptance. It has been shown that the separation of these spirochaetes on the basis of susceptibility of laboratory animals and cross immunity reactions is untenable. Agglutination of certain strains by their specific sera, however, is a reliable means of separation. As with European relapsing fever, these fevers are characterized by a sudden onset, intense frontal headache, and pain of back and limbs. This fever remains high for three to five days and falls by crisis, to be succeeded by an apyrexial interval of approximately one week. There may be several of these alternating febrile and afebrile periods. The spirochaetes are in the peripheral circulation during the febrile period but not in the afebrile one. The spleen is enlarged and tender. Cases showing jaundice seem more grave.
=Synonyms.=—Febris recurrens. Tick fever. French: Typhus recurrent. German: Rückfallfieber.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—Although Hippocrates described the clinical features of relapsing fever quite accurately this knowledge seems to have been lost until about the eighteenth century.
The causative spirochaetes were first seen by Obermeier in the blood of a patient in 1868 but he did not publish his discovery until 1873.
Ross and Milne, in 1904, found that African tick fever was a spirillar fever while Dutton and Todd established the fact of its transmission by ticks.
=Geographical Distribution.=—Relapsing fever was epidemic in the U. S. in 1869, since which time it has not reappeared. There have been many epidemics in Ireland, Russia, Turkey and other parts of Europe. It was a disease of importance during the Balkan War of 1912-1913. China and India have frequently been visited by epidemics as well as the Philippine Islands and the Dutch East Indies. Uganda, Congo State and German East Africa, as well as Egypt and Algeria, are important centers. There is also a relapsing fever of Colombia and Central America.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—Relapsing fevers are caused by organisms generally considered as protozoal in their nature and belonging to the flagellates.
Transmission by the tick.—The generic name Spiroschaudinnia is preferred by some to the more commonly accepted Spirochaeta. Recently, authorities give these organisms the name Spironema. East and West African relapsing fever, or tick fever, is caused by Spironema duttoni and the transmission is through the bite of an argasine tick, Ornithodoros moubata. Not only does the tick itself become infected by the taking in of blood-containing spirochaetes but likewise transmits the infection to its progeny. Leishman considers that when the spirochaetes are taken into the alimentary tract of the tick there is a breaking up of the spirochaetes into small granules which reach the Malpighian tubules. They also invade the ovary and the ova. It was thought that these granules were the infecting agents and that they were excreted in the fluid of the coxal glands or passed out with the faeces. More recently it has been claimed that these granules have no relation to the infection, which is due to spirochaetes as such.
It may be stated that spirochaetes as such may be found in the secretion of the coxal glands as well as in the faeces. This coxal fluid dilutes the thick faeces and makes an emulsion which is smeared out by the body of the tick in the area of the bite puncture.
At any rate this infection of man seems to be the contamination method, the material from faeces and coxal glands being rubbed into the wound made by the tick-bite. The ticks hide in the cracks about the old native huts and bite the sleeping inmates. There may be quite a local reaction at the site of the bite. Spironema duttoni has been cultured by Noguchi, by utilizing his methods for culturing the organism of syphilis. In such cultures he has noted longitudinal division rather than transverse, this fact rather favoring a protozoal as against a bacterial nature. This spirochaete is from 24-30 microns long, about 0.45 micron broad and has a corkscrew motility. It is readily transmissible to a number of laboratory animals, as monkeys, white rats, etc. The spirochaete of Northern African relapsing fever, S. berbera, causes the disease as seen in North Africa and Egypt. It is transmitted by lice, Nicolle and others having shown that the spirochaetes make their way from the alimentary tract to the body cavity of the louse. They have shown that the bite alone of an infected louse is innocuous and also that the faeces are non-infective, when injected into monkeys. Emulsions of infected lice, however, when rubbed into wounds, produce the disease in monkeys.
Transmission by the Louse.—The spirochaetes taken in by a louse disappear in a few hours and the insect remains harmless until about the fifth day, when it becomes infectious, and so remains until the twelfth to fifteenth day. Spirochaetes reappear in the coelomic fluid of the louse about the sixth day and continue present until about the twentieth day.
A striking fact is that infection can be brought about a day before spirochaetes appear and that after a period of a few days these spirochaete-containing lice lose their power to infect. It would seem that the infecting stage was an invisible one. Have we then a symbiosis between a spirochaete and an invisible virus, possibly filterable? Wolbach has shown that certain spirochaetes will pass through a Berkefeld filter as spirochaetes but this would not affect the possibility of the existence of some granule or chlamydozoal stage. It may be that the infecting stage is not an invisible one but a granule one.
Mode of Infection.—It is by crushing the louse, by scratching or otherwise, that the spirochaetes contained in the coelomic fluid reach and penetrate the wound of the bite. This is therefore a contaminative method of infection. Mackie has shown that the Indian relapsing fever, which is caused by S. carteri, is probably transmitted by the louse, and it is probable that the conditions under which the infection takes place are similar to those occurring with S. berbera infections. With the European relapsing fever, bedbugs may possibly act as transmitting agents. The probabilities however are that this infection is transmitted by lice alone.
A relapsing fever of Persia is transmitted by a tick of the genus Ornithodoros, which is also true for the relapsing fever of Panama. There is great variation in the description of the different spirochaetes, and frequently measurements are given for short forms and long forms. They also vary from wave-like lines to corkscrew spirals. Again, different species have different types and different activities of movement. As a rule they are about 20 × 0.4 microns. The spirochaetes of the relapsing fever of Panama varied in length from 4.6µ to 22µ. Of these the most common were those measuring 13µ. Transverse division of the longest forms was seen in dark-field preparations. The monkey is susceptible to all species of relapsing fever spirochaetes. White mice and white rats are readily infected by S. duttoni and the Panama spirochaete but are refractory to S. recurrentis except after passage through monkeys. S. carteri causes only a transient infection in these small rodents.
=Epidemiology.=—With tick fever the epidemiology rests upon the life history of the tick O. moubata. This tick infests the rest houses along the route of travel, hiding in the crevices of floors and walls during the day and coming out at night to bite the sleeping inmates. The feeding occupies a long time, more than an hour. Both sexes bite man. The female lays about 100 eggs, from which nymphs emerge in about twenty days. The larval stage takes place in the egg. Shortly after emerging the nymphs suck blood. An important fact is that the female transmits the spirochaete to its ova, so that the ticks from such ova may transmit the disease.
Natives seem to suffer severely from tick fever in childhood but in adult life possess a sufficient degree of immunity so that the disease shows itself in a very mild form in those harboring spirochaetes.
The immunity conferred by an attack is not lasting and a second infection may occur within a year. Such second attacks, however, do not present the relapses so important in a clinical diagnosis. As a matter of fact there may be no symptoms and such cases with spirochaetes in their blood make ideal carriers for the infection of ticks or lice. Ticks can be infected by these carriers. In some of the rest houses 50% of the ticks may be infected. While the tick does not tend to leave its habitation it may be transported in the bundles of native porters. The transmitting agent of the North African relapsing fever and probably of the Indian type is the louse. The body louse deposits about 75 eggs in the clothes of the host, which hatch out in about four days and become adults in about two weeks. The head louse deposits its eggs or nits on the hair of the host’s head. Hagler has noted that, in Servia, typhus fever disappeared when lice were gotten rid of but relapsing fever continued to prevail until they also exterminated the bedbugs.
The Relapsing Fever of Panama.—Bates, Dunn and St. John have demonstrated that a tick, Ornithodoros talaje, transmits the relapsing fever of Panama. This tick seems to prefer the crevices and open joints of bamboo beds, laying its eggs and moulting in the hiding places. It comes out at night to feed on the occupants of the bed. Two white rats were inoculated with an emulsion made from ticks taken from a suspected bed. Both rats developed a spirochaete infection. A man inoculated with blood of one of these rats developed relapsing fever on the sixth day. A second man was inoculated subcutaneously with an emulsion of ticks collected from a bed and showed spirochaetes in his blood on the eleventh day.
Another man was bitten by ticks from the same source and was instructed not to scratch the bite. The ticks engorged in about 15 minutes, some of them secreting coxal fluid which mixed with blood from the bite made a scab. This man was positive for spirochaetes on the fifteenth day.
PATHOLOGY AND MORBID ANATOMY
The spirochaetes disappear from the peripheral circulation during the apyrexial period, notwithstanding which such spirochaete-free blood, when injected into monkeys, may bring about infection. Either a granule stage or an invisible stage of the parasite may be present. The relapse is probably due to the existence of resistant strains which are not destroyed by the lytic substances, developed during the attack.
Agglutinating and lytic substances show themselves chiefly during the apyretic intervals.
The spleen is enlarged and soft. There are frequent infarctions. The spirochaetes are found phagocytized in the macrophages of the spleen and elsewhere. Parenchymatous degeneration of kidney and heart muscle, and especially of liver, may be noted.
SYMPTOMATOLOGY
East and West African Relapsing Fevers.—In African tick fever after a period of incubation of from three to ten days the disease sets in rather suddenly with dizziness, marked headache and general body pains. The temperature quickly rises to 104°-105°F. and remains elevated during this primary febrile period, except for slight morning remissions. Vomiting is quite a feature of this disease and may be bilious in character.
There may be rather marked praecordial oppression and a bronchial catarrh. The pulse in particular and the respiration in less degree are accelerated. Herpes and epistaxis may be noted. The bronchial manifestations seem to occur chiefly in the first febrile accession. The spleen is somewhat enlarged and tender but in many cases this is not noted. Spirochaetes are found in the peripheral circulation during the febrile accessions but not during the apyrexial intervals. There is great variation as to the abundance of spirochaetes. In some cases we may have to search several hundred fields before finding a single spirochaete. Severe cases may show them in abundance. A rather marked leucocytosis may be present in cases showing high fever and bronchitis. After about four days the fever falls by crisis, often below normal, and possibly with great prostration and cardiac weakness.
A critical sweat is a feature of this rapid fall of temperature. During the afebrile period, which lasts from three or four days to eight to ten days, the patient feels much better and his appetite and strength return. With the onset of the second pyrexial wave the severe symptoms of the first days are repeated, as with the first febrile period. This second one terminates by crisis. Iritis is not uncommon. Manson and Thornton have reported transient cranial nerve involvements coming on late in the course of the disease.
In European relapsing fever the second febrile accession is usually shorter and of less severity than the first. Furthermore there are rarely more than 2 or 3 relapses. In tick fever, however, there may be as many as 10 of these febrile recurrences, although there are usually only 4 or 5. In natives there is usually only one febrile period, this probably being due to an immunity resulting from previous infections.
North African Type.—In the relapsing fever of North Africa the attacks are less severe and the number of relapses rarely exceeds three. A fever of Egypt, generally known as the bilious typhoid of Griesinger, is believed to have been a form of relapsing fever. In this there was marked bilious vomiting with great tenderness of the liver, late jaundice, albuminuria, bone pains, especially about the knees, and a high death rate. The symptoms rather suggest yellow fever but this disease has never been reported from Egypt.
Indian Type.—In the relapsing fever of Asia there is a marked tendency for the patient to collapse at the time of the crisis. There are rarely more than two relapses and in probably 25% of cases there is no relapse. There seems to be a greater tendency to liver complications in the Asian types than elsewhere and such cases form a large part of the death rate from this disease. Bilious vomiting and jaundice, with a typhoid-like state and the occurrence of various inflammatory complications, especially parotiditis, are noted. The mind is usually clear, but delirium may be present in severe cases.
Relapsing Fever of Panama.—In three experimental cases the temperature of the first accession varied from 102°F. to 104.5°F. Frontal headache and general body aches were the chief symptoms. Vomiting was noted in one case. The spleen was not enlarged. The first relapse was cut short in each case by arsphenamine.
The Symptoms in Detail
The Temperature Curve.—This is the chief point in the clinical diagnosis of relapsing fever. The onset of the first febrile accession is abrupt and the temperature rapidly rises to 104°F. or higher. After a continued high temperature for three or four days the fever drops by crisis, which is at times productive of collapse. Following an apyrexial period of four to eight days we have a second febrile accession, and there may be several of these wave-like alternations of fever and apyrexia.
The Nervous System.—Very marked frontal headache is a striking feature and the pains in back and limbs may be of great severity. Cranial nerve involvement has been noted. There may be apathy, but on the whole the mind is clear.
The Digestive System.—Anorexia and vomiting are features of the febrile periods to cease in the fever-free periods. In some types bilious vomiting may be marked.
The Circulatory and the Respiratory System.—The pulse rate is much accelerated, and there may be some praecordial distress. A bronchial catarrh is frequently present in the first febrile paroxysm.
The Liver and Spleen.—Splenic tenderness and moderate enlargement are fairly constant features. The liver may suffer severely in the so-called bilious typhoid and marked jaundice may ensue with a typhoid state.
The Blood Examination.—This is the most important point in diagnosis. The spirochaetes, which are only found in the peripheral circulation during fever periods, are not so numerous in tropical relapsing fevers as in the European forms. When spirochaetes are scarce it is more satisfactory to examine Romanowsky-stained specimens, especially with the Giemsa staining. The spirochaetes show a varying number of undulations. There is no chromatin staining in the line of the spirochaetes. The disease when severe shows a well-marked polymorphonuclear leucocytosis, with at times an increase of large mononuclears. This latter, however, may be connected with malaria or amoebiasis.
DIAGNOSIS
The disease most likely to be confused with relapsing fever is malaria and for this differentiation the finding of the parasites of either disease is of first importance.
The blood of a suspected case even during the apyrexial period should be injected into a mouse or white rat (guinea pigs are refractory to infection). Spirochaetes should appear in the blood of the mouse in about twenty-two hours and persist for about two days. Relapses occur but recovery is the rule.
Dengue may be suspected, but the leucopenia, lack of splenic tenderness, lack of tendency to vomiting and presence of post-orbital pains should differentiate. As there is a leucocytosis in both relapsing fevers and smallpox, and similar headache and backache, confusion might exist were the parasites not found.
Yellow fever has many features in common with the bilious type of relapsing fever, but there is no leucocytosis in yellow fever, and there is no characteristic albuminuria and slow pulse in relapsing fever. Influenza has many points in common with relapsing fever.
In a case of relapsing fever with jaundice confusion might arise with Weil’s disease inasmuch as a blood smear might show spirochaete-like organisms.
Typhus fever shows a less abrupt onset and the marked mental symptoms (stupor) and dark macular eruptions about the trunk, on the 4th to 6th day, should differentiate. If the case is first seen in the apyrexial period one may take a drop of blood from a case showing spirochaetes and one from the suspected patient. After incubation for thirty minutes the spirochaetes should lose motility and agglutinate if the case be one of relapsing fever (Lowenthal’s Reaction).
In blood examinations we may use the dark-field illumination, although the spirochaetes stain readily with Wright’s stain. The India ink method is a good one. Hagler recommends smearing out a mixture of one loopful of blood and a collargol preparation made by diluting one part collargol with two parts water. The diluted collargol should stand 24 hours and be filtered before use.
PROGNOSIS
The mortality is usually given as about 2 to 5% with the exception of the very serious form in which jaundice is present when the death rate may exceed 50%.
A serious feature of the disease is the length of its course, this often extending from six weeks to two months.
Since salvarsan and neosalvarsan have been found to be practically specifics in the treatment of the disease the mortality has been reduced to exceedingly low figures.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The sole question is the avoidance of places infested with ticks, bedbugs and lice. In Africa, the habitations of the natives, where infected ticks may hide themselves in cracks in floors and walls, are to be especially avoided. As the tick feeds at night a night light is of value.
Destruction of the spirochaetes by salvarsan injection is important prophylactically as well as therapeutically—the reservoir of infection for lice or ticks being gotten rid of.
=Treatment.=—We have in salvarsan, or neosalvarsan, a specific. The drug should be given so soon as the spirochaetes are found—in the period of onset of the fever. If given at the end of the fever it may intensify the critical manifestations, especially collapse. Unless given early it does not abort the relapse. Neosalvarsan, being less toxic, is better adapted to the treatment of the icteric type of the disease. Atoxyl has practically no value in treatment and the same is true of antimony.
Conseil has treated cases with galyl and ludyl, in doses of 4 to 7 grains, with results as good or better than with salvarsan. The pains in the head and back are relieved by aspirin, although a hypodermic of morphine may be necessitated. Cool sponging and fresh-air treatment are desirable. On the whole, treatment, other than the specific one, is symptomatic.
Administration of the Arsphenamines.—Although arsphenamine (salvarsan) is probably the drug of choice when immediate therapeutic effect is desired, neo-arsphenamine is more popular because it is more simply prepared and administered, is tolerated better by the patient and has a slightly higher therapeutic index. It is, however, less stable, and both the powder and its solutions should be inspected carefully for signs of decomposition, namely, a darkening in color, a strong odor, and insolubility. Ampules containing either drug should be immersed in 95% alcohol for 15 minutes in order to detect any crack. Should a breach be found, or suspected, the ampule should be rejected.
Myocarditis, advanced non-syphilitic renal or hepatic disease, advanced arteriosclerosis and Addison’s Disease are regarded as generally contra-indicating the employment of these drugs. Cases in which the syphilis is of long standing should receive mercurials for at least a week prior to the first injection of arsenic, in order to avoid the possibility of activating lesions in vital organs (Herxheimer), and should be closely questioned regarding the occurrence of symptoms following previous injections (idiosyncrasy).
Prior to each injection, a patient should have a complete uranalysis, receive a cathartic on the evening preceding, and be allowed only liquids for the meal preceding. Subsequently to the injection, he should be allowed only liquids for the succeeding meal, and be retained under observation for at least twelve hours. Untoward symptoms following the injection are treated usually with epinephrin solution (0.6 to 1.2 cc.) or atropin.
Arsphenamines are administered intravenously, usually in the median cephalic or the median basilic vein at the bend of the elbow. This method requires aseptic technic throughout. All apparatus should be thoroughly washed before sterilization, since it is believed that symptoms may arise from substances extracted from glassware and rubber tubing. The water used must be distilled, preferably twice, and freshly boiled. The dose of arsphenamine is 0.3 to 0.6 gm., that of neo-arsphenamine is 0.3 to 0.9 gm. Until tolerance is ascertained, the dose should be small and not repeated in less than a week.
NEO-ARSPHENAMINE
1. Only a single ampule should be dissolved at a time. The powder should be dusted over the surface of a small portion of the water and permitted to dissolve without agitation. The solution is then made up to bulk. Specimens which do not dissolve readily are to be rejected.
2. Cold water only is to be used.
3. The solution should not be stronger than 0.1 gm. of the drug in 2 cc. of water.
4. A very small needle should be used, and the time of the injection should not be less than five minutes.
ARSPHENAMINE
1. Cold Water Should be Used in all Cases.—(Exception. “Arsenobenzol” requires hot water. Consult instructions issued by individual manufacturers for possible departures from these directions.)
2. Neutralization and Alkalinization of the Solution.—With a graduated pipette or burette add 0.9 cc. of normal NaOH, standardized against normal acid, for each 0.1 gm. of the drug. The alkali should be added all at once, the amount specified being slightly in excess of that required to redissolve the flocculent precipitate first formed.
3. Concentration of the Drug.—It is important that the concentration of the drug is not greater than 0.1 gm. to 30 cc., i.e., 180 cc. of water for the usual dose of 0.6 gm.
4. Method of Injection.—The gravity method only should be employed. When several patients are to be injected from the same solution, the container for the solution should be graduated. A glass stopcock is of value in controlling the flow of solution, but in its absence the rate of injection can be governed by the elevation of the fluid and by the size of the needle. A needle of 18 or 20 B. & S. gauge is best.
5. Rate of Injection.—Operators should pay particular attention to the rate of administration since it is believed that rapidity of injection accounts for more unfavorable results in the use of arsphenamine than any other one thing. In no case should the rate exceed 0.1 gm. of drug (30 cc. of solution) in two minutes, i.e., twelve minutes for the average dose of 0.6 gm.
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.
=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.
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.
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.
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.
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.
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.
VI. INFECTIOUS JAUNDICE
DEFINITION AND SYNONYMS
=Definition.=—Infectious jaundice is a spirochaete infection, caused by Leptospira icterohaemorrhagiae. This spirochaete is a common parasite of rats in various parts of the world and man possibly receives his infection from this source. There is a sudden onset with rather high fever, headache and vomiting. The jaundice appears about the third or fourth day when the urine shows albumin and bile. Haemorrhages, especially epistaxis, are common and the liver rather than the spleen shows enlargement. A polymorphonuclear increase is a feature.
=Synonyms.=—Epidemic jaundice. Spirochaetosis icterohaemorrhagica. Typhus bilieux. Weil’s disease.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—This disease was probably the form of jaundice noted in the forces of Napoleon during the Egyptian campaign. It was first recognized as a distinct disease by Weil, in 1886, who described it as a peculiar form of acute infectious disease characterized by jaundice, swelling of spleen and nephritis. Inada and his Japanese colleagues discovered the causative spirochaete in 1915 and noted the frequency of this parasite in rats. Infectious jaundice was an important disease of the soldiers of the recent war.
=Geographical Distribution.=—Japan and Egypt may be considered as the parts of the world in which the disease is most common. It is endemic in West Africa and cases have frequently been reported from the shores of the Mediterranean.
During the Russo-Turkish war (1877) cases of jaundice seen in the Balkans by Sandwith were probably infectious jaundice as the disease was frequently noted in that region during the recent war. Cases were noted in Flanders during the war. A few cases have been reported from the United States.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—The spirochaete causing infectious jaundice, Leptospira icterohaemorrhagiae, is the type species of a genus described by Noguchi as having minute elementary spirals running throughout the body and failing to show either flagella or undulating membrane. The caudal portion of the spirochaete is remarkably flexible and when in motion the whole body seems drawn into a straight line except for the hook formation of one or both terminal portions. Propulsion seems to occur by the rotary motion of the hook and progresses in the direction of the straight end. If both ends become curved progression ceases.
It is insoluble in 10% saponin thus differing from the other blood spirochaetes. The constituent spirals are closely placed and the total length may reach 15 to 20 microns. The dark-field illumination is preferable for its demonstration although it shows up well by various staining methods. To culture use a medium of one part of rabbit’s serum with three parts of Ringer’s solution inoculating with citrated plasma. The organism is found in the blood during the first three or four days of the disease. It is also present in the urine. Young guinea pigs are particularly susceptible and in them we have, following injection of the blood of a case, jaundice, albuminuria and haemorrhages. At autopsy the spirochaetes are best demonstrated in a liver emulsion. Infection with this spirochaete is common among rats in various parts of the world so that it may be considered a natural infection of rats, but they do not seem to suffer from it.
=Epidemiology.=—It is considered that the infection is transmitted through the urine of infected rats or men. The spirochaetes may gain entrance through the skin or by mouth. The fact that the spirochaetes seem to die in urine within 24 hours makes infection by the contaminated urine questionable but experiments with various arthropods have failed to indicate their connection with the transmission of the disease.
In Japan it has been noted that the disease is most common in wet mines, disappearing when the mines are pumped dry. Before we knew the cause of the disease attention was directed to the connection between the infection and working about defective sewers. Trench warfare, with the accompanying rats and wet conditions, seemed to favor infection.
PATHOLOGY
The liver shows enlargement and fatty degeneration, but less marked than in yellow fever. The organisms are found in the liver and also in the kidneys, which latter show an intertubular congestion together with haemorrhages in this region. Haemorrhagic areas may be present in various portions of the alimentary tract and elsewhere.
SYMPTOMATOLOGY
After an incubation period of from 5 to 7 days the disease sets in abruptly with rigors, headache, muscular pains and vomiting. The patient is prostrated and has the appearance of extreme illness; the face flushed and the conjunctivae injected. There is fever of an irregular type usually running between 102° to 104°F. for the first three or four days, when it begins to fall by lysis although occasionally by crisis about the fifth day. Following a few days of moderate fever or normal temperature there is a tendency for a second rise toward the end of the second week, which continues for approximately another week when a slow convalescence sets in in favorable cases. The secondary fever shows rather marked oscillations.
Jaundice appears about the third or fourth day with marked tenderness of the liver and slight or moderate enlargement of the spleen. The urine is scanty and high colored showing albumin and bile pigments. Early in the second week urine of a low specific gravity is excreted in large amounts. The pulse is rapid at first to become slow with the appearance of the jaundice. There is a tendency to sleeplessness and nocturnal delirium and in unfavorable cases the “typhoid state” comes on. Pains in the nape of the neck and calf muscles are common features.
Haemorrhages, starting as epistaxis, are commonly observed. Next to epistaxis intestinal haemorrhage is the most frequent. Haematuria is rarely observed. The red cells and the haemoglobin fall in percentage with an increase in the polymorphonuclears. The leucocytosis runs about 15,000.
The spirochaetes may be found with the dark-field illumination early in the disease in a blood examination and later on in the urine.
DIAGNOSIS
It must be remembered that the causative spirochaete is very scarce in the blood of this disease which is usually not the case with relapsing fever showing jaundice. It is best to inject 2 to 4 cc. of blood into young guinea pigs intraperitoneally and after the development of the infection in the animal we find the spirochaetes rather abundantly in preparations made from liver emulsions and examined with dark-field illumination. Noguchi cultured the organism from the blood early in the disease but found it difficult. Wataguchi states that when the blood is simply diluted with water and kept at a temperature of about 25°C. growth may be obtained by the fourth day, reaching a maximum by the second week.
Agglutinins appear in the blood about the end of the first week and cultures may be agglutinated by such serum diluted as high as 1 to 500.
Bilious remittent fever shows earlier jaundice, a more rapid pulse rate and malarial parasites.
In yellow fever there is more marked rachialgia and earlier and more marked albuminuria. The marked leucocytosis of Weil’s disease should be of differentiating value.
The early jaundice and haemoglobinuria of blackwater fever should distinguish this disease.
Prophylaxis and Treatment
=Prophylaxis.=—As the infection appears to be transmitted through the medium of the urine and faeces, sterilization of these discharges from those sick with the disease should be practised. Extermination of the rat, the host of the parasite, is the important method of eradication of the disease.
=Treatment.=—This would appear to be solely symptomatic. Arsphenamine has no effect on the infection. Hexamethylenamine has been recommended. A serum against the organism has been prepared and seems to show protective value.
VII. RAT BITE FEVER
DEFINITION
Rat bite fever is a relapsing type of fever following the bite of rats infected with Leptospira morsus-muris, which brings about the infection of man with this spirochaete. Following the healing of the wound we have developing in the cicatrix inflammatory signs with lymphangitis and swelling of the tributary lymphatic glands. The onset is sudden with rigors and fever, which latter continues for several days to then fall to normal and after an apyrexial period to be followed by relapse. Numerous relapses follow during the following weeks, months or even years of the disease. In Japan the disease is known by the name of Sodoku.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—In a study of this disease Futaki and others discovered a spirochaete in the tissues of the bite area and the adjacent lymphatic glands (1915). These spirochaetes were about 10 microns long. In the blood of man and infected animals shorter and thicker spirochaetes are found (3 to 6 microns). When cultivated in the media used for other Leptospira we have longer forms up to about 20 microns. The shorter forms are considered as young organisms.
Leptospira morsus-muris is found in the blood of infected mice, rats or guinea pigs during the first two weeks and then becomes distributed in the connective tissues especially that of the lips, bridge of nose and tongue. They are not secreted in the saliva but the transfer seems to occur by a break in the spirochaete-containing tissues and thus inoculated into the bite wound. The organism may possibly be excreted in the urine.
=Epidemiology.=—It has been found that about 3% of house-rats in Japan are carriers of the disease. It is less frequent in other countries although reported from various European countries, America and especially China. The disease has also been reported from Australia. It seems probable that the construction of the Japanese houses gives greater opportunity for the occurrence of bites of rats than elsewhere.
PATHOLOGY
In infected guinea pigs there is swelling of the lymphatic glands and the spleen with the presence of spirochaetes. The liver is congested and may show a few spirochaetes. In human autopsies there are degenerative changes in the liver and kidneys. The infection is rarely fatal in experimental animals although it causes about a 10% mortality in man.
SYMPTOMATOLOGY
Following a rather long incubation period of from six to eight weeks, although cases have been reported where not more than two weeks had elapsed from the time of injury, during which time the wound of the rat bite heals, we have a rather sudden onset with headache, nausea and marked weakness. The cicatrix now becomes inflamed and the surrounding tissues show oedema and at times vesicle formation. Leading from the inflamed areas is a line of tender lymphatics which extend to a group of swollen lymphatic glands.
The onset is often characterized by chills and malaise. A rapid pulse and prostration are present during the pyrexial period.
The fever rises rapidly to 101°F. or 102°F. and within two or three days has reached about 104°F. and remains high for two or three more days. About this time it falls rapidly to normal, attended with profuse sweating. The temperature remains normal for a few days, during which time the local swelling and inflammation subside. An eruption of purplish spots may accompany the fever, appearing chiefly on chest and arms. There may be urticarial lesions. Joint pains, together with motor and sensory disturbances, may be noted.
Symptoms of nephritis may appear.
After the critical fall of temperature there is usually an apyrexial period of several days during which time the local manifestations about wound and glands subside. The fever again comes on, to later disappear and reappear.
The successive paroxysms are usually of less severity.
The fever is suggestive of the relapsing fevers. The pulse is rapid and weak. There may be as many as twelve of these febrile accessions and the course of the disease may extend over several months. There is an eosinophilia and during the febrile paroxysm a leucocytosis of about 15,000. The spirochaetes should be looked for in the blood during the early febrile periods. The dark-field illumination is the best method for their demonstration.
TREATMENT
Treatment is entirely symptomatic. Some success seems to have followed the administration of salvarsan.
Strychnine for the heart weakness and tonics during convalescence are recommended.
Aspirin is often necessary to relieve the headache and joint pains.
As prophylactic measures the same precaution should be taken as to cauterization of the wound as one would observe in rabies.
VIII. THE LEISHMANIASES
DEFINITION AND SYNONYMS
=Definition.=—Under this designation we group three diseases, two of which are general infections and one a cutaneous affection. It is now thought that the visceral leishmaniasis of adults or Indian kala-azar and that of young children or infantile kala-azar are one and the same disease. The cutaneous leishmaniasis of the Near East or oriental sore and the various leishmania ulcerations of tropical America are grouped with the others solely by reason of their cause, this being a protozoon of the same genus, Leishmania tropica for the skin leishmaniases, and L. donovani for the visceral ones. Most authorities assign to infantile kala-azar a distinct species, L. infantum.
The visceral leishmaniases are characterized by a chronic course, marked splenic enlargement, progressive anaemia and emaciation together with leucopenia. The cutaneous leishmaniases can only surely be differentiated from other tropical sores by the finding of the leishman bodies from smears made from the granulomatous tissue of the sore.
=Synonyms.=—Dum-Dum Fever, Tropical Splenomegaly (for Indian Kala-azar), Splenic Anaemia of Infants, Ponos (for infantile kala-azar), Oriental Sore, Biskra Button, Bagdad Boil, Bouton d’Orient, Aleppo Boil, Granuloma Endemicum (for the Eastern cutaneous leishmaniasis), Espundia, Bubas Braziliana, Uta, Forest Yaws (for the American cutaneous leishmaniasis).
GENERAL CONSIDERATIONS OF HISTORY, ETIOLOGY AND RELATIONSHIP
=History.=—In 1869 the English medical authorities in India became familiar with a very fatal disease among the natives of Assam but regarded it as a very malignant form of malaria. The native designation for the disease was kala-azar. In 1889 Giles investigated this disease and finding hookworm ova in almost all of the cases he came to the conclusion that it was ancylostomiasis.
Rogers (1896) and Ross (1898) after studying the disease were of the opinion that it had to do with malaria, the former regarding it as a malignant form of malaria and the latter that it was malaria plus some secondary infection.
Owing to the very similar temperature charts and misled by agglutination tests of the serum of kala-azar patients, which he regarded as showing agglutinins for the Micrococcus melitensis, Bently, in 1902, claimed that kala-azar was a malignant form of Malta fever.
In 1903 Manson suggested that the disease might be caused by a trypanosome, the absence of malarial parasites and non-response to quinine being against the then usually accepted malarial etiology.
A few months later in the same year, May, 1903, Leishman reported findings which he considered as degenerated trypanosomes in the spleen pulp of a soldier who died in 1900 at Netley Hospital of dum-dum fever. Although first noting the peculiar bodies in 1900, at the time of making the autopsy, he was at a loss to explain their significance but in 1903, while examining a trypanosome-infected rat, he came to the conclusion that there was a similarity in the parasites of the two infections and published his paper entitled “On the possibility of the occurrence of trypanosomiasis in India.”
In July, 1903, Donovan reported the finding of similar parasites in material from splenic puncture of cases of dum-dum fever and taken during life.
There was much discussion as to the true nature of these leishman, or leishman-donovan bodies, Laveran regarding them as piroplasms while others thought them to be trypanosomes.
In 1904 Rogers succeeded in cultivating these parasites in citrated salt solution and noted that the cultural forms were those of flagellates. In 1903, Wright, of Boston, found similar parasites in the granulation tissue of a tropical ulcer in a little Armenian girl.
In 1905, Pianese found leishman bodies in smears from liver and spleen of children dying with infantile splenic anaemia in Italy. About the same time Laveran in examining spleen smears made by Cathoire from an infant dying of an undetermined disease in Tunis found these bodies. Later investigations have shown this infantile leishmaniasis to be rather prevalent in the Northern part of Africa and Southern part of Europe.
Quite recently it has been determined that not only is the classical oriental sore a form of leishmaniasis but, as well, certain skin ulcerations found in South and Central America, such as espundia and uta in Peru, bubas in Brazil and forest yaws in the Guianas.
=Etiology.=—The parasites which cause a general infection in kala-azar and leishmania infantile splenic anaemia but a local one in oriental sore are usually separated as distinct species, Leishmania donovani for kala-azar, L. infantum for infantile splenic anaemia and L. tropica for oriental sore.
These parasites are grouped with the haemoflagellates and occur in their vertebrate hosts exclusively as small, oval, cockle-shell-shaped bodies, measuring 2.5 × 3.0 microns. The protoplasm stains a faint blue and contains a rather large trophonucleus which is peripherally placed and gives the appearance of the hinge of the cockle shell. Besides this macronucleus we have a second chromatin-staining body which is often rod-shaped and set at a tangent to the larger nuclear structure. It is called the blepharoplast or micronucleus and stains a more intense reddish than the rather fainter stained pinkish macronucleus. One or more vacuoles are common in the cytoplasm.
Some consider these nonflagellated bodies, which are usually found packed in endothelial cells of spleen, liver, lymphatic glands and bone marrow, as resting stages, the flagellate existence occurring in some other host than its vertebrate one. Patton has carried on an immense amount of experimental work with the bedbug and has noted the development of flagellate forms from the 5th to the 8th days in bugs which fed on kala-azar patients showing leishman bodies in their peripheral circulation. If the bugs are allowed a second feeding after the infecting blood meal the flagellates disappear within twelve hours, so that for full development in the bedbug a single feeding is requisite. He states that the flagellate forms change to post-flagellate ones by the twelfth day. At the same time, although much evidence exists in favor of the bedbug as host for the flagellate forms, it has not been shown experimentally that the bedbug is definitely connected with the transmission of the disease.
Donovan is disposed to incriminate Conorhinus rubrifasciatus as the transmitting agent and furthermore he feels that there has not been sufficient investigation of mosquitoes along this line.
Canine Leishmaniasis.—In the regions where leishmaniasis of infants occurs there is also found a similar disease of dogs and Basile has claimed that the disease is transmitted from dog to dog by the dog flea. As the dog has been regarded by some as the reservoir of the virus, so naturally the transmission of the disease from dog to child through the flea has been considered.
Wenyon, however, tried to infect two young dogs with great number of fleas which had previously fed on dogs infected with canine leishmaniasis and at autopsy, five or six weeks later, was unable to find parasites in smears from spleen, liver or bone marrow and did not succeed in obtaining cultures from this material inoculated into tubes of N. N. N. medium.
Basile states that a temperature of 22°C. is necessary for the development of the parasite in the flea and that negative experiments have been due to their not having been conducted in the winter. Patton has had fleas feed on a heavily infected dog, whose peripheral blood showed hundreds of parasites per film. These experiments were made in the winter and although examining 200 of these fleas he failed to find any evidence of the flagellates after eight hours.
Views have been entertained that the canine infection is one with a flea herpetomonad distinct from Leishmania, but as dogs can be infected with L. infantum and then show manifestations similar to canine leishmaniasis the parasites are probably the same.
Patton fed great numbers of fleas on a dog experimentally infected with L. donovani and found that the flagellates had entirely disappeared from the alimentary tract of fleas dissected after eight hours, although fleas dissected within four to six hours showed degenerating Leishmania.
As regards oriental sore Wenyon has found that bedbugs and Stegomyia will feed from the sores and take up parasites which develop into flagellate forms in the gut of the insects.
Proof of transmission by these agents however is lacking and others are inclined to suspect the house fly or some species of moth midge.
In Brazil there exists some evidence that the cutaneous leishmaniasis found there may be transmitted by species of the tabanid family.
It must be understood that there is always a suspicion that the flagellate forms noted in arthropod experiments may be those of nonpathogenic herpetomonad or crithidial species as such forms are common in arthropods and are difficult to distinguish from the flagellate stage of leishman bodies.
Cultural Forms.—Very definite is our knowledge of the cultural forms of Leishmania. Rogers first cultured material from splenic juice of kala-azar patients in 10% sodium citrate solution at a temperature of 17° to 24°C. The medium was slightly acidulated with citric acid. There was no satisfactory development at blood temperature. In forty-eight hours the oval parasites have developed into herpetomonad flagellates, from 20 to 22 microns long by 3½ microns broad, with a 20-micron flagellum which takes origin from the blunt anterior end of the body near the blepharoplast. The peripheral blepharoplast and centrally placed macronucleus are at a distance from one another as opposed to the approximation of the crithidial blepharoplast to the centrally placed nucleus in a body with pointed anterior end.
Formerly it was thought that there were differences in the three species of Leishmania from the standpoint of growth on various culture media, L. donovani not growing on N. N. N. medium while L. infantum grew well on N. N. N. medium but not in citrated blood. It is now known that both species will grow on these two media.
It is absolutely essential in culturing L. donovani or L. infantum that the blood agar or citrated blood be sterile, as any bacterial contamination prevents growth. With the parasite L. tropica, however, bacterial contamination does not inhibit development and statements have even been made that growth is favored by a staphylococcal symbiosis. L. tropica, it would seem, will develop into flagellated forms in cultures at 28°C. while it will be remembered that Rogers in his original experiments failed to obtain other than commencing signs of division at 27°C., 22°C. being the temperature necessary for the development of flagellate forms.
L. tropica from South American cutaneous leishmaniases seems to grow more luxuriantly on N. N. N. medium than does that of oriental sore of Asia and Africa.
Giugni tried N. N. N. media made with human, rabbit and dog blood, respectively. The parasites grew well on dog and rabbit blood media but not on that made with human blood. He found growth best when he added salt in quantity from 5 to 9 grams per liter. When red corpuscles are laked in a medium the growth is less favorable.
While differences in development on different culture media may obtain not only with different species but with different strains of the same species, it would appear that such variations cannot be utilized as a means of separating the three species.
Animal Inoculation.—With animal inoculations we formerly thought that the parasite of kala-azar could be differentiated from that of infantile leishmaniasis by the fact that dogs could not be infected with L. donovani, while they were susceptible to infections with L. infantum. Recently Donovan and Patton have successfully inoculated dogs with kala-azar splenic material. Patton found the parasites in the liver, spleen and lymphatic glands as well as bone marrow of the inoculated dogs. Consequently we cannot separate the two visceral leishmaniases from a standpoint of susceptibility of the dog. Monkeys are susceptible to both diseases. It is important to recognize the fact that animal inoculations, even with spleen-juice, rarely give rise to infection.
As regards separating oriental sore from the visceral leishmaniases Gonder has shown that white mice may be infected with both kala-azar and oriental sore, there being produced in each case a general infection with the presence of parasites in spleen and liver. A point of difference, however, is that the oriental-sore mice develop lesions on feet, tail and head which was not observed with the kala-azar mice. There are some reasons for thinking that in human cutaneous leishmaniasis a generalized infection may precede the local manifestations.
Dogs and monkeys can be infected with L. tropica as well as mice, but in them we have only cutaneous lesions produced. Inoculation should be made intraperitoneally.
A very interesting point is that the dogs in India never show a natural infection with L. donovani, while in the regions where L. infantum is responsible for human infections the natural infection of dogs is not uncommon, indeed many think the dog the reservoir of virus for both L. infantum and L. tropica. It has been suggested that the dogs of India, where kala-azar prevails, may be immune.
Morphology.—As regards morphology it is usually stated that the parasites of the three species of Leishmania are practically identical. In cultures it has been noted that the flagella of L. tropica are longer and more twisted than those of L. infantum. Again it has been observed that the parasites of the Oriental and South American skin lesions may at times show a flattened or band-like trophonucleus instead of the constant round or oval one of the visceral leishmaniases.
Escomel has reported the finding of flagellated Leishmania in the South American sores.
Relationship.—Within the past year the view has been generally accepted that Indian kala-azar and infantile kala-azar are one and the same disease, the points of difference between L. donovani and L. infantum which had been advanced from cultural and animal inoculation standpoints having been disproved.
It has been suggested that the Mediterranean basin may have been the original focus of visceral kala-azar and that it spread thence to India by way of Greece and the Russian Caucasus, cases having been reported from districts which would join the two foci.
Just as children bear the brunt of malaria in old malarious districts and adults suffer in places in which the disease has been more recently imported, so by analogy we may consider the disease as of more recent introduction in India. We now know that visceral leishmaniasis is widely distributed in China, north of Yangtse, as well as in the Sudan, and quite recently a case of kala-azar has been reported from South America, in an Italian, who had lived in Brazil from 1897 to 1910.
In the Mediterranean basin there is a natural canine leishmaniasis and some think the human form may be contracted from the dog through the medium of the flea. This dog kala-azar exists in two types, one acute and the other chronic.
Some entertain the view that the virus of oriental sore is that of a modified visceral leishmaniasis and there has been experimental work along the line of determining whether the cutaneous infection immunized against the visceral or vice versa as with vaccinia and small pox.
Manson has suggested that as oriental sore is common in camel-using countries it might be that a passage through the camel lowered the virulence of the parasite as passage through the bovines does variola, so that such an infection was of a mild type.
More recently there has been some evidence to indicate that oriental sore may simply be a manifestation of a visceral infection as shown in Gonder’s work with mice and from the fact of the long period of incubation in oriental sore with the appearance in some cases of general symptoms as well as the cutaneous ones.
The South American leishmaniases differ clinically from oriental sore in that, following the primary lesions, ulcerating granulomatous processes of nasal and buccal cavities frequently set in subsequently, at times even after the primary manifestations have healed.
VISCERAL LEISHMANIASIS
=General Considerations.=—There are two types of kala-azar, as the visceral leishmaniasis is termed, one the Indian kala-azar, which prevails in Assam, Madras, Indo-China, China and the Sudan and characterized by a subacute or chronic febrile course and splenomegaly in older children or adults and the other, the infantile type, which in over 90% of cases occurs in children under four years of age.
In 195 cases reported from Assam, by Mackie, 100 were in children between six and ten years of age so that it is hardly true to call Indian kala-azar a disease of adults.
The infantile type, which occurs chiefly in the countries bordering the Mediterranean, is usually stated to be caused by Leishmania infantum while the adult type is said to be caused by L. donovani. If, as is now thought, the two parasites are identical it will be necessary to drop the name L. infantum.
=Epidemiology.=—Whether Indian kala-azar is transmitted by the bedbug or infantile kala-azar by the flea are points which have not been experimentally proven. It must be admitted that epidemiological evidence supports the bedbug transmission view for the former.
On the other hand, Mackie dissected 322 bedbugs which he had fed on kala-azar cases with practically negative results. He also injected material from 588 bugs into two monkeys with negative results. Mackie was likewise unsuccessful with lice, mosquitoes and sand flies.
Rogers, investigating the disease in Assam, found that the usual history in the villages was that someone with the disease came to a village and subsequently other cases appeared. It was shown that where a village escaped while others near at hand suffered there was a history of nonintercourse with the infected villages. The natives took extreme steps to eradicate the infection, it having been reported that the Garos even burned the patients as well as their huts. All evidence shows that the infection is contracted by sleeping in an infected house. House epidemics and family epidemics are often noted.
At the same time various observers have frequently noted instances where an advanced case may associate intimately with his relatives for months or years and yet none of these develop the disease.
There is little to support the view that it is a contact infection, as such does not occur in hospitals where verminous insects are absent. By isolating the sick and moving the uninfected to new houses, only a short distance away, there is no spread of the disease. The disease practically appears only in those Europeans who live with or among natives.
In view of the fact that Leishmania may be found in the intestinal ulcerations or in the kidneys there have been suggestions that the disease may be spread through the medium of faeces or urine. There is not the slightest evidence that the parasites could live in water which they might contaminate and the view that some sort of transmitting host might take up parasites from the faeces or urine is improbable, as the parasites have never been found in faeces or urine.
The fact that a distance of 300 yards seems to suffice for permanent protection of the uninfected excludes from consideration such transmitting agents as the mosquito or house fly.
The tendency of some to incriminate soil factors can be explained by the well-known fact that bedbugs can live for months without food, being ready to bite those entering an infected house even after long disuse as a habitation of man.
Infantile kala-azar may possibly be connected with the disease in dogs and may be transmitted by the agency of the flea but there is nothing like the evidence for this view that obtains for the bedbug theory in Indian kala-azar.
=Pathology.=—At autopsy there is noted marked emaciation with greatly enlarged spleen and liver, dropsical effusions and ulceration of the large intestine. The spleen is often enormously enlarged, rather firm but quite friable. The liver may at times show cirrhosis but the usual change is a distention of the endothelial cells of the intralobular capillaries with great numbers of parasites, as many as 100 or more parasites being at times found in a single cell. Not only do the endothelial cells of the liver contain parasites but those of the spleen, particularly the cells lining the venous sinuses as well as those of the pulp cords, the lymphatic glands and bone marrow. The parasites are present in the intestinal ulcerations of the terminal stages. Less frequently they are found in kidneys, adrenals, testicles, pancreas and lungs. Rarely, parasites may not be found at the autopsy of advanced cases. It is possible that the finding of coccus-like bodies in the cells of such cases may represent degenerated leishman bodies. The mesenteric and prevertebral lymph glands are swollen. The bone marrow is red.
When the phagocytic endothelial cells rupture the parasites are taken up by other cells and if by large mononuclear or polymorphonuclear cells may appear in the peripheral circulation. In possibly 80% of cases the parasites may be found after prolonged search in smears of peripheral blood. The leucopenia and large mononuclear increase are the blood features.
SYMPTOMATOLOGY
Indian kala-azar.—As with all diseases tending to a chronic course it is difficult to be sure of the length of the period of incubation of kala-azar and various authorities have given it as from two to three weeks to several months. Manson states that one of his cases developed the initial fever of the disease ten days after arriving in the endemic area. As a rule the period of onset is rather indefinite. There may be a history of daily rigors, so that malaria is suspected, but it is found that the fever does not respond to quinine. The fever is usually of a low remittent type, rarely a low continued fever, in which the temperature does not exceed 101°F. At times however in the early stage the remittent fever is of a high type, the temperature reaching 104°F.
Rogers attaches particular importance to the fact that four-hour charts will show a double or even triple rise of fever in the twenty-four hours instead of the single one in typhoid fever. The patients also show a striking absence of typhoid malaise and apathy often stating that they feel well when the temperature may approximate 104°F.
The febrile accessions last from two to six weeks to be followed by periods of apyrexia and apparent improvement. Then follow further waves of fever and apyrexia so that the fever chart may resemble that of Malta fever.
In the early stages of the disease the loss of weight is apt to be marked. Later on, owing to improvement in appetite and increase in spleen, this is not so manifest.
The spleen begins to enlarge early in the disease and has usually reached the level of the umbilicus by the third month. In some cases there is little if any enlargement of the spleen even in the chronic stages. At times we note only an irregular fever with weakness, anaemia and emaciation. The liver does not usually become distinctly enlarged until about the sixth month.
The course of the disease in India is chronic often covering a period of one or two years. In the Sudan, however, Bousfield noted that the symptoms ran an acute course, the average duration being only about 5 months. Rarely he encountered chronic cases with greatly enlarged spleen.
As the disease progresses anaemia and emaciation become marked so that the bulging spleen and liver in a dusky or earthy colored, skeleton-like native (black fever) make a striking picture. The lymphatic glands of cases in North China show enlargement.
Symptoms referable to intestinal ulcerations, such as diarrhoea or dysentery, are often noted at the end. Bleeding from the gums and nose is not infrequently noted.
The marked leucopenia, with accompanying decrease in the polymorphonuclears (the bacterial phagocytes), makes septic infections and pneumonia especially common in the course of kala-azar.
These complications frequently bring about a fatal termination so that we do not get the typical terminal cachexia with emaciation, exhaustion, dry brittle hair, petechiae, oedema and ascites. On the other hand the tendency of a bacterial infection to cause a leucocytosis may bring about a cure.
Infantile kala-azar.—The symptoms on the whole are similar to those of the adult type of kala-azar and differ only to the extent that might be expected in a disease occurring in very young children instead of in those older.
The onset is insidious with some fever and gastro-intestinal upset. The spleen enlarges, the child becomes apathetic, anaemic and emaciated. Irregular attacks of fever occur and the child often suffers from epistaxis, bleeding from the gums or haemorrhages into the skin. According to Nicolle a peculiar pallor of the skin is characteristic. Ulcerations of the intestines and noma may bring about a fatal termination. The liver does not enlarge to the extent that the spleen does. The finding of the parasites is necessary for the distinction of this infantile splenomegaly from those of other origin. The lymphatic glands are not usually enlarged.
Symptoms in Detail
Onset and Fever Chart.—The disease commences in a rather indefinite manner, often with gastro-intestinal symptoms or possibly daily rigors. The fever chart is that of a remittent fever with rather marked oscillations and in particular a double rise in the 24 hours, which Rogers regards as characteristic. The absence of a high continued fever and this double daily rise assist in differentiating typhoid. Waves of fever separated by apyrexial periods often simulate the fever chart of Malta fever.
The Spleen, Liver and Lymphatic Glands.—The splenic enlargement, which may reach the umbilicus by the third month, is the most characteristic clinical sign of kala-azar. The diagnosis was formerly made by spleen puncture but owing to many fatalities the liver puncture is to be preferred, although the results of such exploratory examinations are often negative, the liver being involved to a less extent than the spleen and rarely showing appreciable enlargement before the third month. It is during the pyrexial periods that the spleen and liver enlarge.
Cochran has brought forward the importance of examining smears from excised lymph glands for the parasites and others have shown that gland puncture is of value. The glands in the infantile type of the disease often do not show enlargement.
The Blood.—Marked anaemia is only found in the later stages and the color index is about normal. The number of red cells rarely falls below 2,000,000.
Leucopenia is characteristically marked, this having been below 2000 in 62% of Rogers’ cases. This authority considers the finding of 1 white to 1000 red cells, in a case of fever, very significant of kala-azar.
There is also an increase in the large mononuclear percentage which would aid in differentiating typhoid.
The coagulability of the blood is decreased and this may be a factor in the fatal results which at times follow spleen puncture.
Parasites are found in the peripheral circulation in about 80% of cases, after prolonged search, and may be phagocytized by either large mononuclears or polymorphonuclears.
Patton found parasites in the peripheral blood in the examination of a single slide in 42 out of 84 cases and with three slides in 25 of those not showing parasites with the first slide. By repeated examinations up to the seventeenth slide, he got positive results in all 84 cases.
The Sudan commission found that the alkalinity of the serum of their patients was diminished.
Rogers has noted an acidosis in unfavorable cases of kala-azar while those showing improvement only showed slight or no acidosis.
Respiratory and Circulatory Systems.—There is very little that is constant, the lungs being quite normal in 90% of Rogers’ cases. The pulse rate is rather variable, although usually accelerated.
Diagnosis
Clinical Diagnosis.—Cases of kala-azar are usually diagnosed as malaria and it is in the lack of response to quinine that we have our best point of differentiation.
In children showing splenomegaly the probability of the case being kala-azar rather than malaria is indicated if the case has shown progressive deterioration of health.
Malta fever shows a rather similar succession of febrile and afebrile periods but the spleen of the former rarely shows marked enlargement and the bronchial catarrh, sweatings, transient joint swellings and neuralgic manifestations are characteristic of Malta fever. Kala-azar may show muscular pains and slight sweatings and the differentiation has at times only been made by the laboratory diagnosis.
Typhoid and the paratyphoids are best differentiated clinically by the presence of a continued fever, the absence of a double daily rise and the existence of a more marked apathy.
The recent statements that hookworm disease may show enlargement of the spleen would make this a condition to differentiate. Hookworm ova and an eosinophilia indicate ancylostomiasis but there is always the question here as with malaria as to the existence of kala-azar and some other affection.
Laboratory Diagnosis.—The leukemias can be easily differentiated by the blood picture, an important matter because the spleen of spleno-myelogenous leukemia is very friable and the danger from splenic puncture is far greater in this condition than in kala-azar. Banti’s disease with its leucopenia shows a rather similar blood picture and can only be surely differentiated by the finding of leishman bodies in kala-azar.
While malaria may at times show a leucopenia below 4000, a polynuclear percentage below 50 and a large mononuclear one of 20 or more, yet the simultaneous appearance of all three is rare in malaria while common in kala-azar.
Malta fever, typhoid and the paratyphoids are best differentiated by blood cultures or agglutination tests.
Until recently it was recommended that for diagnosis our best procedure was to make a splenic puncture. Manson and others have pointed out the dangers from splenic puncture in kala-azar and have rather preferred puncture of the liver, although recognizing that the chances of obtaining parasites from a liver puncture, are less than from a splenic one.
Statistics have been given where a mortality approximating 1% has followed spleen puncture. Bousfield, however, using an all-glass syringe with a 1½ inch needle did not have a fatality in 120 spleen punctures.
For diagnosis the spleen or liver juice, rather than pure blood, is smeared on a slide and stained by some Romanowsky method, preferably that of Giemsa.
Cultures on N. N. N. medium can also be made.
Human blood seems to inhibit growth so that N. N. N. medium for cultivating Leishmania should be made from rabbit blood.
The culture should be kept at a temperature of about 22°C.
One should always first examine a smear of the peripheral blood for parasites in polymorphonuclear or large mononuclear leucocytes. The Sudan Commission found leishman bodies in the peripheral blood of 13 out of 15 cases so examined, but rarely did they find more than one parasite-containing leucocyte to a slide.
It is well to select a time when some pyogenic infection causes a leucocytosis.
Quite recently Wenyon and others have noted the desirability of culturing the peripheral blood in N. N. N. medium. Diagnosis may be made in this way, provided one wait from two to three weeks before reporting negatively as to the presence of flagellated Leishmania in the cultures. As before stated, strict asepsis and a room temperature are requisite for flagellate development.
It has been noted that artificial pustulation might assist in diagnosis by giving a multitude of polymorphonuclear leucocytes for examination for phagocytized Leishmania.
Cochran has recently noted the advisability of excising a lymphatic gland and making gland smears to examine for Leishmania. Others have reported success with gland puncture as utilized in the gland of trypanosomiasis.
Animal inoculation has no place in diagnosis as such a procedure is but rarely successful. Ray has recently proposed a turbidity test in which about 2 drops of blood are added to 20 drops of distilled water. Instead of giving a clear solution of haemoglobin we have a turbidity followed later by a white flocculent precipitate. It is now thought that this turbidity is due to excess of serum globulin in the blood of this disease and the test can be carried out with serum instead of whole blood.
=Prognosis.=—Kala-azar is a chronic disease in the great majority of cases although both the adult and infantile types may show cases rapidly running to a fatal termination. Marked intestinal disturbance makes for a bad prognosis as does also a low large mononuclear percentage. A marked leucopenia is a bad sign particularly when associated with such low polymorphonuclear percentages as ten to twenty. Rogers notes that in children the polymorphonuclears several times did not give more than 5% of the total leucocyte percentage.
The mortality is usually given as about 95% although Rogers states that he has reduced this to 75% by large doses of quinine. The action of antimony is that of a specific. Patients often succumb to complicating septic conditions or pneumonia.
Prophylaxis and Treatment
Prophylaxis.—The best results in India have been obtained by abandoning infected houses and establishing new ones for the non-infected villagers, which need not be more than 300 yards from the old ones, thus showing that mosquitoes and flies are probably not concerned in transmission. Measures directed against the bedbug seem to offer the best chance of success. Often, however, the bugs are so deeply located in cracks of thick-walled houses that they may not be reached by sulphur fumigation. Flaming of such crevices with a plumber’s lamp has been recommended.
Treatment.—Rogers has recommended quinine in doses of 60 to 70 grains daily, claiming thereby to have reduced the mortality of the disease to 75%.
Castellani recommends a combination of quinine and atoxyl, while Manson has reported success with atoxyl in 2 cases, giving 3 grains intramuscularly every other day.
Salvarsan has been tried, but without much success, as is also true of X-rays.
Some have tried cinnamate of soda with the idea of increasing the leucocytes.
With the purpose of increasing leucocytes Rogers has tried hypodermic injections of sodium nucleate and killed staphylococcus vaccines as well as splenic substance tablets. The sodium nucleate injections were most painful and did not increase the leucocytes. He had some success with tabloids of spleen substance.
If the blood serum shows a lessened alkalinity the intravenous injection of solutions of bicarbonate of soda should be tried.
Rogers reports very favorable results from the administration of alkalies by mouth.
Recently hectine has been recommended in infantile kala-azar.
Following the successful employment of intravenous injections of antimony tartrate in American leishmaniasis it has been used in Indian and infantile kala-azar.
Rogers has used the same treatment in Indian kala-azar with a considerable degree of success. He has also used a 5% ointment of finely divided antimony. The treatment should be continued until the temperature has been normal several weeks and the leucocyte count approach the normal.
Antimony may now be considered as a specific in the treatment of the leishmaniases.
Knowles, at Shillong, has had long experience and striking success with the intravenous administration of tartar emetic in kala-azar. The heavy powder alone should be used—not the light powder. A 1% solution is prepared in normal saline and the solution autoclaved for 10 minutes at 110°C. If there is any opalescence or deposit discard the solution. Knowles begins with the intravenous injection of 3 to 4 cc. for an adult and gives the injections on alternate days, increasing the dose until we are giving from 10 to 12 cc., the maximum dose. It will be noted that the dosage ranges from 3 to 10 centigrams (½ to 1½ grains). The amount of drug given for a complete course of treatment is 200 cg. (33 grains). In the latter part of the course of treatment the effects on the patient are more marked so that caution must be observed, and it may be necessary to lengthen the interval or reduce the dose. The injections should not be given within two hours of a meal. Organic disease of the heart or kidneys contraindicates the antimony treatment. Coughing, a metallic taste in the mouth and constriction of the chest are frequently noted following the injection. Nausea, colic and diarrhoea show that the limit of the drug has been reached and albuminuria and jaundice are signs of warning to decrease the dose or stop the treatment. Christopherson considers that 5 to 8 grains will cure oriental sore, but for kala-azar 60 grains may be necessary. This authority considers 3 grains of tartar emetic as the maximum dose intravenously. For children under 1 year of age the intravenous dose of the 1% solution is ¼ to 1 cc., from 1 to 5 years old 1 to 3 cc. and from 5 to 10 years of age 1 to 5 cc.
Manson-Bahr has reported the successful use of an organic preparation of antimony, the sodium salt of p-acetylaminophenylstibinic acid. It is a powder, readily soluble in water and has the trade name of “stibenyl.” It can be injected intravenously up to 0.8 gram. The drug contains 36% of antimony. Knowles advises the use of tonics and, when indicated, of anthelminthics. He also recommends cod liver oil to increase the weight.
CUTANEOUS LEISHMANIASIS
=General Considerations.=—There is good reason to believe that much that was written about oriental sore prior to our knowledge of its etiology referred to tuberculous, syphilitic and other ulcerative skin lesions. As regards the work done in the investigations as to etiology Cunningham, in 1885, described deeply staining bodies in cells which were larger than lymphocytes. Later, in 1901, Firth confirmed the findings of Cunningham, but considered the bodies as degenerative changes in the cells rather than entertaining the view of Cunningham that they were parasitic protozoa. The name Sporozoa furunculosa was given these parasites. As previously stated, Wright, in 1903, using his modification of the Romanowsky stain, found round or oval bodies, from 2 to 4µ in diameter, packed in the cytoplasm of endothelial cells, in smears from an oriental sore in a child from Armenia. He called the parasites Helcosoma tropicum.
As the result of our knowledge that such lesions are caused by leishman bodies, Leishmania tropica, we have been forced to include among such sores clinical types entirely different from the classical oriental sore of Fayrer or Tilbury Fox. Even a keloid type of lesion described by the workers in the Sudan is known now to be caused by leishman bodies. In 1909 leishman bodies were demonstrated in ulcerative processes from Brazil and since that time we have divided cutaneous leishmaniasis into two groups, according to geographical distribution, that of the East, or oriental sore, and that of the West, or American leishmaniasis.
Oriental sore is found chiefly in North Africa, Asia Minor, Syria, Persia and India, and more recently cases have been reported from Italy and Greece and New Caledonia. American leishmaniasis is found chiefly in Central America, Brazil, Peru and the Guianas.
=Epidemiology.=—There is nothing definite known as to the epidemiology of cutaneous leishmaniasis. The fact that oriental sore almost always occurs on the uncovered parts of the body would suggest transmission by some insect as the house fly or mosquito rather than by the body louse, flea or bedbug, these latter showing no special preference for the uncovered skin.
There has been a great deal written about the origin of the disease in drinking water, various inorganic constituents having been incriminated as factors. In certain places, as Delhi, oriental sore has decreased among the British troops with the discontinuance of the use of water from certain city wells. We know that oriental sore is rather easily inoculable, it having been stated that certain people of Bagdad inoculated their children in order to insure against the possible appearance of the sore on the face with the resulting scar disfiguration. Wenyon found that the virus would not pass through the unabraded skin.
The disease is most prevalent about the end of summer and in the autumn. It is a disease of towns. Some have thought that it might be transmitted through the medium of the laundry. Not only can man be infected by inoculation but this is also possible with monkeys and dogs when a scarified area about nose or over eyebrows is inoculated with virus from a sore.
The lesions are similar to those in man but last a shorter time.
It has been suggested that the dog may be the reservoir of this virus as well as for that of infantile kala-azar. There is some experimental evidence to show that an animal which has recovered from a visceral leishmaniasis is immune to a cutaneous one.
There has been an idea that lizards or snakes might serve as the reservoir of virus for oriental sore and that species of Phlebotomus feeding on these reptiles might take in the flagellates and subsequently transmit them to man. Laveran, however, has been unable to infect lizards with L. tropica. Patton’s observations point to infection from the crushing of infected sandflies when biting the exposed surfaces of the skin.
The natural infection of man with oriental sore produces a rather lasting immunity.
As regards the American sores there is a great deal of difference of statement as to the probable transmitting agent. These sores seem to occur in forest regions where clearing of the trees is going on. Infections occur in late summer or autumn. Marshy districts appear to favour infection. Brumpt thinks the fact that dogs, which are susceptible as well as monkeys to inoculation with the American leishmaniasis, are often bitten by ticks without the production of the sore, is against the view that ticks act as transmitting agents. He rather favors a tabanid fly and in a case reported by Darling the patient incriminated a tabanid fly.
Five cases are reported by Cerqueira as following the bite of Phlebotomus lutzi.
The disease seems to occur naturally in the dog in the infected regions.
=Pathology.=—In oriental sore there is an infiltration of the corium and its papillae with plasma and lymphoid cells as well as with large phagocytic cells packed with leishman bodies which cells Wright regards as endothelial cells. There is atrophy of the epidermis.
In the keloid type of leishmaniasis noted by the Sudan Commission epithelial cell nests were characteristic although there was no other evidence of epithelioma.
In the American leishmaniasis there is rather constant involvement of the lymphatic glands and often lymphangitis. Histologically the appearance is rather that of granulation tissue with occasionally giant cells.
SYMPTOMATOLOGY
Oriental Sore.—Wenyon inoculated a scarified area on his arm which became infected with pyogenic organisms but eventually healed. It was thought that this inflammation would destroy any Leishmania which might have been present. About six months later he became ill and had fever up to 103°F. for a week with malaise and gastro-intestinal upset. At this time a small red papule was noted upon the site of the original scarification which subsequently enlarged and was found to contain leishman bodies.
The period of incubation is usually given as about two months, although in some instances it may be as short as a week. Usually the earliest appearance of the sore is similar to that of a mosquito bite. The papule continues to enlarge, becoming purplish in color with a glazed surface. It somewhat resembles an inflamed acne lesion. Growing larger, the surface of the blind boil-like lesions now becomes covered with brownish scales and, either from scratching of the rather pruriginous spot or from the development of vesicles, it becomes covered with a yellowish crust, beneath which is an ulcer with raised edges and discharging a thin offensive pus.
The ulceration does not generally occur before the third or fourth month. The ulcer is painless and may be an inch or more in diameter. Healing comes on in about seven to ten months, the yellowish unhealthy granulations giving place to healthy pink ones. The sore tends to run a course of about one year, hence the French designation bouton d’un an.
According to Weber’s statistics about 85% of the sores were located on the upper or lower extremities and about 10% on the face, while the trunk served as the location for only about 5% of the sores. There are generally 2 or 3 sores.
According to Déperet and Boinet the number of sores to a case was one sore in 30%, 2 to 4 sores in 50% and from 4 to 20 in about 20% of cases.
American Leishmaniasis.—Under a number of names such as espundia, uta, bubas and forest yaws there has been found in many parts of Central and South America an ulcerating sore, more or less resembling oriental sore, but often associated with ulcerating granulomatous lesions of nasal and buccal mucosae. Da Silveira states that in Brazil about 20% of cases develop the mucous membrane lesions. He notes an incubation period of two to three months. In Venezuela the mucous membrane lesions are more rare.
The lymphatic glands and lymphatics are commonly affected.
Just as with oriental sore one or more pruriginous papular lesions appear on the uncovered parts of the body. In a few days it develops a pustular summit. This undergoes ulceration and after several months or even after the primary lesions have healed nodules may make their appearance in nose and mouth.
These ulcerate and form fungoid granulations. Even the larynx may be involved. The nasal septum and other cartilaginous portions of the nose are often destroyed and the overlying tissues become swollen and often eroded by ulceration, so that the patients present the appearance of similar cases where syphilis, tuberculosis or leprosy may be the cause.
A point of distinction between syphilitic and leishmaniasis lesions of the nasal mucosa is that the latter do not involve the bony structures.
Rabello noted that a positive Wassermann may be present in cutaneous leishmaniasis which is in agreement with Sutherland’s findings of 27% positives in cases of kala-azar.
The patients suffer from fever, joint pains, bronchitis and general symptoms. After a long period of ten to twenty years, during which they often die of some intercurrent affection, there may be a terminal cachexia.
=Diagnosis.=—The diagnosis in either oriental sore or in American leishmaniasis can only be made surely by the finding of Leishmania, either by scrapings from the edges of the ulcer or by culturing in N. N. N. medium the blood from the immediate site of the sore. Cultures were once obtained from the blood of a finger where the sore was located on the arm of the same side but usually the parasites are absent from the peripheral circulation. Gland puncture in American leishmaniasis may give positive findings of parasites.
=Prophylaxis and Treatment.=—Knowing that the application of material from a sore to a scarified surface will bring about infection, it would seem advisable to cover any abrasions or open wounds with flexible collodion or other protectives so as to prevent flies, which may have fed on oriental sores, from having access to the wound.
It has been recommended to paint the spot of insect bites with tincture of iodine.
Atoxyl and salvarsan have been tried in oriental sore and American leishmaniasis without any particularly striking curative results. Attempts have been made to excise the early lesions but unless one goes well beyond the infected area, severe recurrences may result. Bier’s passive congestion method has been tried without success.
An expectant treatment is usually resorted to, the crusts being softened and removed with antiseptic fomentations with subsequent disinfection of the ulcer with bichloride or potassium permanganate solution and the application of some antiseptic ointment or powder. Thorough cauterization with pure carbolic acid followed by rapid neutralization with alcohol can be tried. The injection of killed cultures of Leishmania does not seem to have been effective.
Wenyon has had good results from an ointment of equal parts of methylene blue, lanoline and vaseline in an American sore.
Carbon dioxide snow has been shown by Mitchell to be an efficient local application for oriental sore.
The remarkable effect of antimony on the parasites of leishmaniasis was first noted in the treatment of the cutaneous types. The treatment is similar to that described under kala-azar. The effect of the drug is less pronounced on the lesions of the mucous membranes.
IX. DYSENTERY
DEFINITION AND SYNONYMS
=Definition.=—The designation dysentery refers to a symptom-complex of (1) small, frequently passed mucous or muco-sanguinolent stools and (2) pains connected with spasm of the sphincter ani (tenesmus) or intestinal gripings (tormina).
The condition may be set up by numerous causes but of these two so outweigh the others that it is usual to have in mind either bacillary or amoebic dysentery when the term is employed.
=Synonyms.=—The Bloody Flux. French: Dysenterie. German: Ruhr.
GENERAL CONSIDERATIONS
As will be noted in the sections dealing with amoebic and bacillary dysentery our present knowledge of these conditions is of recent date. There was so much that was etiologically, epidemiologically and clinically contradictory that the subject was impossible of elucidation until the existence of a group of dysentery bacilli was generally accepted, following the reporting, in 1898, by Shiga, of his bacillus of dysentery.
Although Hippocrates was the first accurately to describe the disease we now know as dysentery yet there is good ground for believing that the disease existed in Egypt and India for centuries before Christ.
Many of the older writers failed to differentiate conditions which showed admixtures of mucus and blood in the stools from those with blood alone.
Commencing with the last century, authorities have considered the association of mucus with the blood as essential in clinical diagnosis.
It is interesting that with a better knowledge of etiology we are now recognizing as of dysenteric nature diarrhoeal conditions in which there is an absence of the typical stool of dysentery.
Our views as to the etiology and epidemiology of bacillary dysentery have been fairly definite for at least twenty years, while those relating to amoebic dysentery, notwithstanding the important researches of Kartulis, Councilman and Lafleur, Schaudinn and others have remained rather chaotic until quite recently.
The Term Dysentery.—By the term dysentery we understand a symptom-complex of more or less characteristic stools and more or less characteristic pains.
As a rule the stool is composed of one or more teaspoonfuls of greenish yellow or dirty brown mucus, the altered blood being intimately admixed with the mucus, or we may have a whitish to grayish muco-purulent mass with streaks or flecks of blood on the outside. These mucoid masses may be found suspended in serous, sanguineous or more or less feculent discharges which are usually small in amount and passed with much frequency.
The terms tormina and tenesmus are the ones used to designate the characteristics of the pains of dysentery, tormina for the griping colicky pains, which center about the umbilicus or run in the direction of the large intestine, and tenesmus for the painful spasmodic contractions of the sphincter ani to which is due the sensation of lack of ability to complete the act of defecation leading to straining and justifying Manson’s description “glued to the commode.”
It is usually stated that the nearer the dysenteric process is to the rectum, the greater the tenesmus and the nearer to the caecum, the greater the tormina.
THE MODERN CLASSIFICATION OF DYSENTERIES IS BASED ON ETIOLOGY RATHER THAN UPON CLINICAL MANIFESTATIONS
Owing to the great importance of the two main kinds of dysentery, amoebic, or that caused by Entamoeba histolytica, and bacillary, or that caused by some strain of Bacillus dysenteriae, we shall consider them separately from the other causes of the dysenteric symptom-complex.
=A. Dysenteries caused by animal parasites.=
Protozoal dysenteries.
1. Amoebic dysentery (Entamoeba histolytica).
2. Flagellate dysenteries (Lamblia intestinalis, Trichomonas intestinalis and Chilomastix mesnili).
While in adults these intestinal flagellates usually cause only a diarrhoea, with at times marked nervousness, they may produce dysenteric symptoms in young children. The onset in children under three years of age may be insidious and attended with fever. The stool contains much mucus with only a little blood.
In cases of amoebic dysentery, the diarrhoeal attacks, which at times occur, are often associated with an abundance of flagellates, which may well be the cause of the complication. Cases of dysenteric diarrhoea have been reported from Gallipoli in which Lamblia (Giardia) were apparently the only parasites involved. Such stools are often of a yellow ochre color. Relapses are common features of Lamblia infections. Lamblia is an inhabitant of the upper intestine while Trichomonas and Chilomastix belong to the large intestine, especially in the region of the caecum. While these last named flagellates are often found in the stools of those convalescent from dysentery there is a general opinion that they are nonpathogenic. These organisms may be present in diarrhoeal conditions in which case it is common to designate such diarrhoeas as flagellate diarrhoeas. Fantham and Porter have reported 187 cases of pure lambliasis.
In diagnosis it is important to recognize the encysted Lamblia. These are oval cysts, about 10 × 7µ and show a curved central line, with two lateral dots. When stained these dots show as chromatin areas. These cysts may be found in the faeces in great numbers. The vegetative Lamblia has 4 pairs of flagella, is about 15µ long and has a tumbling motion. Calomel alone or calomel and ipecac give good results at times. Enemata of organic silver salts may be of benefit.
Porter recommends bismuth salicylate. Low has noted the tendency of lambliasis to recur and thinks many of the reported cases of cures are only temporary. His experience with bismuth, salol, thymol and cyllin has not been encouraging.
It is well known that lambliasis is of rather frequent occurrence in mice and rats so that these rodents may be factors in spreading the infection through the agency of their faeces deposited about human food.
Of other drugs recommended in treatment Dobell and Low have had no success with methylene blue, turpentine or beta-naphthol. These authors failed to find any increase in either large mononuclears or eosinophiles in a case of the infection.
Since Lamblia inhabit the upper parts of the small intestine, it may be that the administration of drugs by the duodenal tube will prove an effective method of treatment. Owens reports successful results in the treatment of amoebic dysentery from ipecac so administered. Stiles has recommended sulphur in lambliasis.
3. Ciliate dysenteries (Balantidium coli).
While various ciliates may cause a severe type of dysentery it is very exceptional that others than Balantidium coli do so. This oval ciliate is from 60 to 100 microns long by about 50 to 70 microns broad. It is a commensal of hogs and the disease in man is usually found in those having the care of hogs. Infections have been reported from various parts of the world, temperate as well as tropical regions. These ciliates may be found in the faeces of persons apparently well but in such cases symptoms may eventually appear. The parasites multiply in the submucosa and the pathologic process is similar to that observed in the large intestine in amoebic dysentery.
The parasite is so large and has such an active motility that it would be impossible to fail to detect it in a microscopic examination of the faeces. Encysted parasites are round. The onset is rather insidious with diarrhoea which may be followed by dysentery. A severe form of anemia may be noted.
Ipecac, emetine, arsenic and quinine appear to be of little value in the treatment, but Walker considers the organic silver compounds, as protargol, etc., of value. Methylene blue enemata (1-3000) and 2-grain pills by mouth have been recommended.
4. There are also dysenteric manifestations noted in the terminal stages of kala-azar (Leishmania donovani) and in algid pernicious malaria (Plasmodium falciparum). These conditions are taken up under the diseases kala-azar and malaria.
Wenyon noted a case of coccidial infection (Isospora hominis) in which there was a dysenteric syndrome. There have been about seventy cases of infection with this parasite reported, chiefly from soldiers serving in Gallipoli. The usual opinion is that they are nonpathogenic parasites. The oocysts are ovoid, with one end narrowed, and measure 28 × 14 microns. There are two sporocysts, each of which contains four sporozoites. The cyst when first passed is unsegmented.
Helminthic dysenteries.—1. In addition to the protozoal causes above noted we may have dysenteric symptoms following infections with trematodes, especially Schistosoma mansoni and S. japonicum. In these cases we have mucus coating the stool with more or less clotted blood in which mucus we may find the diagnostic ova. A rather high eosinophilia is present.
2. Infections with Gastrodiscus hominis also give rise to dysenteric manifestations.
3. A very small cestode, Heterophyes heterophyes, has been noted to cause a condition suggestive of dysentery.
4. In 1902, Brumpt noted the finding of a nematode, Oesophagostomum brumpti, in the large intestine of an African native, which caused dysenteric symptoms and, more recently, another species, O. stephanostomum, has been reported as causing a fatal dysentery in a Brazilian at Manaos.
5. There have also been reported cases with dysenteric manifestations which were apparently connected with intestinal myiasis.
=B. Dysenteries caused by bacteria.=
1. Those caused by either the more toxic, nonacid mannite strain of Shiga, or the less toxic, acid mannite strains of the Flexner group.
2. Morgan has reported as the cause of certain bacillary dysenteries a bacillus known as B. Morgan No. 1. It is motile, produces indol, and in glucose bouillon gives a very slight amount of gas. It does not change mannite and does not produce a primary acidity in litmus milk. This organism is a frequent cause of summer diarrhoea of children. Flies from houses with such cases often show Morgan’s bacillus.
Paratyphoid infections may give the clinical picture of a colitis and such cases at times show a large amount of blood in the dysenteric stools. Usually the symptoms are rather those of an entero-colitis or a gastro-enteritis.
3. In Japan, dysentery-like epidemics of a very fatal disease, termed ekiri, occur among young children. The organism is very motile, producing gas and acid in glucose, but not in lactose media. It is reported at times to show indol production. Apparently a member of the Gärtner group.
4. Spirillar dysentery. LeDantec has reported a type of dysentery which shows the presence of great numbers of spiral forms. These are Gram negative and noncultivable. It is in question whether they belong to the bacteria. There is no fever in this type of dysentery.
5. Other bacterial causes. Cases of dysentery have been reported as caused by B. pyocyaneus, streptococci, atypical B. coli and organisms of the Gärtner group.
In a Pyocyaneus infection the color of the stools would be suggestive. This cause should be borne in mind in the dysenteric infections of debilitated children in the tropics. Some of the cases of so-called ptomaine poisoning due to members of the Gärtner group have clinical similarities to dysentery especially at the commencement of the attack.
=C. Dysenteries resulting from mechanical irritants or poisonous substances.=
A very interesting form of poisoning which gives rise to serious illness or death and is attended with marked abdominal pain and manifestations of dysentery is that reported from North China through the use of short lengths of bristles which are given mixed with the food.
Various irritant metallic poisons as arsenic, antimony and mercury may give rise to dysenteric symptoms. In cancer and syphilis of the rectum there may be a suspicion that the process is an ordinary dysenteric one.
Intussusception shows marked tenesmus with bloody rather than muco-sanguineous stools.
While dysenteric symptoms may be present in the terminal stages of various chronic diseases, especially tuberculosis and cardiac affections, yet it is in chronic nephritis, leading to uremia, that we may see symptoms of a marked catarrhal or even diphtheritic colitis.
X. AMOEBIC DYSENTERY
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—Lambl, in 1859, was the first one to note the presence of amoebae in man, these being found in the stools of a child affected with diarrhoea. It was Lösch, however, who, in 1875, first accurately described the parasite which he found in the intestinal ulcerations as well as in the stool of a patient with chronic dysentery and was able to produce dysenteric ulcerations in the dog, by injecting amoebae-containing faeces into the dog’s rectum.
In 1879 Grassi noted the encysted forms of amoebae, but as he found them in well people, he denied their pathogenic importance. Cunningham found amoebae in the stools of cholera patients and Perroncito in those of typhoid cases, both of these authorities, however, viewing the question of their pathogenicity as did Grassi.
This was the general attitude of the medical mind until Koch, in 1883, while investigating cholera in Egypt, was impressed with the striking penetration of amoebae in the walls of intestinal ulcers and considered that this fact favored the view that amoebae were pathogenic.
Kartulis continued the work of Koch and in 1886 published his findings in 150 cases of dysentery, noting the presence of amoebae in the stools of all these cases. In 1887 he noted the presence of amoebae in liver abscess. In 1891, Lutz noted that amoebae in dysentery contained red cells. In the same year Councilman and Lafleur came to the conclusion that there were two species of amoebae in man, one harmless and the other, which was found in the submucosa of intestinal ulcers, pathogenic, Casagrandi and others put forward the view that amoebae only acted as carriers for bacteria, but in 1893 Kruse and Pasquale injected all the bacterial species isolated from a dysenteric stool into a cat’s rectum with negative result. Hlava and Kartulis first produced dysenteric lesions in cats by injecting per rectum, amoebic stools. Kruse and Pasquale produced dysentery in cats by injecting per rectum bacteria-free pus from a liver abscess which however contained amoebae.
A stumbling block as to the connection between amoebae and dysentery was the fact that many cases of typical dysentery failed to show amoebae. In 1898 Shiga settled this matter by reporting a group of bacilli which were concerned in the production of dysentery. His findings were confirmed all over the world and the distinction gradually obtained of cases of dysentery from bacillary as well as from amoebic infections.
In 1903 Schaudinn reported the existence of two species of amoebae, one harmless and named Entamoeba coli, the other pathogenic and named E. histolytica. In 1907 Viereck described a pathogenic amoeba which, by reason of its four nuclei in the encysted stage, he called E. tetragena.
As the result of the work of Hartmann, Whitmore, Darling, Wenyon and the recent conclusive findings of Walker we now hold the view that Schaudinn was working with E. tetragena and not with a separate species, so that by the law of priority we must drop the name E. tetragena and accept E. histolytica.
=Geographical Distribution.=—Amoebic dysentery seems to be especially prevalent in Indo-China, China and the Philippines, as well as in parts of India. It is also very common in Egypt and Northern Africa. In South America, especially Brazil, it is common, as is also true of the West Indies and Central America. It is an important disease in the Southern States of the United States, as well as in Italy and other parts of Southern Europe. On the whole it is probable that it exists in greater or less degree in most of the tropical and subtropical parts of the world.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—For a long time the authorities in Manila held that it was impracticable to differentiate between a pathogenic and nonpathogenic species, taking the view that the principal factor in the production of dysentery was that of symbiosis between amoebae and suitable bacteria, it having been thought that they observed in cultures of amoebae evidences of both symbiosis and antagonism on the part of amoebae to certain species of bacteria. They furthermore were convinced that pathogenic amoebae could be cultured on a medium of about 1/10th the strength of ordinary nutrient bouillon or agar and that dysentery could be produced by such cultural amoebae. Such views had an important bearing on epidemiology as it was thought that where amoebae could be cultured from green vegetables, fruit, or water supply there was positive evidence of the possibility of infection with amoebic dysentery from such a source.
The above views are no longer entertained and, due to Walker, working in Manila with experiments on man, we now know that cultural amoebae are without effect in the production of dysentery and that there are certainly two well known species of amoebae having man for a host, the one pathogenic, Entamoeba histolytica, and the other a harmless commensal, Entamoeba coli. Two other species, Endolimax nana and Iodamoeba bütschlii, have recently been described but are generally considered nonpathogenic.
Some authorities prefer the generic names Löschia and Endamoeba to Entamoeba.
Schaudinn, in 1903, described the pathogenic amoeba, which he named E. histolytica, as follows: 1. Distinct, highly refractile and tenacious ectoplasm. He considered this tough external portion of the cytoplasm as the explanation of the ability of the pathogenic amoeba to bore its way into the intestinal submucosa. 2. Eccentric nucleus which was indistinct by reason of little chromatin. 3. Reproduction by peripheral budding in which small aggregations of chromatin reached the periphery of the cytoplasm and, enclosed in a resistant capsule, broke off from the parent amoeba and constituted the infecting stage.
For the nonpathogenic E. coli he noted: (1) No distinction between a granular endoplasm and refractile ectoplasm; (2) centrally placed and sharply outlined nucleus, rich in chromatin; and (3) encystment with the formation of eight nuclei, which cysts with their nuclei or amoebulae form the infecting stage.
The pseudopodia of E. histolytica are actively projected as long finger-like processes which show the ectoplasm quite distinctly, while the pseudopodia of E. coli are lobose and sluggishly projected and show a uniformly opaque grayish color. In dysenteric stools E. histolytica tends to show contained red cells. E. coli never contains them but instead shows bacteria and food particles.
In 1907 Viereck and later Hartmann recognized a pathogenic amoeba with four nuclei in its encysted form, to which was given the name E. tetragena.
All authorities now consider that Schaudinn made an error in observation as to the existence of peripheral budding for E. histolytica, so that we recognize but two types of encystment, one with a larger cyst and thicker cyst wall, with eight nuclei and an absence of chromidial bodies—E. coli—the other, smaller, with a thin cyst wall one to four nuclei and chromidial bodies in the encysted stage, the pathogenic amoeba, E. histolytica. Synonym, E. tetragena.
In the vegetative stage the human amoebae are best differentiated by the nuclear structure as shown in stained specimens. In E. coli the nucleus is vesicular with a thick nuclear membrane and the chromatin chiefly deposited on the under surface of the nuclear membrane. This chromatin often seems deposited in quadrant aggregations. The karyosome is eccentric.
For the pathogenic amoeba we recognize a histolytica type of nucleus, which is found in dysenteric stools, and a tetragena type, which is found in diarrhoeal or more or less normal stools. Dobell does not recognize this differentiation.
The histolytica nucleus has a thin nuclear membrane and is poor in chromatin while the tetragena nucleus has more chromatin, showing radial projections from the inner surface of the nuclear membrane, and a loose central spherical karyosome, which contains a central chromatin dot or centriole, with a clear halo surrounding it. Dobell states he has not been able to note this centriole.
The preëncysted E. histolytica has a nucleus resembling that of E. coli. The smaller size and chromidial bodies are differentiating.
Animal experimentation upon kittens with E. coli by Schaudinn, Craig and Wenyon have been unsuccessful as to production of dysenteric manifestations. On the other hand all of these experimenters produced typical lesions and dysenteric manifestations in kittens injected rectally or fed with material containing pathogenic amoebae.
Wenyon as previously stated produced a liver abscess in one of his experiments.
Darling has been so successful in his experimental work with kittens that he compares the colon of a kitten to a test tube and suggests the procedure of rectal injections of material containing amoebae as a means of differentiating the two human amoebae.
On the other hand Walker was unable to infect kittens and monkeys with material containing pathogenic amoebae and he makes the statement that such failures would indicate the greater susceptibility of man to infection, as he was able to infect 17 out of 20 men with one feeding of such material.
Sellards and Baetjer note that inoculation of kittens per rectum or by feeding dysenteric stools rich in amoebae has resulted in infection in about 50% of experiments.
By inoculating the material directly into the caecum they were able to infect every one of their kittens. They were also able to propagate a strain of amoebae through a series of animals for several months.
The intracaecal inoculations yielded positive results in diagnosis of human amoebiasis when the clinical manifestations were obscure and the amoebae in the discharges so few and atypical as to make such an examination unsatisfactory.
Other Intestinal Amoebae.—It is a remarkable fact that one of the most common of the intestinal amoebae, Endolimax nana, has only recently been reported (Wenyon and O’Conner in 1917). In the examination of the stools of American soldiers Kofoid found it present in 28% of his examinations while E. coli was present in 23% of cases and E. histolytica in 9.3%. In examining 156 British soldiers Dobell noted its presence in 33% of them. The general view is that it is not pathogenic but its great importance is in the possibility of its being mistaken in its cyst form for E. histolytica. The living amoeba averages about 8 microns but in stained specimens it is somewhat smaller. In freshly passed faeces the amoeboid motion is sluggish and the nucleus indistinct. This amoeba is best identified by haematoxylin stained specimens when the nucleus shows a measurement of about 2 microns with a large eccentric karyosome which exhibits a variety of form. Unless perfectly fresh material is stained the degenerative changes in the amoebae may give a signet ring appearance of karyosome and ring nucleus. Such an appearance may suggest the limax nucleus. The mature cysts are usually oval, but sometimes round, and contain 4 nuclei, but when newly formed may only have one nucleus. The nucleus is large in the uninucleate form (up to 3 microns) but in the quadrinucleate forms it is about 1.2 microns with a large eccentric mass of chromatin. Chromidial bodies are rarely, if ever, present in these cysts.
Iodine Cysts.—These bodies which stain a deep brown colour when treated with iodine are now recognized as amoebae and have been named Iodamoeba bütschlii. They are most probably nonpathogenic. It is a small amoeba (9 to 13 microns, rarely up to 20 microns) and shows the sluggish movements of E. coli. The nucleus is very difficult to discern, thus differing from E. coli. In stained specimens it has a vesicular nucleus about 2 microns in diameter with a fairly large central karyosome. The cysts are spherical or oval, often of irregular outline and are about 10 microns in diameter. The nucleus is large and eccentrically placed and has a karyosome which tends to show as a peripherally placed mass. There is almost always present a large glycogen mass in the cyst which stains intensely with iodine.
Dientamoeba Fragilis (Jepps and Dobell 1918).—A rare binucleate amoeba averaging 8-9 microns in size. Nuclei show a fairly large, central granular karyosome and no peripheral chromatin. Strands of linin may be seen radiating from karyosome to nuclear wall. This organism is said to be frequently mistaken for Blastocystis when the vacuoles coalesce leaving a thin ring of cytoplasm. Cysts unknown. Considered nonpathogenic. Recently Kofoid and Swezy reported another species of amoeba parasitic in man, Councilmania lafleuri. The adult and cystic stages resemble in many respects the E. coli. Adult said to ingest red blood cells. Stated to be pathogenic but that more evidence is needed on this point.
=Human Experiments.=—Recently Walker and Sellards have published a most important paper.
The experiments were made in men who had been under observation for years at Bilibid Prison, whose food was cooked and the water they drank distilled. Moreover, there were complete records of examination for intestinal parasites, including entamoebae. They were under complete control and the existence or possibility of natural infection with amoebae was reduced to a minimum. All the men fed pathogenic amoebae were volunteers and each signed, in his native dialect, an agreement to the conditions of the experiment.
The first series of experiments was with cultural amoebae, in order to refute statements that amoebae cultivated from water or other nonparasitic sources, as well as from dysenteric stools, are capable of living in man parasitically or of producing dysenteric symptoms. Twenty feeding experiments on ten men were made by Walker and Sellards with cultures of amoebae without the development in a single instance of dysentery or the finding of such amoebae in the stools upon microscopical examination. In 13 cases they recovered the amoebae in cultures from the faeces from the first to the sixth day, but never afterwards. They stated definitely that cultural amoebae are nonpathogenic.
The next experiments were with Entamoeba coli. In the 20 cases fed with material containing Entamoeba coli there was a uniform failure to recover them culturally and in no instance was dysentery produced. Seventeen became parasitized as the result of a single feeding in from one to eleven days, the entamoebae being found in the stools and persisting in their appearance in the stools for extended periods. They concluded that Entamoeba coli is an obligate parasite, nonpathogenic, and cannot be cultured.
The third series of 20 feedings, carried on by Walker alone, was with Entamoeba histolytica. The material was mixed with powdered starch or magnesium oxide and given in gelatin capsules. In these experiments they obtained tetragena cysts in the stools of men fed only motile Entamoeba histolytica, and motile Entamoeba histolytica in the stools of men who were fed only tetragena cysts and, finally, an alternation of motile E. histolytica and tetragena cysts in the stools of a man having a recurrent attack of amoebic dysentery.
=Results.=—Seventeen of the men became parasitized after the first feeding; 1 required three feedings, and 2, who did not become parasitized at the first feeding, were held as controls. The average time for parasitization was nine days. Only 4 of the 18 parasitized men developed dysentery, which came on after twenty, fifty-seven, eighty-seven, and ninety-five days, respectively, after the ingestion of the infecting material.
In 4 cases fed with material from acute dysenteric stools or from amoebae-containing pus from liver abscess, and containing motile amoebae, there was no resulting dysentery, the 4 cases of experimental dysentery resulting from feeding of material from normal stools of carriers.
As regards the cases which became parasitized, but did not develop dysentery, it is suggested that the amoebae live as commensals in the intestine of the host and only penetrate the intestinal mucosa and become tissue parasites when there occurs depression of the natural resistance of the host or as the result of some lesion of the intestine. That the pathogenic amoebae are more than harmless commensals, however, is shown by the fact that they alone, and not the nonpathogenic Entamoeba coli, are capable of penetrating a possibly damaged intestinal mucosa.
=Epidemiology.=—The chief factor in the spread of amoebic dysentery would seem to be the encysted amoebae in the stools of convalescents, or symptomless carriers, rather than the motile amoebae in dysenteric stools. When such carrier has to do with the preparation of food, he becomes a particular source of danger.
This probably explains the endemic rather than the epidemic characteristics of the spread of amoebic dysentery because, if the innumerable vegetative amoebae in dysenteric stools were equally operative with the more sparsely eliminated cysts, there would be epidemics of amoebic dysentery similar to those of bacillary dysentery. The old idea that water, fruit or vegetables, from which one can isolate amoebae on culture, are sources of infection must be abandoned, as such cultural amoebae are known to have no pathogenic relation to man.
Vegetative amoebae undergo disintegration in a short time after the stool is passed, so that they are probably rarely concerned in amoebic infections but the resisting cysts may be washed from a dried stool into a water supply or even be transported in dust to lodge on unprotected foodstuffs.
Flies may possibly act as transmitting agents. As bearing on the probable importance of such flies as Musca domestica and Fannia canalicularis in transmitting amoebic infections may be noted the findings of Wenyon that the faeces of such flies, as well as Lucilia and Calliphora, after feeding on cyst-containing human faeces, teem with such cysts. In a dissection of 1027 house flies caught in Mesopotamia Buxton found ova of parasites of man in 4.09%. The percentage of infection with E. histolytica cysts was O.3%.
PATHOLOGY
Wenyon thinks that the pathogenic amoebae work their way into the tubular glands of the intestines and multiply and subsequently, either by pressure of their pseudopodia or through the disintegrating action of some toxic substance elaborated by them, they force their way into the underlying submucosa. In this location they produce a gelatinous, oedematous necrosis, which shows a marked absence of polymorphonuclears, but a proliferation of connective tissue cells. The process is regenerative rather than inflammatory.
Small hemispherical elevations of the overlying mucosa mark the location of the deeper-lying necrotic process. With the multiplication of the amoebae and the extension of the necrotic process in the submucosa we have thrombi formed in the terminals of the portal vein and possibly in those of the mesenteric arteries, which in the former case may result in emboli being swept up the portal vein to lodge in the liver and form a starting point for a similar necrosing process there or, as the result of interference with the blood supply of the overlying mucosa, cause this to undergo necrosis and be cast off as a slough, leaving an oval or irregular ulcer with deeply undermined edges and a floor formed by the muscular coat. The ulcers may be no larger than a pin’s head or they may be 1 or 2 inches in diameter or by coalescence be still larger. The gelatinous necrosis in the submucosa always extends beyond the limits of the necrosis of the mucosa, thus explaining the undermining. At times the muscular coats of the intestines are involved thus leading to a slough which involves all coats except the serous one. Bacterial infection, with coagulation necrosis of the mucosa overlying the amoebic process, is also responsible for some of the tissue destruction.
The amoebic ulcerations rarely extend above the ileo-caecal valve but may involve the entire large intestine. Rogers and Lafleur found the lesions most often in the caecum and ascending colon, often limited to this area.
The appendix was involved in 7% of the Manila autopsies. Often mild cases may only show lesions in the caecum. When there is a tendency to perforation the omentum will often be drawn over to the location of the threatened perforation. There is often thickening of the intestine in one place with cicatricial contraction of the lumen and thinning in another, so that there is an appearance of great irregularity.
SYMPTOMATOLOGY
The great majority of cases of amoebic dysentery run a chronic course with periods of improvement alternating with recurrences of pains and dysenteric stools. From Walker’s experiments the period of incubation would appear to be from one to three months. The onset in such cases is very insidious and the patient may complain more of diarrhoeal than dysenteric manifestations. Such patients often give a history of passing three or four pultaceous stools daily and complain of tenderness in the region of the caecum or along the course of the large intestine. One may determine some thickening of the colon in a thin subject.
Fever is absent and there are very few of the toxic manifestations which often accompany bacillary dysentery, such as headache, nausea and a mildly delirious state. There is progressive loss of weight and strength with the development of neurasthenic symptoms. The skin becomes dry and earthy and we have the picture of a more or less marked secondary anaemia. It is in these cases that we should be on the lookout for grayish green or grayish brown mucoid masses which can usually be found during an exacerbation. Sloughs of the gelatinous-like necrosis in the submucosa usually contain amoebae.
The X-ray has been utilized to give location of amoebic ulcerations. Bismuth is used for several days prior to taking the photograph and fills the sites of ulceration.
Such cases usually show a moderate leucocytosis in which the percentage of large mononuclears is increased and a very important point is that with tenderness about the caecum, plus a leucocytosis, one may diagnose appendicitis and operate on a normal appendix. Autopsy records however have shown that the appendix is not infrequently invaded by amoebae but in some of these cases, other than finding amoebae in the lumen of the appendix, I have been unable to note any change. Cases of amoebiasis confined to caecum and ascending colon may only show symptoms of slight anaemia.
Besides the more common insidious chronic type we may have amoebic dysentery setting in quite acutely with severe griping and frequent scanty grayish green to reddish brown mucoid stools.
Such cases may show anorexia and nausea with some fever but there is not present the manifestations of toxemia one associates with a severe case of bacillary dysentery in the tropics.
Very confusing cases are those in which a bacillary dysentery sets in upon an amoebic one and this possibility should always be thought of when a severe bacillary dysentery does not respond to serum therapy or an amoebic one to emetine.
Gangrenous lesions may occur in amoebic dysentery although more common in bacillary infections. Such cases will show extreme prostration and even give the clinical picture of cholera.
=Complications.=—By far the most important and serious complication of amoebic dysentery is liver abscess, which occurs in about 20% of cases. This condition is treated of separately. Besides liver abscess quite a number of cases of amoebic abscess of the brain have been reported, 26 such cases occurring in Egypt alone. These abscesses almost always occur in those cases which have developed liver abscess and may appear after the liver abscess has healed.
The pus of such abscesses is viscid and blood-tinged, resembling liver abscess pus. The amoebae are found in the abscess wall. The symptoms are those of brain tumor, meningitis not occurring. Necrotic processes of skin and muscles have also been reported in which amoebae have been found.
Perforation of the large intestine is not rare, Strong having noted 12 perforations in 77 autopsies. These usually occur in the region of the sigmoid flexure.
Adhesions are common complications of amoebic dysentery.
DIAGNOSIS
=Clinical Diagnosis.=—In the clinical diagnosis it is well to remember that many cases of chronic tropical diarrhoeas are really due to amoebic ulcerations of the intestines.
We can as a rule differentiate bacillary from amoebic dysentery by the more sudden and acute onset of the former together with fever and other evidences of toxaemia. The pulse rate is more rapid in bacillary than amoebic dysentery. Again the number of stools in bacillary dysentery is usually greater and the amount of each stool less in quantity. The stool of bacillary dysentery is of a milky whiteness from the large number of pus cells or composed of gelatinous, reddish mucus, while that of amoebic dysentery is tinged with disintegrated blood giving it a grayish-green or brown color. The mucopurulent mass in bacillary dysentery may be flecked or streaked with blood. The therapeutic results following emetine injections are of value in diagnosis.
Gangrenous types of dysentery are similar whether due to bacillary or amoebic infection. Chronic dysentery of bacillary origin is much like amoebic dysentery clinically.
Manson-Bahr and Gregg recommend the use of the sigmoidoscope in the diagnosis of chronic amoebic ulcerations. In the evening the patient takes ½ ounce of castor oil and the next morning a soap and water enema is given followed by 15 minims of laudanum. The patient is put in the lithotomy position. No anaesthetic is used. The pain in introducing the instrument is greater in chronic bacillary ulceration cases than in amoebic ones. Scrapings can be made for microscopic examinations. Nisbet has reported the diagnosis of a case of balantidial ulceration by use of the sigmoidoscope.
=Laboratory Diagnosis.=—The mucoid mass of amoebic dysentery is often brownish. The pathogenic amoeba shows active finger-like processes and in acute attacks often shows contained red cells. In the fresh specimen of the milky mucopurulent mass of bacillary dysentery one observes large numbers of pus cells and particularly very large phagocytic cells which greatly resemble amoebae. Upon staining with Gram’s stain one may find numerous Gram-negative bacilli in the cytoplasm of this cell.
These large cells which resemble amoebae are often vacuolated, thus intensifying the similarity. They are nonmotile, however, and do not show the small ring nucleus which is so characteristic of the vegetative human amoebae. The nucleus of the confusing cells is also larger, approximating one-fourth the size of the cell.
Bacillary dysentery stools show an absence of Charcot-Leyden crystals which are often present with amoebic stools.
For bringing out the nuclear characteristics of human amoebae Walker recommends fixation of thin moist smears in Giemsa’s sublimate alcohol (absolute alcohol 1 part, sat. aq. sol. bichloride 2 parts) for 10 to 15 minutes. These smears are then well washed with water and stained with alum haematoxylin for five minutes. The nuclear characteristics are noted under etiology. In such staining the preparations, which are best made on cover-slips, should never be allowed to become dry.
An excellent iron haematoxylin method is that of Rosenbusch:
Rapidly smear out with a toothpick a small particle of faeces or other material containing protozoa and, while still moist, fix by Giemsa’s method and, after getting rid of the mercury with iodine solution followed by 95% alcohol, treat smears with a 3.5% solution of iron-alum in distilled water for one-half hour or overnight, then wash thoroughly in distilled water.
Then stain from five to twenty minutes in the following haematoxylin stain: (1) 1% solution of haematoxylin in 95% alcohol. It takes at least ten days to ripen. (2) A saturated solution of lithium carbonate. Add to 10 cc. of the haematoxylin solution 5 to 6 drops of the lithium carbonate one. Next wash well and differentiate with about 1% solution of the iron-alum. Again wash in water, pass through alcohols to xylol and mount in balsam. With vegetative amoebae I have obtained beautiful results with vital staining which can best be done by tinging the faeces emulsion with a 1% aqueous solution of neutral red. I have also had good results by emulsifying the faeces in a drop of 1 or 2% formalin and then adding a drop of 2% acetic acid. The mixture is then tinged with either neutral red or methyl green.
For distinguishing the encysted form of Entamoeba coli one can obtain excellent results by emulsifying the faeces in Gram’s iodine solution. Owing to the glycogenic reaction given by E. coli, the round amoeba, with its 8 nuclei stands out very distinctly.
For diagnosing the 4-nucleated cyst of the pathogenic amoeba one gets better results with haematoxylin as this brings out not only the 4 nuclei but the chromidial bodies as well. It was formerly customary to recommend the administration of salts prior to examining for amoebae. Walker warns that such a procedure gives us amoebae which are difficult to differentiate, the nuclear characteristics of E. coli and the tetragena nucleus of E. histolytica being much alike as they both contain much chromatin. In a dysenteric stool the histolytica type of nucleus, containing but little chromatin, does not resemble the nucleus of E. coli.
He prefers the examination of formed stools obtained without a purgative.
DIFFERENTIATING CHARACTERISTICS OF PATHOGENIC AMOEBAE (AFTER DOBELL AND O’CONNOR). MOTILE STAGE
-----+----------------+-----------------+----------------+---------------- | Entamoeba | Entamoeba coli | Endolimax nana | Iodamoeba | histolytica | | | bütschlii -----+----------------+-----------------+----------------+---------------- Size | 20-30µ | 20-30µ | 6-12µ | 9-13µ -----+----------------+-----------------+----------------+---------------- Moti-|Very character- |Usually sluggish |Slow progressive|Slight motility lity| istic. Flows in| but may show | movement when | with movements | almost straight| considerable | freshly passed.| similar to | line across | activity when | Later slight | E. coli. | field. Later | freshly passed. | changes of | Quickly | becomes less |The movement | shape. Soon | degenerates | active pushing | consists chiefly| rounds and | and dies. | out a few, | in changes of | dies. | | large blunt, | shape without | | | blade-like | progression. | | | pseudopodia | | | | which are per- | | | | fectly hyaline | | | | being composed | | | | entirely of | | | | ectoplasm. | | | -----+----------------+-----------------+----------------+---------------- Cyto-|Endoplasm finely|Endoplasm had a |Endoplasm finely|Endoplasm finely plasm| granular and | bulky granular | granular with | granular and | uniform in | appearance and | numerous minute| homogeneous. | appearance. May| contains numer- | food vacuoles |Usually contains | contain red | ous food | containing | numerous food | blood cells but| vacuoles charged| bacteria. |vacuoles charged | bacteria | with bacteria |No sharp line as| with minute | probably never | and vegetable | a rule between | bacteria. Cysts | seen in normal | débris. Never | the endoplasm | of this amoeba | individuals. | contains red | and ectoplasm. | have previously |Ectoplasm clear | blood cells. No | | been described | and well | sharp line be- | | been described | developed. | tween endoplasm | | as “iodine | | and ectoplasm. | | cysts.” -----+----------------+-----------------+----------------+---------------- Nuc- |4-7µ. A delicate| 4-7µ. |1-3µ. Vesicular |2-3.5µ. Small leus | vesicle incon- | Distinguishable.| with delicate | vesicle with | spicuous or | Stained shows | membrane. | distinct mem- | invisible. | larger beads of |Stained shows | brane. Stained |Stained shows | chromatin lining| wall free from | shows wall free | fine beads of | wall. Karyosome | chromatin. All | from chromatin | chromatin | spherical, | chromatin cont-| as a rule. | lining wall. | eccentric and | ained in large,|Typically |Karyosome small,| larger than | irregular, | chromatin cont- | spherical and | that of | eccentric | ained in large, | central. | E. histolytica. | karyosome. | central | | |Variations in | spherical | | | shape of | karyosome. Zone | | | karyosome | between nuclear | | | characteristic.| wall and | | | | karyosome | | | | filled with | | | | single layer of | | | |small granules. -----+----------------+-----------------+----------------+----------------
(Part 1 of 2) ----------------------------------------------------------------- ENCYSTED STAGE -----------+------------------------+---------------------------+ | Entamoeba histolytica | Entamoeba coli | -----------+------------------------+---------------------------+ Size | 7-15µ | 15-20µ | -----------+------------------------+---------------------------+ Shape | Round. | Round. | -----------+------------------------+---------------------------+ Wall | Thin. | Thicker than E. | | | histolytica. | -----------+------------------------+---------------------------+ Nuclei |Typically shows four |Typically shows eight | |nuclei. May show one to |nuclei. May show one to | |four. Nuclei at rest |twenty. Structurally | |structurally similar to |similar to adult nucleus. | |that of adult nucleus. | | | | | -----------+------------------------+---------------------------+ Chromatoids|Large chromatoids |Large chromatoids may be | |common. |present but usually absent.| -----------+------------------------+---------------------------+ Glycogen |Diffuse but not |Relatively abundant in the | |abundant. |early stages. Scanty or | | |absent in mature cysts. | -----------+------------------------+---------------------------+
(Part 2 of 2) ----------------------------------------------------------------- ENCYSTED STAGE -----------+---------------------------+------------------------- | Endolimax nana | Iodamoeba bütschlii -----------+---------------------------+------------------------- Size | 7-9µ | 9-12µ -----------+---------------------------+------------------------- Shape | Usually oval. | More or less rounded. -----------+---------------------------+------------------------- Wall | Thin. | Relatively thick. | | -----------+---------------------------+------------------------- Nuclei |Very small. May show from |One relatively larger |one to four nuclei. Rarely |nucleus. Differs struct- |eight. Structurally similar|urally from the adult |to adult type of nucleus. |type in that the granules | |in the clear zone become | |massed at one pole giving | |an eccentric karyosome. -----------+---------------------------+------------------------- Chromatoids|Absent. |Absent. | | -----------+---------------------------+------------------------- Glycogen |Rarely present. |Dense glycogen mass is | |characteristic. | | -----------+---------------------------+-------------------------
Walker also notes the advantages of examining a specimen with a ⅔ inch objective as encysted amoebae are easily picked up. In opposition to the usual recommendation of text-books to report only on motile amoebae, he recommends the making of a differential diagnosis on nonmotile encysted forms. This however is now generally accepted by experienced workers as true.
The preëncysted E. histolytica has a nucleus much resembling that of E. coli. The presence of the same chromidial bodies one notes in the cysts is an aid in recognizing this stage. The 4 nuclei of the cysts are much smaller than the nucleus of the preëncysted or vegetative stage.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The main consideration is a knowledge of the importance of the carrier problem. The stools of all persons preparing food in localities where amoebic dysentery is prevalent should therefore be examined for the 4-nucleated cyst of the pathogenic amoeba. It must be remembered that while emetine controls the dysenteric manifestations of amoebiasis it does not seem to cause the disappearance of the parasite, so that patients who have had amoebic dysentery tend to become carriers.
As a matter of fact there is a question as to the possibility of the emetine treatment acting as a factor for the increase of carriers.
Vedder considers that while emetine will kill the amoebae deeply placed in the submucosa it has no effect on the more superficially located cysts and suggests that it may be possible to treat carriers by colonic irrigations with quinine or silver salts.
Emetine bismuth iodide has recently been highly recommended as our best agent for eradication of E. histolytica cysts of carriers.
=Treatment.=—The emetine treatment may now be considered as the specific one for amoebic dysentery. In Brazilian ipecac about 72% of the total alkaloids is emetine, so that it is better than Carthagena ipecac which contains only about 40% of emetine. Emetine was recommended for dysentery as long ago as 1817, but owing to the impossibility of differentiating between bacillary and amoebic dysentery, until recently, this method of treatment was little advocated.
In 1910 Vedder found that emetine was practically without power in its action on dysentery bacilli but that it would kill amoebae, even in dilutions of 1 to 100,000. He also found that deëmetized ipecac was quite inert in its action on amoebae.
In 1912, Rogers, who had for years been an ardent advocate of the ipecac treatment of amoebiasis, took up the treatment of amoebic dysentery and its liver complications with emetine. Reports from all over the world now attest the value of this drug in the treatment of the acute manifestations of amoebiasis but unfortunately note the inefficacy of this treatment on the encysted forms of amoebae.
It is usual to give from ⅓ to ⅔ grain of emetine hydrochloride, dissolved in sterile saline, by hypodermic injection into the subcutaneous tissues. Some now give as high as 1 grain daily for about ten days, but Vedder prefers ⅓ grain repeated 3 times daily. In these doses there is practically no nausea.
It was found by Baermann and Heinemann that subcutaneous injections of from 2 to 2½ grains daily caused indisposition and anorexia. The subcutaneous injections are less painful than the intramuscular ones.
Rogers has used emetine intravenously in doses of 1 grain without bad effect.
Vedder calls attention to the fact that the minimal fatal dose of emetine is several times less when administered to rabbits intravenously than when given subcutaneously, so that after seeing rabbits die with what was apparently centric paralysis immediately after intravenous doses of comparatively small amounts of emetine hydrochloride he would hesitate before administering 1 grain intravenously in a human case.
Levy and Rowntree think emetine should not be given intravenously except in extreme cases. Among ill effects of emetine they note peripheral neuritis. Kilgore has reported such cases where even wrist-drop was seen.
Low has treated cases successfully with keratin-coated tabloids of emetine hydrochloride, giving ½ grain every night. Vedder has not obtained satisfactory results with the drug by mouth.
Rogers considers that 15 grains of emetine is the fatal dose for an adult man and as there is possibly a cumulative action it would seem safer to continue the drug only for ten days and then later repeat the course of hypodermics. Of course emetine cannot cure the ulcerative lesions of amoebic colitis and as bacillary infections are apt to set in when damaged tissues are present and, as such infections do not yield to emetine, one must be prepared for failure in treatment of symptoms in such cases.
Recognizing the great importance of immediate treatment to prevent extension of the ulcerative process, as well as against abscess, the rule was adopted in the medical care of the English forces, in the Mediterranean, to give emetine so soon as a case of dysentery was seen, not waiting for a determination of etiology. The treatment ordered was 1 grain of emetine, hypodermically, every day for ten days, or ½ grain morning and evening for ten days. There must not be any intermission of a single day.
Before the introduction of emetine the usual treatment was with ipecac.
It was customary to give 20 to 50 grains of powdered ipecac in capsule, cachet or keratin-coated pills to a patient with an empty stomach and who had had a dose of morphine or laudanum about 20 minutes before the time for giving the ipecac. The salol-coated ipecac pills are generally used in America. The patient should be in bed and should try to yield to the soporific influences of the opiate. Any flow of saliva should be removed with gauze as its swallowing would provoke nausea. Some use a mustard poultice to the epigastrium. It is remarkable the change which this treatment will effect in the number and character of the stools.
Many now think it advisable to give emetine hypodermically to reach the amoebae deeply seated and, at the same time, to give ipecac by mouth to destroy more superficially situated ones, or those in the lumen of the gut. Alcresta ipecac has been recommended as a good method of giving ipecac by mouth.
We do not have now the same confidence in emetine injections that we formerly entertained. In Egypt the combination of emetine injections with ½ grain keratin coated tablets of emetine by mouth seemed to give better results in the more chronic stages of amoebiasis.
Very favorable reports have come from the use of emetine bismuthous iodide. This drug is given by mouth in doses not exceeding 3 grains in a day. It is put up in gelatine capsules and a course of treatment is one 3 grain capsule each night for 12 nights. It is supposed that there is no action on the drug in the stomach as it is insoluble in dilute acid but as a matter of fact nausea and vomiting frequently occur and slight purging is common after its administration. During the twelve-day course of treatment the patient should remain in bed and be given a milk diet.
We have recently had success with the administration of ipecac by the duodenal tube and it might be that bismuthous emetine iodide could be given in the same way.
Ross thinks that the flushing action of salines, thus washing away amoebae and necrotic material, is of advantage in amoebic as well as in bacillary dysentery. He also thinks liquid petrolatum of value. Some advise the bismuth treatment recommended by Deeks of giving a large teaspoonful of bismuth subnitrate, in a glass of water, 3 or 4 times during the day.
A decoction made by boiling for 15 minutes one teaspoonful of powdered chaparro in 8 ounces of water and given one-half hour before each meal has been reported on favorably. The powdered roots, stems and leaves of “Chaparro amargosa” are used. This is a plant of Texas and is named Castela nicholsoni. A decoction of about one-half strength of that taken by mouth is recommended for enemata. Simaruba bark is recommended by some practitioners. Its action is similar to chaparro. Benzyl benzoate is recommended for the pains and tenesmus of amoebic dysentery as well as bacillary dysentery. Twenty drops of the 20% alcoholic solution are given three times daily.
Many drugs have been recommended for colon irrigation of which the favorite is probably quinine muriate in dilution of 1 to 1000 or 1 to 2500. Inject 2 or 3 pints slowly by gravity. Protargol in 1 to 500 solution is better than silver nitrate in 1 to 2000. Emetine enemata do not seem to be of much value.
In very serious cases, particularly when gangrenous change in the mucosa may be present, the operation of appendicostomy seems indicated, following which a catheter is inserted and the large intestine irrigated with a 1% solution of bicarbonate of soda to wash away the mucus and later with a boracic acid solution of 1 to 125 or 1 to 10,000 of potassium permanganate.
In a discussion as to certain surgical considerations in connection with appendicostomy Muller notes that the right rectus incision is to be avoided on account of danger of gangrene from pressure of rectus on the stitched-up appendix. He also thinks that appendicostomy is much safer than caecostomy on account of the frequent thinning of the walls of the caecum. For irrigation he prefers a 1 to 500 solution of collargol.
In treating dysentery cases rest in bed and the use of a nonirritating diet are advisable.
The return of the increase of large mononuclears to normal may be used as an index to cure.
Walker and Emrich have recently reported success in treatment of cyst carriers by giving oil of chenopodium in 3 hourly doses of 16 minims, followed by castor oil and preceded by a dose of magnesium sulphate.
XI. LIVER ABSCESS
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—Although Hippocrates noted the method of evacuating abscess of the liver by caustics there was very little known about the condition until during the last century.
The history in connection with the finding of amoebae in liver abscesses is of very recent date (1887) and is taken up under the history of amoebic dysentery.
=Geographical Distribution.=—Concisely one may state that the distribution of liver abscess is in relation to the existence of amoebic dysentery. It is particularly prevalent in those centers of amoebic infection where there are many white men having little knowledge of the conditions necessary for the maintenance of health in the tropics.
In liver abscess, as with blackwater fever, it is education rather than acclimatization that brings about a diminution of these tropical diseases.
For several years subsequent to the American occupation of the Philippines amoebic dysentery and liver abscess were common but in more recent years liver abscess has become rare in Americans and amoebic dysentery much reduced in prevalence.
More temperate living results in less storing up of fat in the liver and an organ more resistant to infection.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—The dislodgment of amoebae-containing material from amoebic intestinal ulcerations and the plugging of the portal capillaries by such emboli give us the starting point of a liver abscess. The exciting cause is Entamoeba histolytica which in the liver continues the same production of a gelatinous necrosis as is carried on in the submucosa of the large intestine or appendix.
This pathogenic amoeba is fully described under amoebic dysentery.
As to obtaining a history of amoebic dysentery in liver abscess cases we have the following statistics:
500 cases with dysentery findings in 60% (Kartulis). 444 cases with dysentery findings in 59% (Zancarol). 500 cases with dysentery findings in 85% (Kelsch and Kiener). 63 cases with dysentery findings in 90.5% (Rogers). 38 cases with dysentery findings in 85% (Seamen’s hospital autopsies).
Amoebic liver abscess is exceedingly rare among children and probably 10 times less common among women than men.
Of 40 cases of liver abscess Waring noted intemperance in 67.5% and authorities generally insist upon the importance of the abuse of alcohol as a predisposing factor.
Natives of India very rarely develop liver abscess but it has been noted that when they begin to follow the customs of Europeans, as to eating and drinking, such lesions become more common in them.
As to the proportion of cases of amoebic dysentery which give rise to liver abscess only the statistics of those who have differentiated between bacillary and amoebic dysentery are of any value. Such statistics would indicate that about 20% of the cases of amoebic dysentery are complicated by liver abscess.
Liver abscess may be present without demonstrable lesions in the large intestines, such lesions having healed or the intestinal involvement having been so slight as not to have caused other than microscopic changes.
It is a well-known fact that liver abscess may set in years after a patient has left the tropics and years after the occurrence of any dysenteric manifestations.
PATHOLOGY
There seems little doubt but that the amoebae in the thrombosed terminals of the portal vein are carried by way of the upward current into the liver where they lodge in the liver capillaries, Councilman and Lafleur having found amoebae in such emboli.
Another view is that the amoebae may wander across the abdominal cavity and enter the liver in this way. This seems as improbable as that view which considers a possible entrance by way of the bile duct. Bile is toxic to amoebae and it would be difficult to explain their presence in the small intestines.
In 639 cases Roux found the abscess in the right lobe in 70% of the cases.
Other statistics give about 75% for the right lobe, 10% for the left lobe, 4% for the lobus Spigelii and in about 10% of cases abscesses are found in both right and left lobes.
In 562 cases Zancarol found a single abscess in 60% of the cases.
In 288 cases Waring found a single abscess in 61.5%, double abscesses in 11.5% and multiple abscesses in 27%. The favorite site of liver abscess is the superior and posterior part of the right lobe and near its surface.
The abscesses vary enormously in size, some being no larger than a walnut while others may contain a quart or more of pus, exceptionally as much as a gallon. The pus is typically of a chocolate color and contains degenerated liver cells, granular débris and often haematoidin and Charcot-Leyden crystals. There is an absence of polymorphonuclears. It may however be creamy in color.
In Strong’s cases about 50% of the abscesses showed bacteria upon culturing, the organisms noted being staphylococci, streptococci, B. coli and B. pyocyaneus.
The walls of liver abscesses are rather shaggy and the amoebae are found deeply located.
It is probable that the necrotic process, set up by the amoebae, begins in the interlobular capillaries although it may at times begin within the lobule.
Microscopically, the necrotic abscess wall shows amoebae in its depths but necrosis of the surrounding tissue beyond the zone of the amoebae is noticeable which would suggest the elimination by the amoebae of some toxic substance. There is an absence of polymorphonuclear infiltration around the abscess.
Surrounding the abscess wall there is a zone of marked hyperaemia. Amoebae may be found in this area as well as in the abscess wall.
If the liver abscess is not treated by emetine or with this drug and some surgical procedure the tendency is for rupture to occur and Cyr’s statistics show that of 159 cases rupture occurred as follows: lungs 59, pleural cavity 31, peritoneal cavity 39, intestines 8, stomach 8, vena cava 3, kidneys 2, bile ducts 4, pericardium 1 and externally 2.
SYMPTOMATOLOGY
Although the statistics would indicate that a history of amoebic dysentery has been obtained in only from 60 to 90% of cases of liver abscess, yet, when we consider that amoebic lesions of the large intestines have been frequently noted at autopsy in those who had never shown symptoms of dysentery during life, we are forced to believe that amoebic lesions of the appendix or large intestines are necessary factors in the production of liver abscess. Consequently, a history of amoebic dysentery is one of the most important points to consider in the making of a diagnosis of tropical liver abscess.
=Tropical Liver.=—There is also much evidence to be obtained from statistics and otherwise to support the view that the amoebic infection of the liver is only possible in a person whose liver has been functionally impaired. To this condition the designation tropical congestion of the liver or simply tropical liver has been applied. There is much to support the view that, in the tropics, the intestines and liver take the place of the thoracic organs in being subject to congestion. In temperate climates excesses and exposure to debilitating influences result in coryza or pneumonia. In the tropics we have diarrhoea and congestion of the liver. Tropical liver is recognized by vague digestive troubles, high-colored urine, loss of energy, irritability, with a sensation of fullness in the region of the liver which is generally described by the patient’s statement that he feels his liver. There may be pain referred to the right shoulder and the liver may be tender on palpation.
By the discontinuance of alcohol and highly spiced foods, with treatment by phosphate of soda or sodium sulphate, together with general care of the health, the patient may recover completely.
Rogers recognizes a condition which he terms the pre-suppurative stage of amoebic hepatitis in which the amoebae from dysenteric lesions have lodged in the portal terminals of the liver but in which abscess formation has not taken place.
At this stage we have a leucocytosis in which the polymorphonuclears are but little increased in percentage with a low remittent fever. At this time Rogers considers that the disease may be cured by emetine or ipecac and liver abscess avoided.
=A Typical Case of Liver Abscess.=—Following a case of amoebic dysentery, during the period of convalescence or subsequently, a rather irregular type of fever is noted, which shows an evening rise with sweatings which tend to become colliquative. From a marked feeling of weight in the region of the liver there may later develop tenderness or pain upon palpation of the liver. Of importance is the fact that there is no associated splenic enlargement. In the majority of cases the right side of the liver enlarges in an upward direction. A tape-measure will often show enlargement of the right side. Pain referred to the right shoulder is often complained of when the abscess is located in the upper convex part of the liver but, when nearer the inferior concave surface, there may be pain referred to the region of the appendix. When located in the left lobe the symptoms may be considered as of gastric origin.
The upward enlargement of the liver as shown by X-rays is of great value in diagnosis, but an abscess located in the center of the liver is not indicated by such rays.
There is a marked tendency to splint the liver so that the patient tends to lie towards the right side and when walking applies his right arm and forearm to his side, which led Koch to remark, “It is as if he carried his abscess under his arm.” The right rectus often shows rigidity.
Auscultation of the base of the right lung reveals a moist crepitation which, together with a dry cough (tussis hepatica), the fever, evening sweats, anaemia and emaciation, may suggest tuberculosis. The respirations are shallow as deep inspiration tends to cause pain. It must be remembered that cases of liver abscess have been reported where there were practically no symptoms.
Insomnia is a marked feature in many cases. Jaundice is rare, but an earthy color or subicteroid tinging is often noted. The superficial veins may be enlarged.
The urine is scanty and high-coloured, frequently with a marked increase in the ammonia nitrogen. Urobilin may be present in considerable amount.
There is a rather constant but low leucocytosis of from 12 to 20 thousand, which shows only about 70% of polymorphonuclears with an increase in large mononuclears up to 10 to 15%.
The final proof is the obtaining of the chocolate-coloured or anchovy sauce-like pus by exploratory puncture.
This pus does not contain pus cells but only granular débris, cholesterin crystals and is often bacteriologically sterile. The amoebae, being in the abscess wall, are not apt to be found when pus is at first withdrawn. Owing to the tendency of liver abscess to rupture into the lungs the first indication of the true nature of a prolonged hectic fever may be obtained when the characteristic pus is expectorated by the patient.
Attended with progressive emaciation and exhaustion the patient, as a rule, after a prolonged illness, dies, unless operative procedures cure him or some intercurrent disease brings about his death.
Symptoms in Detail
Onset and the Fever Chart.—The onset is at times so insidious that there may be no symptoms and yet a liver abscess be found at autopsy. Usually following convalescence after amoebic dysentery an irregular fever sets in which becomes hectic in character. Profuse sweats accompany the evening rise. The morning temperature is frequently normal and there may be frequent apyretic intervals.
The Respiratory System.—Crepitation at the right base, a dry cough (tussis hepatica) and shallow respirations are features of the disease.
The Nervous System.—Pains in the right shoulder are connected with irritation of the branches of the phrenic nerve.
The patient is irritable and often complains of insomnia.
The right rectus tends to be somewhat rigid and decubitus is dorsal or toward the right side.
The Liver and Spleen.—The liver is tender and as the abscess in nine-tenths of the cases is located in the right lobe and generally toward the upper convex surface we have an enlargement upward. There is very rarely any jaundice.
The urine shows an excess of urobilin and of nitrogen eliminated as ammonia. When the abscess is in the left lobe the condition is apt to be considered as some gastric disturbance. The spleen, as a rule, shows no enlargement.
Examination of the Blood.—There is usually a moderate leucocytosis with normal polymorphonuclear percentage and increase in the large mononuclears.
DIAGNOSIS
=Clinical Diagnosis.=—Of greatest importance is a history of a previous dysentery although it must be remembered that liver abscess may appear in one who has never had dysenteric symptoms. Fever of a hectic type with crepitation at right base, pain and upward enlargement of the liver are most significant.
The X-ray may confirm the diagnosis of upward enlargement which may be as high as the angle of the scapula. The majority of conditions causing enlargement of the liver give a downward enlargement.
The amelioration of symptoms by giving emetine hypodermically for two or three days is diagnostically exceedingly important.
Syphilitic gummata may give the picture of liver abscess, especially as regards the fever and loss of weight. Iodide of potash is said to be of use in differentiating, as it controls the fever of syphilis. The gummatous enlargement, however, is irregular and projects downward.
Suppurative pylephlebitis generally arises from infections of the colon or appendix. This condition as well as pyaemic (multiple) abscesses of the liver is apt to show jaundice.
In suppurative cholangitis and cholecystitis we get a history of biliary colic, jaundice and usually a marked point of tenderness at the tip of the ninth rib and a tumor in the region of the gall bladder. Abscess of the left lobe may give the symptoms of gastric trouble.
In differentiating empyema we usually have a history of pleurisy or pneumonia.
Suppurating hydatid cyst which may be confused with liver abscess is most surely differentiated by finding echinococcus hooklets.
Then too the complement fixation test for hydatid disease will differentiate.
Tuberculosis is often thought of, particularly when a liver abscess ruptures through the lungs. Malaria is also usually suspected. Abscess in the kidney or perinephritic region may be very confusing. In an abscess of the abdominal wall an exploring needle does not move up and down with respiration as it does when penetrating a liver abscess cavity.
=Laboratory Diagnosis.=—The chocolate-colored pus of a liver abscess, when there has been no bacterial contamination, shows an absence of polymorphonuclears and does not at first show amoebae. These appear in the pus coming from the drainage tube about the third day. Cholesterin and haematoidin crystals may be found in the granular débris of a fresh drop of pus used for examination for amoebae.
Liver abscess usually shows a moderate leucocytosis with a normal polymorphonuclear percentage and an increase of large mononuclears and transitionals to about 12 to 20%.
According to Schilling-Torgau we may have a perfectly normal white count and polymorphonuclear percentage and yet have evidence of the presence of liver abscess in his modification of Arneth’s index, so that in an apparently normal differential count we may find that ½ or more of the polymorphonuclears are of a less mature type and in cases where there are many immature polymorphonuclears we have indications which force a very cautious or unfavorable prognosis.
Thus a differential count of 33% band-form polymorphonuclears and 39% of normal nucleated ones would make us give a cautious prognosis, while one with 1% myelocytes, 22.5% immature polymorphonuclears, 21% band-form nucleated ones and 30% of normal ones would make for a very bad prognosis. We have a displacement to the left. Normally there are 63% of normal polymorphonuclears, 4% of band-form and no immature ones or myelocytes.
One may find an iodophilia in liver abscess.
Of the functional liver tests we may determine the ammonia quotient, the percentage of N eliminated as ammonia being increased in abscess of the liver. The same is true of the lipase test. Probably the most specific test for disturbances of the hepatic function is that for urobilinogen. The test is made by adding 5 to 10 drops of Ehrlich’s aldehyde reagent to 5 cc. of perfectly fresh urine when a positive reaction gives a fine cherry-red color.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The prophylaxis is the same as that for amoebic dysentery plus avoidance of anything which reduces the functional power of the liver, such as overfeeding, alcoholic excesses, etc.
It is well to remember that abscesses may occur months or even two or three years after an attack of amoebic dysentery, consequently it is well to give a grain of emetine on two or three successive days of each month following an acute attack.
=Treatment.=—Leaving out of consideration the pre-suppurative stage of amoebic hepatitis which, according to many authorities, responds to injections of emetine, it may be stated that the treatment of liver abscess is entirely surgical and such treatment should be instituted the moment the diagnosis is made. The earlier a liver abscess is drained the less run down will be the patient, the more rapid the convalescence and the better the prognosis.
Until recently surgical authorities condemned severely the trocar and cannula method of operation, but with the introduction of emetine there are now those who believe that such a procedure may suffice and a more radical operation not be necessitated.
Prior to introducing the trocar and cannula the usual procedure is to use an aspirating needle of about ⅛ inch bore and 3½ inch length. If the needle happens to be longer it should not be passed deeper than 3½ inches, in a person with a 32-inch chest, in order surely to avoid the vena cava. If there are no distinct localizing signs the needle should first be introduced in the eighth or ninth interspaces in the anterior axillary line and pushed backward, inward and slightly upward. Manson recommends at least 6 punctures before abandoning exploration. Cantlie does not think that a moderate degree of haemorrhage from the puncture of the liver will do harm in a case which is simply a liver congestion. One should always be ready to operate in case pus be found in the exploring needle. Leaving the needle in situ a small skin incision is made and a 4 or 5 inch by ⅜ inch trocar and cannula introduced along the line of the needle. Withdrawing the trocar some of the pus is allowed to escape through the cannula and there is then introduced a 6 × ½ inch piece of strong rubber drainage tubing, one end of which has lateral fenestrations but a closed tip in order that a long steel pin may put the tubing on the stretch so that it passes the smaller lumen of the cannula.
The cannula is then slipped out over the tubing and the external stretched end of the tubing released so that the contracting rubber fills the puncture. The steel pin used for introducing the rubber tube is then withdrawn and the tubing transfixed close to the skin with a safety pin.
After the cavity has drained of pus a dressing is applied. There are some who advocate aspiration alone without subsequent drainage. The dressing should be changed frequently and a connecting tube, draining into an antiseptic-containing bottle, should be attached to the tube in the cavity in order to obtain a syphoning action. Some aspirate and inject into the cavity about 2 ounces of 1 to 1000 emetine solution.
Some report favorably from the use of 1 to 1000 quinine irrigations. At present the hypodermic use of emetine will probably obviate the necessity of any irrigation.
There are those who think that a preliminary aspiration, followed by incision, after a few days of improvement in general condition, is the best method in serious cases.
It is usual to recommend a general anaesthetic when introducing the aspirating syringe or trocar and cannula. Local anaesthesia with quinine and urea hydrochloride, however, will usually suffice and lessen the dangers of shock in bad cases. Rib resections and even intra-abdominal procedures are best done under local anaesthesia provided the operator is familiar with the technic.
Newman has recently warned against the use of the small aspirator for diagnosis, pointing out that it is unreliable and that the diagnosis should be made by other diagnostic aids, including hypodermic use of emetine. He notes the occurrence of death from internal haemorrhage, the interference of the needle with the surgical incision and, further, the obscuration of the field of operation by pus where no adhesions exist and, finally, the danger of general peritoneal infection from a leak. He notes that the cavity may be under tension and that the pus may force itself along the track of the needle. He recommends incision and packing with gauze where adhesions do not exist and the exploration of the liver with dressing forceps instead of cutting into the liver with the knife.
USUAL OPERATION FOR LIVER ABSCESS
Either a vertical incision about the middle of the right rectus (Bevan) or a Kocher incision, parallel with the costal margin, may be used. The latter incision favors hernia if prolonged drainage is required. The hand is introduced into the abdominal cavity and the liver palpated. Often the borders of the site of a liver abscess give a hard feeling on palpation. If adhesions are not present the area should be packed off with gauze and the cavity opened by a dressing forceps, haemostat or thermo-cautery. It is often advisable to introduce a trocar and cannula and to drain off the excess of pus.
Where the abscess is situated far back or high up in the liver the transpleural route is to be preferred to the abdominal one. Make a 3 or 4 inch incision over the 9th rib with its center in the line of the angle of the scapula. Excise about 2 inches of rib subperiosteally. An assistant presses a roll of gauze against the tissues above the line of incision to prevent air entering the pleural cavity. Later the upper flap may be sutured to the endothoracic fascia. Even if the pleural cavity should be opened and air enter no serious result will follow although it is an accident to be avoided if possible. The diaphragm is now cut through and the liver exposed and after packing gauze around the area to be opened, the abscess cavity is entered and drained as previously described.
McDill prefers to resect 2 or 3 inches of both 9th and 10th ribs in the midaxillary line. The muscle wounds made in resection are then closed by catgut. This movable wall is now forced against the diaphragm with a roll of gauze pressed inward by an assistant. A 3-inch incision is now made through this bone-free wall near the upper border of the 11th rib, going through diaphragm and exposing the liver. The edges of the wound in the thoracic wall and diaphragm are now clamped together by haemostats to close off the pleural cavity. Later catgut sutures are substituted for the forceps. The liver often bulges into the wound. Finding the abscess by a palpating finger as a rather firm area in a less resistant liver surface we introduce a forceps or aspirating needle or trocar and proceed as above noted.
There are indications that the use of emetine subcutaneously may make the more radical operations unnecessary. In a recent symposium on liver abscess many of the papers would indicate a preference for aspiration without drainage coupled with emetine subcutaneously.
Rogers, in a recent article, notes that a case of liver abscess was cured by emetine without any form of operation. Recent experience, however, would indicate that it is necessary to evacuate the pus to effect a cure.
SECTION II
DISEASES DUE TO BACTERIA