ETIOLOGY OF OROYA FEVER
Authors: Noguchi Hideyo 
Published: June 2004

The experiments reported here were carried on in the main with passage strains of Bartonella bacilliformis, and the results indicate that the virulence of the organism has been considerably enhanced by passage through susceptible animals. While the animals of the earlier experimental series showed no anemia, some of the present group manifested a definite reduction in the number of red cells and in hemoglobin, and in one instance (M. rhesus 25) anemia was of the extreme type so often associated with Oroya fever in man. The anemic condition appeared to be secondary in character, however, nucleated red cells being few in number. In this animal also Bartonella bacilliformis was readily demonstrated in the erythrocytes by means of stained smears, though the number of cells invaded by the parasites was by no means so great as in the human infection.
In most instances of experimental Bartonella infection so far induced the demonstration of the parasites by ordinary routine examination of stained film preparations is possible only when the titer of the blood exceeds 1:1,000. Prolonged search of many slides has not been attempted, however. The number of microorganisms in the blood, as shown by culture tests of ascending dilutions, was in most instances highest (1:100,000 to 1:10,000,000) during the early period of the infection coincident usually with the period of highest fever, falling to a titer of 1:10 during the last half of the disease. In one of the fatally infected monkeys, however, the titer increased from 1:10 on the 4th day to 1:1,000,000 on the 24th day. The titer of the blood was equally great in Monkeys 5 and 6, although the former was inoculated locally, the other intravenously and intraperitoneally. The largest proportion of infected red cells was found in Monkey 25, while the blood titer, as shown by culture test, was highest in Monkey 7.
The febrile reaction varied in the animals of this series from a severe continuous fever of 104–105°F., lasting 2 to 3 months, in one instance, with a remittence during the 3rd to 5th weeks, to the acute high fever (106°F.) of 1 day's duration in the fatally infected monkey, No. 25. The more usual reaction, however, is an irregular course of moderate fever with one or more periods of high temperature (105°).
Bartonella bacilliformis was constantly demonstrated, both microscopically and by culture tests, in the lymph glands of animals sacrificed 2 to 3 months after inoculation, and in two of three instances it was present also in the spleen, bone marrow, and heart blood. In the case of M. rhesus 6, which died 26 days after inoculation, the microorganism was obtained also in culture from the lymph glands, spleen, and heart blood taken at autopsy. In the other animal which died, a terminal bactelial infection, while not obscuring the effects of the Bartonella infection, made it impossible to isolate the parasite from either blood or tissues.
The skin lesions, whether of the nodular type, induced by introduction of the virus intradermally or by application to the scarified skin, or of the miliary character occurring spontaneously as a result of systemic infection, always yielded cultures of Bartonella bacilliformis, and stained sections of such lesions revealed the parasites in large numbers in their characteristic situation in the endothelial cells.
A chronic, systemic infection, in which the lymph glands are enlarged and Bartonella bacilliformis is present in the blood in high titer, may be induced by local inoculation, as shown in the case of M. rhesus 5.
The local lesions induced in one instance by introduction of a passage strain, both intradermally and by scarification, attained within 2 months extraordinary size, the nodules arising at adjacent sites of inoculation on the right eyebrow having coalesced into a large pedunculated mass which overhung the eye. This type of reaction had not been observed hitherto in the course of the present study but has been described by earlier investigators as a result of the inoculation of monkeys with human verruga tissues.
The striking fact brought out in the present study is the variety of responses to inoculation which animals of the same species may manifest. The clinical features of the infection may be typical of Oroya fever or may resemble those of verruga peruviana, and in M. rhesus 25 we have an instance of a type of infection in which the characteristic phenomena of both conditions are simultaneously present. Whether the appearance will resemble those of the one or the other condition appears to depend on the susceptibility of the individual as well as on the virulence of the organism. Moreover, it seems probable that different degrees of resistance to the invasion of the parasite on the part of the blood cells, internal organs, or skin of a given animal may determine the predominant clinical manifestations of the infection. The factor of variation in susceptibility of different individuals or different tissues of the same individual would account for the variety of types of human Bartonella infection.