rats is the presence of a reaction at the site of inoculation in the
majority of cases where the organism is introduced subcutaneously, and
in about a third of the cases where the infectious material is rubbed on
the shaven skin (cutaneous inoculation). The local reaction may exist
only as a yellowish-brown crust, overlying a granulating surface, and
associated with a trifling thickening of the skin and subcutaneous
tissue. It may appear as one or more firm papules 3 or 4 millimeters in
diameter. The most frequent appearance is a brawny œdematous and
blood-stained reaction which extends over an area perhaps an inch in
diameter; at times purulent change may be well advanced. Very rarely one
finds so extensive an œdema as to cause the lesion to somewhat resemble
the widespread gelatinous reaction seen so commonly in the guinea pig.
On one or two occasions we have seen an extensive slough at the site of
inoculation.
BUBO.
It is very exceptional that one finds in cases of induced plague the
typical, firm, caseous bubo surrounded by an infiltrated area, as is so
commonly seen in natural infection in rats. The glands are sometimes
enlarged and injected without other changes. The commonest lesion,
however, is a markedly enlarged gland which upon close inspection is
seen to have a number of yellowish points just under the capsule. These
points are especially well seen when a section is made through the
gland. The gland may be squeezed out of the capsule and it breaks down
readily enough when pressure is made upon it; but the uniform necrotic
process that one sees so often in natural rat plague is absent.
LIVER.
Granular lesions precisely like those found in natural infections are
very common. If the rat has died on the sixth day or later, the ordinary
lesions are apt to be replaced by necrotic foci that may be as much as 2
millimeters in diameter.
SPLEEN.
This organ is found mottled more frequently than in natural plague
infection, and large granules are much more common.
The subcutaneous injection is rarely so well marked as it is in natural
infections.
Pleural effusion of the same nature as that found in natural plague is
common. Hemorrhagic foci are not rare in the lungs, and occasionally the
organs are partly consolidated.
CHRONIC PLAGUE DUE TO ARTIFICIAL INOCULATION.
Occasionally a rat that has been inoculated but has survived a week or
longer, will show, when killed, only an abscess at the site of the
injection. Stained smear preparations may show a large variety of
bacterial forms. We have not been able to demonstrate the presence of
_B. pestis_ in these lesions, yet there is no doubt but that the lesion
is the result of the inoculation.
A lesion more frequently found is a caseous or a purulent lymphatic
gland. If the inoculated rat has been killed about ten days after the
inoculation, in some cases one or more of the peripheral lymph glands
will be found to be surrounded by an infiltration, and the gland itself
will be purulent or less frequently caseous. Such lesions are
occasionally met with in rats in which there is no suspicion of plague
infection; but they are seen so frequently among rats that have survived
artificial inoculation with _B. pestis_, there is no doubt but that in
these cases they are the result of the inoculation. In several such
cases pest-like organisms have been demonstrated in smears, and acute
plague has been produced in guinea pigs by inoculation with the pus
found in these lesions. Not infrequently in these cases the spleen will
be found enlarged and looking very much like the organ in acute plague,
but cultures from this organ in such cases have in my experience
remained sterile.
In other cases the only lesions will be found in the spleen. The organ
is enlarged and contains a number of caseous nodules. These nodules vary
in number from four or five to thirty or forty and in size from the head
of a pin to a lesion 0.3 centimeter in diameter. In a number of such
cases the nature of the lesion has been demonstrated by animal
inoculation. For example, in a series of experiments carried out to
determine the susceptibility of San Francisco rats to plague infection a
large _Mus rattus_ died on the eleventh day after inoculation. The
post-mortem examination showed nothing except an enlarged spleen which
contained about a dozen caseous nodules, the largest of which was not
over 2 millimeters in diameter. The nodules were very firm and the
capsule smooth, so that they were held with difficulty with dressing
forceps. Cultures from the liver and the spleen remained sterile, but a
piece of the spleen was placed beneath the skin of a guinea pig. This
animal died of acute plague, and a pure culture of _B. pestis_ was
isolated from its liver. In some of these cases the liver will show
large, distinct, whitish caseous foci. In another case a small _Mus
norvegicus_ was killed on the twelfth day after a cutaneous inoculation
from an artificially infected squirrel. No lesion was found except in
the spleen which was not materially enlarged, but which presented two
small whitish caseous granules on the surface, neither being over 1
millimeter in diameter. A piece of the spleen containing one of these
granules was put under the skin of the belly of a guinea pig. The guinea
pig died on the fourth day with the usual lesions of acute plague.
Occasionally in these cases of chronic plague punctate hemorrhages or
even areas of consolidation are found in the lungs.
THE HISTOLOGY OF RAT PLAGUE.
The most recent and satisfactory work on this subject is that of
Ledingham [14], who has studied the lesions of both natural and induced
plague in rats. The following is a very brief abstract of his work. The
reader is referred to the original for a full study of the subject.
NATURAL RAT PLAGUE.
Two groups of cases are distinguished, first, those in which a large
number of _B. pestis_ are found in the liver and in the spleen. In the
spleen this is accompanied by hemorrhages and congestion of the pulp
sinuses and in the liver with congestion of the capillaries. These are
early cases.
In the second group, or the later cases, there are extensive reaction
changes in the tissues. In the spleen this leads at times to distinct
abscess formation, but more frequently to a walling off of the foci of
necrosis. In the liver more or less focal necrosis is found; sometimes
the areas of “necrosis” may be so extensive that little healthy liver
tissue remains. Bacilli are usually to be demonstrated in these areas of
necrosis. Giant cells of the Langhans type may be found in the
neighborhood of these foci.
The granular appearance of the liver is attributed to “hemorrhages and
the focal necroses, together with the fatty changes in the liver cells.
It must be understood, however, that a peculiar honeycomb-like vacuolar
degeneration of the liver cell protoplasm was far more frequent than any
actual, coarse, fatty infiltration. The granular appearance of the
spleen is due partly to endothelial catarrh and partly to subcapsular
changes.”
In experimental rat plague Ledingham found the lesions to resemble those
of the first group of cases referred to above. There is usually marked
bacteraemia; focal necroses of the liver are scanty.
In a chronic case, minute abscesses were found scattered through the
spleen. In the center of the abscesses were found clumps of degenerated
bacilli. The areas were walled off by epithelioid and spindle cells and
numerous giant cells of the tubercular type.
IMMUNITY OF RATS.
Contrary to the general impression the wild rat is not an animal
especially susceptible to plague infection. The Indian Plague Commission
[19] found that when rats are inoculated by the cutaneous method from
the spleen of infected rats 59 per cent are immune to infection. A
series of experiments conducted in the federal laboratory in San
Francisco showed that when inoculated with highly virulent cultures of
_B. pestis_ there is an immunity which is, however, more frequent among
the large rats. When inoculated cutaneously with tissue containing large
numbers of _B. pestis_ from plague infected human beings, rats, or
squirrels, about 15 per cent of small rats and about 50 per cent of
large ones were found to be immune. There is no good reason for
believing that this immunity of San Francisco rats was due to a previous
attack of the disease. Indeed, it was known beyond a doubt that some of
the immune rats had never had an opportunity of becoming infected with
plague in nature and thereby establishing an acquired immunity. We may
mention here the fact that has been observed by many workers, and which
we have amply confirmed, that rats are readily immunized by antiplague
serum.
The subject of the transfer of infection directly from rat to rat by
cutaneous or subcutaneous inoculation through a series of the animals is
one that is evidently intimately associated with the preceding subject,
as it is quite evident that an immune rat or several of them might
terminate a series without any actual diminution in the virulence of the
organism transferred. It is quite plain that the success of such an
experiment would depend largely upon the number of rats used in each
transfer. The Indian Plague Commission [19] had no difficulty in
carrying infection through twenty-six transfers, using from six to fifty
rats in each transfer.
Pound [7] in a series of eight experiments, was never able to convey the
infection successfully beyond the sixth rat, using but one rat for each
transfer. There was no apparent lessening of the virulence of the
organism and each series appears to have been terminated abruptly by
encountering an immune rat.
Baxter-Tyrie [15] says:
It is probable that under certain natural circumstances a reduction in
the virulence of the organism is effected and a comparative immunity
is conferred on the rats. The infection of immigrant rats is, however,
severe, and their arrival is heralded by a heavy mortality. In the
same manner an infected rat imported into a fresh locality produces a
similar result. This attenuation of virulence is responsible for the
condition known as chronic rat plague.
Several experiments conducted in San Francisco to determine this point
have given results that I regard as showing merely the presence of a
considerable percentage of immunity among the rats. It was observed that
in each case certain of the rats died of acute plague even in the last
transfer. It was very evident that had certain combinations of immune
rats been encountered the experiment might have terminated at any point.
On the other hand, by being especially fortunate in using nonimmune
rats, the experiments might have given a much higher percentage of cases
of acute plague. Unfortunately it was necessary to terminate these
experiments in each instance before they could be regarded as completed.
The reason for the natural subsidence of plague among rats in any
community is a point about which much more evidence must be obtained
before we can speak with any degree of certainty. It may be due to the
lack of susceptible material, possibly to a loss of virulence of the
organism; but it seems more probable that it is due to a change in the
number or relations of the ectoparasites of the rat.
Adequate measures of rat extermination, while they may never bring about
the ideal condition of a community that is free from rats, are, as is
shown by the recent experience in San Francisco, of the utmost value in
shortening the epizootic.
REFERENCES.
Endnote 1:
Skschivan (Centralblatt für Bacter., etc., 1903, Vol. XXXIII, No. 4,
p. 260).
Endnote 2:
Kister & Schumacher (Zeit. für Hyg. u. inf. Krank., Vol. LI, 1905).
Endnote 3:
Indian Plague Commission (Journal of Hygiene, 1907, Vol. VII, No. 3).
Endnote 4:
White (Medical Record, vol. 67, No. 4, Jan. 28, 1905).
Endnote 5:
Kitasato (Philippine Journal of Science, Vol. I, No. 5, 1906).
Endnote 6:
Wherry, Walker & Howell (Journal Am. Med. Assn., April 11, 1908, Vol.
L, No. 15).
Endnote 7:
Pound (1907, Report on Plague in Queensland, B. B. Ham, p. 134).
Endnote 8:
Dunbar & Kister (1904, Centralblatt für Bact., etc., Vol. XXXVI, No.
1, p. 127).
Endnote 9:
Kolle & Martini (Deut. Med. Woch., Jan. 2, 1902, Vol. XXVIII).
Endnote 10:
Kister (Centralblatt für Bact., etc., July 24, 1906, Vol. XLI, No. 7).
Endnote 11:
Neumans (1903, Zeit. f. Hyg. u. inf. Krank., Vol. XLV, No. 3, p. 451).
Endnote 12:
Kister & Schmidt (1904, Centralblatt für Bact., etc., Vol. XXXVI, No.
3, p. 454).
Endnote 13:
Aujeszky (1904, Centralblatt für Bact., etc., Vol. XXXVI, No. 5, p.
603).
Endnote 14:
Ledingham (Journal of Hygiene, 1907, Vol. VII, No. 3).
Endnote 15:
Baxter-Tyrie (Journ. of Hygiene, Vol. V, 1905, p. 315).
Endnote 16:
Wherry (The Journal of Infect. Diseases, Dec. 18, 1908, Vol. V, No.
5).
Endnote 17:
Klein (The Bacteriology and Etiology of Oriental Plague, MacMillan and
Co., London, 1906).
Endnote 18:
Indian Plague Commission (Journal of Hygiene, 1907, Vol. VII, No. 6,
p. 761).
Endnote 19:
Indian Plague Commission (Journal of Hygiene, 1906, Vol. VI, No. 4).
RAT RECORD CARD.
[Legend: O = Ordinary; W = White belly; R = Red; Go. = Gopher rat; S =
Small; M = Medium; L = Large; M. R. = Mus rattus; M. N. = Mus
norvegicus.]
───┬────────┬───────────────┬─────┬────────┬────────────┬─────┬─────────
No.│ Date. │District No. 6.│Sex. │ Size. │ M. N. │M. R.│Pregnant.
───┼────────┼───────────────┼──┬──┼──┬──┬──┼──┬──┬──┬───┼──┬──┼─────────
„ │ „ │ „ │M.│F.│S.│M.│L.│O.│W.│R.│Go.│O.│W.│ „
───┼────────┼───────────────┼──┼──┼──┼──┼──┼──┼──┼──┼───┼──┼──┼─────────
19 │Dec. 10,│ 401 Fillmore │1 │ │ │1 │ │ │ │1 │ │ │ │
│ 1908 │ street │ │ │ │ │ │ │ │ │ │ │ │
20 │ do │ do │ │1 │ │ │1 │1 │ │ │ │ │ │ [S]7
───┴────────┴───────────────┴──┴──┴──┴──┴──┴──┴──┴──┴───┴──┴──┴─────────
Footnote S:
Number of fœtuses.
PLAGUE RAT CARD.
PLAGUE RAT NO. 50.
Date: June 20, 1908.
Species: _M. norvegicus_.
From District No. 6, sewer, Haight and Steiner Streets.
Condition: Badly injured by trap; thorax crushed.
Subcutaneous injection: General, marked.
Lymphatic glands, bubo or other lesions: Right inguinal bubo, caseous.
Liver: Typical whitish granules.
Spleen: Large, dark, firm.
Pleural effusion: Unable to say.
Purulent or caseous foci:
Diagnosis from gross lesions: Plague.
Diagnosis from smears: Plague (spleen and bubo).
Cultures: _B. pestis_ recovered from liver culture.
Inoculation, guinea pig No. 50 A, +6.25.08.
Vaccination, guinea pig No. 50 B, +6.26.08.
Date suspicious:
Date positive: June 20, 1908.
Date negative:
[Illustration:
A HOEN & CO BALTIMORE.
NECROPSY APPEARANCE OF PLAGUE-INFECTED RAT
]
[Illustration:
A HOEN & CO BALTIMORE
NECROPSY APPEARANCE OF NORMAL RAT
]
RAT LEPROSY.
By WALTER R. BRINCKERHOFF, S. B., M. D.,
_Assistant Director Leprosy Investigation Station, United States Public
Health and
Marine-Hospital Service, Honolulu, Hawaii_.
INTRODUCTION.
The leprosy-like disease of the rat is of great interest to leprologists
because of its close similarity to the disease leprosy in man. Its
practical importance to those engaged in the study of the human disease
is increased by the fact that it can be artificially propagated under
laboratory conditions from animal to animal and, still more important,
can be transferred from the species in which it occurs naturally (_Mus
norvegicus_) to a more tractable laboratory animal (_Mus albus_). The
brief description of the affection which follows is intended to assist
in its recognition and to stimulate the interest of investigators in the
disease, which presents problems replete with interest to the study of
pathology or bacteriology and of great promise to those engaged in the
investigation of human leprosy. It is earnestly hoped that the
investigation of this disease will be undertaken in general medical
research laboratories, as it is extremely probable that certain of the
most difficult problems presented by leprosy in man can be studied in
this disease of the rat, and if solved there the information gained can
be directly applied to the solution of the analogous problems in the
human disease.
REVIEW OF LITERATURE.
The first publication on rat leprosy was made by Stefansky (1903), who
observed the disease in Odessa during an antiplague campaign against
rats.
Rabinowitch (1903) found the disease among rats in Berlin and confirmed
the work of Stefansky.
Dean (1903) discovered the disease independently in London, and in a
later publication (1905) reports success in transferring the disease by
artificial inoculation.
Tidswell (1906) reports a case of the disease in a rat caught in Sydney,
New South Wales, Australia.
The English Plague Commission observed the disease in India in 1907
(Wherry).
Wherry (1908) and McCoy (1908) report upon the finding of the disease in
rats caught in San Francisco, Cal.
Mezincescu (1908) has studied the disease and attempted to determine its
relationship to known human lepra by complement fixation tests.
DESCRIPTION OF DISEASE.
_Geographical occurrence._—It would be premature at present to make
didactic statements as to the geographical distribution of the disease,
for its discovery has usually depended upon antiplague measures, which
are not world-wide in their scope. In spite of this it seems profitable
to briefly review the known occurrence of the disease in relation to
that of human leprosy. When such a comparison is made we note that the
disease is present among the rats of Berlin, a city which is practically
free from human lepra. On the other hand in Honolulu, which is an
endemic focus of human leprosy, in the examination of 16,000 rats,
during an antiplague campaign, no case of rat leprosy was encountered.
In addition to the scrutiny of the rats examined for plague in Honolulu,
an attempt was made to obtain leper rats by offering a reward for a rat,
dead or alive, infected with the disease. This offer was given wide
publicity in the Territory, but brought no results.
_Occurrence of the disease._—The proportion of rats infected with the
disease in different localities varies greatly, as will be seen in the
following table:
TABLE 1.—_Proportion of leper rats to the total rats examined._
───────────────────────────┬───────────────────────────┬───────────────
Place. │ Observer. │ Proportion.
───────────────────────────┼───────────────────────────┼───────────────
│ │ _Per cent._
Odessa │Stefansky [301] │ 4–5.000
Sydney │Tidswell [305] │ .001
San Francisco │Wherry [308] │ .210
Do │McCoy [310] │ .160
Honolulu │Currie[T] │ .000
───────────────────────────┴───────────────────────────┴───────────────
Footnote T:
Personal communication.
Rats in the late stage of the disease are easily recognized by the
presence of a patchy alopecia associated with cutaneous and subcutaneous
nodules, which may or may not be the site of open ulcers. The diagnosis
can be readily confirmed by a microscopic examination of a smear from an
ulcer or a nodule, which will show the specific bacillus of the disease
in enormous numbers.
Stefansky[301] describes two clinical types of the disease, the one
localized particularly in the lymph nodes, the other in the skin and
muscles. The glandular type was the more common. Dean[304] thinks that
no line of demarcation can be drawn between these clinical types.
Dean[304] and Wherry[307] both mention that attention was attracted to
the diseased animals by the fact that they were seen abroad during
daylight in an obviously sick condition.
The skin, in a well-developed case of the disease, presents a patchy
alopecia coincident with thickening and nodule formation, which is
situated in the subcutaneous tissue. The cut surface of the nodules or
thickenings is light yellow in color, is clean, dry, and cheese-like. In
the region of the nodules the skin is atrophic, and ulcers often form on
the prominent parts of the affected area. The subcutaneous fat tissue is
diminished in amount. Histologically the process is seen to be
practically confined to the subcutaneous tissue and to consist
essentially in the presence of cells rich in protoplasm, with vesicular
nuclei, whose cell body is more or less completely filled with slender
acid-fast bacilli. The subcutaneous fat is replaced by such a tissue.
All investigators who have studied the disease agree in emphasizing the
similarity of the histology of the lesion to that in leprosy in man.
When the musculature is involved the muscle fibers atrophy and the
fibers are infiltrated with the specific bacilli. The affected muscle is
friable, and macroscopically grayish white in color.
The peripheral lymph nodes are commonly involved, though McCoy[310]
reports a case in which only the pelvic and mesenteric nodes were
diseased, and in the Tidswell case[305] the peripheral nodes were not
enlarged. The typically affected nodes are enlarged, sometimes measuring
as much as 3 centimeters in the greatest extent, firm, and, on section,
opaque pale yellow-white in color. In the experimental disease the
writer has frequently found the characteristic bacilli of the disease in
peripheral lymph nodes which were very slightly enlarged and presented
no macroscopic lesion. Dean[304] has observed invasion of the
submaxillary or salivary glands by extension from infected cervical
lymph nodes. Wherry[308] notes that in his cases he did not find the
submaxillary or cervical glands involved, which fact he contrasts with
two early cases in which the skin and adjacent axillary or inguinal
nodes were involved.
Microscopically the lymph nodes show large numbers of cells in the
sinuses similar to those in the skin lesions. Multinuclear giant cells
are frequently observed which may measure as much as 70 to 80
microns[304]. The protoplasm of the cells is loaded with the specific
bacilli of the disease. The lymph follicles, trabeculæ, and capsule of
the glands are also invaded by the bacilli.
The internal organs are relatively slightly affected in the natural
disease. Small foci have been found in the liver by Dean[304] and in the
liver and spleen by McCoy[310]. Wherry[307] reports finding the bacilli
in smears from both the liver and spleen. The writer has found
microscopic lesions containing the characteristic bacilli in the liver
in a case of the experimental disease.
Lesions have been observed in the bone marrow by Dean[304], and the same
author states that the nerves are invaded by the bacilli of the disease.
McCoy[310] found the bacilli in the urinary bladder in one case.
With a disease showing such a striking similarity to human leprosy,
attention has naturally been directed to the bacteriological examination
of the nasal mucus. Dean[304] and Wherry[307] have both found the
characteristic bacilli in the nasal mucus, while McCoy[310] has failed
to do so. The writer’s experience has been confined to the experimental
disease, and in his animals the nasal examinations have been negative.
ETIOLOGY.
The accepted etiological factor in the disease is an acid-fast bacillus
3 to 5 microns in length and 0.5 micron wide. The bacilli resemble very
closely the lepra bacillus of man, but seem to have somewhat greater
power to hold carbol-fuchsin stain against mineral acids. The bacilli
often have rounded ends and may be curved. The beaded appearance so
often seen in lepra bacilli is common. The bacilli show the same
tendency to form bundles that is such a marked characteristic of
_Bacillus lepræ_. To one familiar with the microscopic appearance of
smears from the discharges and lesions of human leprosy the picture
presented by similar preparations from the disease of the rat is most
striking.
The organism does not grow on the usual culture media—Stefansky [301],
Rabinowitch[302], Dean[304], Tidswell[305]—or on certain special
media—Dean[304].
The organism is not pathogenic for the guinea pigs—Dean[304],
Tidswell[305]—rabbit, mouse, monkey—Dean[304]. The disease can be
transmitted to black and white rats—Dean[304], Wherry.
SUMMARY.
In the leprosy-like disease of rats we have an affection which closely
resembles, both in its etiological factor and in its pathology, the
disease leprosy in man. The fact that the disease is readily propagated
in a laboratory animal permits of its investigation in any laboratory.
It is earnestly hoped that the study of this disease will be taken up by
bacteriologists and pathologists, as in this way valuable information
may be gained which will be applicable to the problems presented by
leprosy in man.
BIBLIOGRAPHY.
Endnote 301: