Chapter 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.