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Journal of Experimental Medicine

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ETIOLOGY OF OROYA F E V E R
XV. EFFECT OF IMMUNE SERUM ON THE COURSE OF BARTON'ELLA
BACILLIFORMIS INFECTION IN ~¢IAcACUSRHESUSBY HIDEYO NOGUCHI, M.D., HENRY R. MULLER, M.D., EVELYN B.
TILDEN, PH.D., ANDJOSEPH R. TYLER(From the Laboratories of The Rockefeller Institute for Medical Research)
PLATES19 AND20(Received for publication, June 14, 1929)
Very early in the course of the work on Carrion's disease, experiments were begun (Noguchi) to test the effect of an immune serum,prepared in rabbits, or obtained from recovered monkeys, on thecourse of experimental infection with Bartonella bacilliformis in
Macacus rhesus. While these early results were not altogether promising, owing probably to the use of small doses of immune serum,
there was some indication that the introduction of the serum simultaneously with the infective material inhibited the development of
the infection, at least, temporarily (Table 1), the controls showing
skin lesions and positive Mood culture earlier than the treated animals.
Recently, studies were undertaken to determine the effects oflarger doses (20 cc.) of convalescent serum given 24 hours before
intradermal and intravenous inoculation of a highly virulent strainof BartoneUa bacilliformis isolated from phlebotomi. 1 This procedure
was found to have a marked inhibitory effect (Table 2). While thecontrol animal developed severe skin lesions within 2 weeks, and its
blood yielded cultures of Bartonella bacilliformis in a dilution of
1:10,000 after periods of 10 and 17 days, the treated animals remainedf r e e from lesions for 25 days, and cultures of the blood were sterile.
However, in two of the three treated animals, typical nodules eventually developed (after 25 days) at one Or more sites of intradermal
inoculation, and after 26 days the blood of one animal yielded culturesin a fitre of 1:100. The third treated animal escaped infection.
t Noguchi, H., Shannon, R. C., Tilden, E. B., and Tyler, J. R., J. Exper. Med.,
1929, 49, 993.
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Apparently the microorganisms had, in the two instances, remained
dormant at the sites where they were intradermally introduced until
the lapse of the period of passive immunity. This conclusion has
been confirmed, by another experiment, as likewise the view t h a t
blood invasion was inhibited.
Four animals received an injection 24 hours before inoculation of 20 cc. ofconvalescent serum, another injection of the same amount 11 days after inoculation, and two subsequent injections of 4 cc. and 5 cc., respectively, 15 days and26 days after inoculation. The control animals developed definite nodules in 11days, which progressed rapidly and had reached very large size 12 days later.
At this time the treated animals were still free from any lesions,and the blood wassterile. Theseconditionswere maintained for a period of 38 'daysafter inoculation(13 days after the last serum injection). At the end of this period, although blood
cultures were still negative, definite nodules appeared at the sites of intradermal
inoculation in 3 of the 4 monkeys; in the fourth animal nodules appeared 5 days
later. The development of the lesions thereafter followed the usual course ofexperimental verruga, but Bartonella bacilliformis was recovered from the bloodof the treated animals ouly in one animal (S-4) and then only once, 61 days
after inoculation.
The experiment is recorded in detail in Table 3. It will be notedthat the material used for inoculation was varied. Each monkey wasinjected intradermally at 3 or 4 sites on one side of the abdomen witha suspension of nodular tissue from a monkey infected with Phlebotomus Strain 1 of Bartonella bacilliformis, and each received similar
inoculations on the other side with cultures of Phlebotomus Strain 3or Strain 4. While the control animal for the nodule suspension
responded in the usual way, only one of the 3 treated animals reacted
to this material, though all showed the delayed reaction to the culture
inoculations. But for the precaution taken to use varied material,
the cultures in this instance proving to be of the maximum virulence,
the results might have been interpreted as indicating that 3 of the 4serum-treated animals were completely protected against infection.
The one monkey which showed a delayed reaction (58 days) to theinoculation of the moderately virulent nodule suspension was evidently
the most susceptible animal of the four, since it was the only one
which was not completely protected against invasion of the blood byBartonella bacilliformis.
The results recorded in Tables 2 and 3 indicate that while the360

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H. NOGUCHI, ]~. R. MULLER, E. B. TILDEN, A N D J. R. T Y L E R363

convalescent serum was not potent enough to protect completelyagainst the inoculation of highly virulent cultures, it had a marked
inhibitory action, as shown by the long delay in the development ofthe lesions, and that only occasionally did it fail to prevent invasionof the blood by the Bartonella.
The effect of large doses of convalescent rhesus serum given after
local lesions had started to develop following the inoculation of cultures, was tested as follows:
In two rhesus monkeys, S-8 and S-9, treatment with convalescent serum wasstarted 5 days after intradermal inoculation with a virulent strain of Bartonella
badlliformis, that is, when definite nodules had appeared, and when blood culture
in both animals was positive in a dilution of 1:10. The serum was given intravenously in a dose of 20 cc. Notwithstanding the treatment, the nodules
progressed rapidly, but 8 days later blood cultures were negative. At this time asecond intravenous injection of 20 cc. of convalescent serum was given to eachanimal. Bloodcultures continued negative throughout the remaining course of
disease, but the local lesions progressed, and each animal was given anotherintravenous injection of 10 cc. of the immune serum on the 17th day. There
was no perceptible effect of the serum treatment on the growth of the nodules,
which matured about the 36th day after inoculation. Recoverywas completeon the 67th day. At no test after serum was given were positive blood cultures
obtained.
This experiment, recorded in detail in Table 4, shows that convalescent serum, given after the development of the nodules, sterilized
the blood stream but had no effect on the nodule formation.
SUMMARy

Experiments are reported on the effect upon the course of experimental verruga peruana in Macacus rhesus of the injection of (1)small quantities of rabbit immune serum simultaneously with living
cultures, (2) one large dose of convalescent monkey serum 24 hours
prior to inoculation, (3) a similar preliminary dose followed bythree subsequent injections of the serum, (4) three large doses ofconvalescent serum, following the inoculation. The convalescentserum was found (1) to prevent the multiplication of Bartondla
bacilliformis in the blood in most instances, and (2) to delay .thedevelopment of the skin lesions for considerable periods, whengiven before inoculation. When the serum treatment was not begun

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E T I O L O G Y OF OROYA PEVER.

XV

until after the appearance of the skin lesions, it had no effect on theprogress of the nodules, although the blood became free from Barto-nella bacilliformis.
Since the severe effects of verruga peruana (Carrion's disease) arebelieved to be due to the multiplication of Bartonella bacilliformis
within the blood, the injection of convalescent serum in cases ofCarrion's disease in m a n would appear to offer promise.
EXPLANATION OF PLATESPLATE 19

Figs. 1 and 2. Two of the control animals, S-7 and S-5, 24 days afterinoculation.
Figs. 3 and 4. Treated animals, S-1 and S-2, 24 days after inoculation. Compare with Figs. 1 and 2.
Figs. 5 and 6. Treated animals, S-1 and S-2, 54 days after inoculation, when thelesions were comparable with those of the controls at 24 days (Figs. 1 and 2).
PLATE 20
Figs. 7 and 8. Treated animal, S-5, 24 and 54 days after inoculation,respectively.
Figs. 9 and 10. Treated animal S-4, 66 days and 100 days after inoculation,respectively. At 66 days the lesions had just become definite.
Figs. 11 and 12. Rhesus S-8 and S-9 (treatment begun after development ofthe lesions), 22 days after treatment was begun.

THE JOURNAL OF EXPERIMENTAL MEDICINE VOL. 50

PLATE 19

(Noguchi eta/.: Etiology of Oroya fever. XV)

THE JOURNAL OF EXPERIMENTAL MEDICINE VOL. 50

PLATE 20(Noguchi et al.: Etiology Of Oroya fever. XV)