quartan — the parasites always undergoing the same cycle of
development. The fourth and fifth cases need not be described
here.
These beautiful studies were quickly confirmed by W. Osier
14] FUNDAMENTAL OBSERVATIONS 65
[1886, 1887], by many Italian workers, and by Mannaberg.
Such facts have also now become a commonplace of clinical
medicine.
(4) The different types of malarial fever are caused by different
species of parasites. Since the time of the ancients clinicians
have been acquainted with three different types of fever, the
quartan, the tertian, and the irregular or malignant type. This
variation of type was equally surprising and inexplicable until
Golgi, after elucidating quartan fever, commenced a study of
tertian, and showed that it is produced by a parasite which
is morphologically different from the quartan parasite, and
reaches maturity every two, instead of every three, days. As
in quartan, however, the patient's fever begins at the moment
when the spores are liberated [1886, 1889]. Golgi also suggested
that the third variety of fever is associated with a third variety
of parasite — that which produces the well-known " crescents " ;
and this was proved to be the case by P. Canalis [1890] and
Marchiafava and Celli [1890], who made a detailed study of the
organism. Numerous confirmations followed, and the observa-
tions are now in general use for clinical diagnosis.
(5) Both parasites and the fever may be reproduced in healthy
persons by the inocidation of infected blood. This has been done
successfully in fifty-one cases, which will be described in the
following section,
(6) Both the parasites and the fever may be reproduced in
healthy persons by the bite of infected mosquitos. This has been
done successfully in thirty-six cases, which will be described in
section 17.
These facts are more than suflficient to prove that the
parasites cause the disease. Additional but less precise
arguments are : —
(7) The severity of the illness depends roughly on the number
of parasites present. First suggested by Laveran and Golgi
[1886], this theorem is now generally accepted, but rather on
the grounds of common experience than on precise estimations.
E
66 OBSERVATIONS AND EXPERIMENTS [Sect.
(8) Quinine reduces both the parasites and the fever. This
theorem, first suggested by Laveran, is now accepted every-
where, but still requires more precise study.
(9) Certain secondary symptoms are caused by the accumulation
of the parasites in certain organs. As frequently proved in the
case of the malignant parasites.
(10) Both the parasites and the fever tend to disapt>ear in a
locality if the carryitig A nophelines are greatly reduced in number.
As shown in many places, notably Ismailia.
15. Experimental Blood Inoculations. — These classical
experiments, commenced independently of Laveran's discovery,
and giving independent proof of a contagium vivum in malaria,
are of fundamental importance.
The first experiments were those of A. Dochmann [1880].
One drop of the contents of vesicles of Herpes labialis of a boy
suffering from quartan was inoculated subcutaneously into a
healthy man on 8th February (?) 1880. The man had rigors
and fever the same evening and on nth February, and malaise
on 14th February, no symptoms occurring in the intervals.
Subsequently three men were similarly inoculated with herpetic
serum from a girl with quotidian. This was followed by five
days' quotidian in one of the men, and none in the others.
Lastly, a girl was similarly inoculated on 12th April, and had
fever on 14th and i6th April. There appears to have been
no incubation period, and I agree with Laveran that the cases
must be rejected. The admissible cases are now given and
numbered for reference.
Case I. Gerhardt [1884]. — Source, quotidian fever; i c.cm.
of blood taken at end of rigor and injected subcutaneously into
B. S. on nth August 1882. Subject had slight fluctuations of
temperature 22nd to 26th August, and severe rigor and fever on
27th, 28th, 29th August. Quinine 2 grams on 29th ; recovery
after two days.
Case 2. Ibid. — Source, quotidian fever ; blood (? quantity)
15] BLOOD INOCULATIONS 67
taken during attack, and inoculated into K. G. at 2.15 P.M. on
4th July 1883. Subject attacked at 6 P.M. on loth July, and
again at about 3 P.M. on nth, 13th, 17th, 23rd, 25th, 28th, 29th,
30th (severe), 31st July. Quinine 2 grams daily, ist to 6th
August. Recovery followed.
Note. — The author appears not to have heard of Laveran's
discovery ; but his work was careful and good.
Case 3. Marchiafava and Celli [1885]. — Healthy subject
was inoculated subcutaneously with 0*5 c.cm. of blood taken
from quotidian cases during attack on i8th July and
15th August (?) 1884. Again, intravenously with 0*5 c.cm.
taken from a quotidian case during rigor on 21st August.
Again, intravenously, with i c.cm. taken from a case of double
tertian (? malignant) six hours before attack, on 26th August.
Subject had strong rigor one hour after this last injection, and
further attacks on 27th, 30th August, and ist, 3rd September,
when quinine was given. Isolated attacks occurred up to
October.
Case 4. Ibid. — Subject, who had previously had malaria and
was said to have been cured, was inoculated intravenously with
06 to 3'0 c.cm. of blood from various cases on 31st August, 4th
and 6th September. Left hospital. Returned to hospital with
fever on loth September. Daily attacks like those of the source
of blood inoculated on 6th September, the period of incubation
being said to be seven days.
Case 5. Ibid. — Healthy subject inoculated with I'O c.cm. of
blood from three cases, subcutaneously or intravenously on 6th,
9th and 13th September. Strong rigor on 20th September, and
fever till 25th.
Note. — Confused experiments. Type of parasites not
clearly seen (before Giolgi's work). Mariotti
and Ciarrochi, in whose clinics the work was
done, also reported it.
68 OBSERVATIONS AND EXPERIMENTS [Sect.
Case 6. Gualdi and AntoHsei [1889, No. 225]. Source
reputed to be quartan ; 3 c.cm. injected intravenously. Subject
attacked ten days later with malignant parasites.
Case 7. /did. — Same source, dose and injection. Another
subject. Attacked twelve days later, also with the malignant
parasites.
JVote. — In these two cases the quartan of the source seemed
to have produced malignant in the subjects ; but
the authors stated later [1889, No. 264] that
the source was subsequently found to contain
malignant as well as quartan parasites, the former
also being observed microscopically — so that the
result of the experiments was not surprising.
Case 8. Antolisei and Angelini [1889, Nos. 226, 227]. —
Source, mild tertian ; blood (? quantity) taken at beginning of
fever ; injection intravenous. Subject attacked with fever after
eleven days ; mild tertian parasites.
Case 9. ll>td. — Same source as previous case ; i 5 c.cm. of
blood taken at the same time ; injection intravenous. Subject
attacked almost at same hour as previous case. The same
parasites.
Case 10. Gualdi and Antolisei [1889, No. 264]. — Source,
quartan ; 3 c.cm. of blood injected intravenously. Subject
attacked after twelve days; quartan parasites.
Case II. /did [1889, No. 274]. — Source, malignant parasites
with apyrexia and (?) crescents only ; 2 c.cm. of blood, intra-
venous. Subject attacked with irregular fever on ninth day,
and asexual malignant parasites on tenth day. Crescents on
eighteenth day.
Case 12. Di Mattel [1891, No. 121]. Source, malignant;
(?) quantity of blood injected intravenously. Subject, a case of
quartan which had (?) recovered spontaneously. A few days
15] BLOOD INOCULATIONS 69
later small unpigmented asexual forms, and crescents twenty-
five days after inoculation.
Case 13. Ibid. — Source, quartan ; (?) quantity of blood,
intravenous. Subject, a case containing crescents only. Subject
attacked after fifteen days with quartan parasites, the crescents
diminishing in number.
Note. — These two cases show that a second species of
parasite can be added to a previous invasion.
The disappearance of the crescents in Case 13
need not have been due to the new invasion.
Case 14. Calandruccio [? 1891]. — Source, quartan ; i c.cm.
of blood, subcutaneously injected on ist December 1890.
Subject, the author himself, attacked with quartan on iSth
December ; relapses after two and three months.
Case 1 5. Ibid. — Source, a case showing (?) only crescents ;
r5 c.cm. subcutaneous. Subject, the author after recovery from
previous infection. After fifteen days was attacked by severe
rigor and fever, and then crescents after three days. No young
asexual forms found. Several relapses.
Case 16. Ibid. — Source, quartan ; i c.cm. of blood (?) sub-
cutaneous. Subject attacked after twelve days with quartan.
Case 17. Ibid. — Source containing only crescents ; i"5 c.cm.
(?) subcutaneous. Subject the same as in previous case, four
months later. Crescents found in spleen on eighteenth day,
and in peripheral blood on twentieth day. No asexual forms.
Note. — Author seems to have believed with Grassi and
Feletti that the crescents were a species by them-
selves {Laverania).
Case 18. Bein [1891]. — Source, mild tertian. Blood drawn
by leeches, taken out by a syringe, and injected to the amount
of 2 c.cm. in this and the three following cases. Subject
attacked on twelfth day with mild tertian parasites.
70 OBSERVATIONS AND EXPERIMENTS [Sect.
Case 19. Ibid — Source, mild tertian. Same procedure.
Subject attacked on twelfth day with mild tertian parasites.
Case 20. Ibid. — Source, mild tertian. Same procedure.
Subject attacked on tenth day with mild tertian parasites.
Case 21. Ibid. — Source same as in last case. Same pro-
cedure. Subject attacked on tenth day with mild tertian
parasites.
Note. — Four attempts failed. The injection was intra-
venous in one case, subcutaneous in the others.
The type of fevej- was not always the same as
that of the source, being sometimes simple and
sometimes double tertian ; but this is easily
explicable. The same parasite was always
found in the subject.
Case 22. Baccelli [1892]. — Source, tertian ; 3 c.cm. of blood
injected intravenously. Subject attacked with double tertian
parasites after six days.
Case 23. Ibid. — Source, quartan ; 4 c.cm. of blood contain-
ing few parasites, intravenous. Subject attacked with single
quartan after eleven days.
Case 24. Sacharofif [1894]. — Source, malignant. Blood
drawn by leeches, which were kept on ice for four days ; 1/4 c.cm.
of this blood injected subcutaneously on 4th October (?) 1893.
Subject, the author himself, had rigor and fever on i6th and
17th. Malignant parasites found on latter date.
Note. — This experiment was made during the course of
study of the vitality of the parasites in leeches
kept at freezing point. A second experiment,
with blood kept thus for seven days, failed.
Case 25. Bignami and Bastianelli [1894.] — Source, malig-
nant ; 2 c.cm. taken at close of paroxysm ; numerous parasites.
Subject attacked after (?) three days with the same parasites.
15] BLOOD INOCULATIONS 71
Case 26. Ibid. — Source, malignant; 5 c.cm. of blood with
moderate number of parasites, at close of paroxysm. Subject
attacked after (?) four days with the same parasites.
Case 27. Ibid. — Source, malignant ; 3/4ths c.cm. of blood
with moderate number of parasites ( ? scanty). Subject attacked
after five days with the same parasites.
Case 28. Ibid. — Source, malignant; i/Sth c.cm. with (?)
numerous parasites. Subject attacked after four days with same
parasites.
Case 2<^. Di Mattei [1895]. — Source, quartan; 2 c.cm. sub-
cutaneous, on 14th August (?) 1894. Subject attacked with
simple quartan on ist September (sixteen days).
Case 30. Ibid. — Same source and same injection on same
date. Subject attacked with simple quartan on 25th August
(eleven days).
Note. — Two other cases, injected subcutaneously with 0*5
and I'O c.cm. failed.
Case T^i. Ibid. — Source, malignant; 2 c.cm. of blood from
epistaxis injected subcutaneously in two places on i8th
September. Subject attacked with malignant parasites on
3rd October. Fever on 3rd, 4th, 5th, 9th, loth October.
Crescents on nth; quinine on i6th. Fever again on 17th;
quinine ; recovery.
Note. — In this paper author re-describes his earlier experi-
ments [1891], and also describes eight negative
attempts to transfer the malaria of birds from
bird to bird or bird to man, and four negative
attempts to infect birds from men.
Case "^^2. Bignami [1898]. — Source, malignant; less than
one drop of blood, subcutaneous. Subject attacked after six
days with the same parasites.
Case 33. Ibid. — Similar to the above. Subject attacked
after ten days with the same parasites.
72 OBSERVATIONS AND EXPERIMENTS [SECT.
Case 7,4. Mannaberg [1905]. — Source, benign tertian; 0'2
c.cm. of centrifugated blood taken during paroxysm ; sediment
injected subcutaneously. Subject attacked after twenty-one
days with the same parasites.
Case T,^. — Celli and Santori [1897]. Source, quartan;
4 c.cm., subcutaneous. The same parasites in subject after
twenty-five days.
Case 36. Idz'd. — Source, quartan ; 4 c.cm., subcutaneous. The
same parasities after twenty-five days.
Case 37. /(^/^. — Source, quartan ; 4 c.cm., subcutaneous.
The same parasites after twenty-five days.
Case 38. Id/d. — Source, malignant ; i'5 c.cm., subcutaneous.
The same parasites after thirty days.
Case ^g. Ibid. — Source, malignant ; r5 c.cm., subcutaneous.
The same parasites after six days.
Case \o. Ibid. — Source, malignant ; r5 c.cm., subcutaneous.
The same parasites after seventeen days.
Note. — In all these six last cases the blood was mixed
with sera of horse, buffalo or cattle before being
injected, in the hope of immunising the subject.
Case Of! . — Elting [1899]. Source, benign tertian; 3 c.cm,
of blood containing half-grown parasites injected intravenously
on 7th August (?) 1898 at (?) Baltimore. Subject had a slight
rise of temperature next day and sharp rise to 39*9° C. on loth.
Benign tertian parasites next day.
Case 42. Ibid. — Same source ; 2 c.cm. taken and injected
'he same day. Fever on fifth day ; benign tertian parasites on
the previous day.'
Case 43. Ibid. — Source, malignant, with numerous asexual
forms and a few sexual ones. Blood injected (?) 1-5. to 4-0 c.cm.
15] BLOOD INOCULATIONS 73
(?) intravenously on 28th August (?) 1898. Fever night of 30th
to 31st ; malignant parasites on 31st; crescents on 6th September.
Case 44. Ibid. — Same source, method and date. Asexual
malignant parasites found in subject ist September with
commencing fever. High fever on 3rd, and crescents on 8th.
Case 45. Ibid. — Same source and method. Inoculation of
subject 29th August, followed by a short rise of temperature in
ten hours, after which there was no fever till 5th September.
Asexual malignant parasites on previous day (4th), and crescents
on nth.
Case 46. Ibid. — Source, malignant — Case 43 above. Blood
(?) quantity taken a few days after appearance of asexual forms,
and (? how) injected on 1st September. Asexual malignant
parasites found on third day after injection, and thirty-two hours
before first rise of temperature. Crescents on ninth day.
Case 47. Ibid. — Same source, method and date. Fever on
4th September, and asexual malignant parasites on same day.
Crescents on 1 1 th.
Case 48. Ibid. — Source, malignant — Case 46. Blood
contained numerous asexual forms, and 1*5 c.cm. injected
intravenously on 9th September. Asexual malignant parasites
on 13th, fever on 14th, crescents on 20th.
Case 49. Ibid. — Two sources — malignant and benign tertian.
Two or three drops of blood containing only malignant parasites
injected subcutaneously (?) date. Next day 4 c.cm. from benign
tertian case injected intravenously. Short rise of temperature
two hours after second injection ; then normal for five days.
Fever seventh day after first injection, and malignant parasites
next day. Benign tertian parasites ten days after second
injection ; both flourished together. Crescents seventeen days
after first injection.
Case 50. Ibid. — Two sources — benign tertian and malignant
74 OBSERVATIONS AND EXPERIMENTS [Sect.
later. Blood from former, 4 c.cm. containing numerous
parasites, injected subcutaneously. Slight rise of temperature
six hours later. Marked fever on seventh day, and benign
tertian parasites on tenth day.
On the third day after first rise of temperature ( ? ten
days after first inoculation) the subject was inoculated with
( ? quantity of) blood containing numerous asexual malignant
parasites — intravenously. These were recovered in blood of
subject four days later, together with numerous tertian parasites.
Fever suddenly ceased eighteen days after first injection ; then
seven days apyrexia with only one or two tertian parasites
each day. But twenty-six days after first injection, quotidian
fever with both parasites began. Quinine and cure.
Case 51, Rosenau, Parker, Francis and Beyer [1904]. — At
Vera Cruz. Source, double benign tertian (" heavy " infection) ;
2 c.cm of blood during rigor, mixed with equal part of salt
solution, injected intravenously into subject at 2 p.m. on 6th
November 1903. Slight reaction within an hour. Typical fever
and parasites at 7 a.m. on loth November, double infection
(section 19 (4)).
This closes the list of positive experiments, but four
important negative ones with blood containing (?") only sexual
parasites remain to be recorded.
Negative Case i. Thayer [1898, p. 75]. — Source, a patient,
convalescent from first attack, had had quinine for four days,
during which none but crescentic and ovoid forms were found
in the peripheral circulation. A hypodermic syringe full of
his blood was injected into median basilic vein of subject in
August (? year). The latter was carefully observed for five
weeks, but never showed fever or parasites.
Negative Case 2. Elting [1899]. — Source, malignant, with
crescents and asexual forms, treated for eight days with four
hourly doses of 5 grains (o'325 grams) of quinine, until only
the crescents were left. Subject, injected intravenously with
15] BLOOD INOCULATIONS 75
3 to 3*5 c.cm. of blood on (?) date, never showed fever or
parasites.
Negative Case 3. Ibid. — Same source, injection and date.
Subject showed neither fever nor parasites.
Negative Case 4. Ibid. — Same source, injection and date.
Subject had slight transient rises of temperature two and six
days after inoculation. No characteristic fever or parasites.
Note. — These four cases give strong reason for supposing
that the sexual forms (crescents) are not in
any way concerned in the reproduction of the
parasites in the blood of the patient who contains
them (section 20 (4) ).
I am much indebted to Professor A. Celli for obtaining for me
from Professor Giulio Galli an account of two interesting experi-
ments performed by the latter, showing that malarial blood may
be inoculated without result into subjects who are taking quinine.
Negative Case 5. G. Galli [ ? ]. — Source, benign tertian,
many parasites ; 0'5 c.cm. of blood was injected subcutaneously
into subject, a healthy woman who had been given 0'4 grams
of "state" quinine daily for five days. The same dose was
continued on ist, 2nd, 5th, 6th, /th, 12th, 13th, 14th day after
inoculation, and then stopped. Subject remained in hospital
for forty-two days after inoculations, but showed no sign of
malarial infection.
Negative Case 6. Ibid. — Same source, amount of blood and
method of inoculation. Subject, a healthy woman, was given
o"4 grams of quinine daily two days before inoculation, and six
days after. She remained in hospital thirty-two days after
inoculation, but showed no sign of malarial infection.^
Remarks. — I have verified most of these cases from the
original literature ; but for a few of them the literature has
not been obtainable. I have also omitted a few cases regard-
ing which I can obtain no references.
^ See also section 65 (5).
76 OBSERVATIONS AND EXPERIMENTS [Sect.
16. The Parasites develop in Certain Mosquitos. — I
commenced the study of the mosquito-theory of malaria in
Secunderabad, India, in April 1895. Numbers of mosquitos
of the genera Odex and Stegomyia were allowed to feed on
patients whose blood contained the sexual forms of the
parasites, and were afterwards dissected in the hope of finding
in them some developmental stage of the organisms. This
investigation was continued without success until August 1897.
Many hundreds of insects of various species (undetermined) of
these genera were thoroughly searched, and many hundreds
more were examined less completely — strong evidence in
favour of the view that the parasites do not develop in these
kinds of gnats.
On the 20th and 21st August 1897, I found the zygotes of
the malignant parasite in two Anophelines (species undeter-
mined) bred from the larvae and fed on a case of crescents.
In September, I found them again under the same conditions
in a mosquito of another species of Anopheline [December 1897
and February 1898.]
About the same time MacCallum and Opie demonstrated
the sexual nature of the crescents [1897].
On the 20th March 1898 I found the zygotes' of one of
the malaria parasites of birds, P. danilevskyz Grassi and Feletti
1 890 {Proteosovia Labbe), in Culex fatigans, and worked out
the life-cycle of these parasites in the insects [1898]. It was
however of fundamental importance to prove that the bodies
found in the mosquitos were really descended from the
parasites found in the birds ; and the following proofs were
obtained : —
(i) The bodies in the mosquitos contained the characteristic
plasmodin (pigment) of the parasites in the birds.
(2) Their growth and development were observed in detail
in the insects.
(3) Out of 249 mosquitos fed on birds with no parasites
or other parasites, not one was found to contain the
17] THE MOSQUITO CYCLE 77
bodies referred to ; but, out of 245 mosquitos fed on
birds showing P. danilevskyi, 178 or 72% contained
them.
(4) Out of 10 mosquitos fed on a sparrow without
parasites, none contained the zygotes. In 10
mosquitos, fed at the same time on a sparrow with
moderate parasites (i/iooo^ haematids), 292 zygotes
were counted. In 10 mosquitos fed at the same
time in a sparrow with many parasites (1/50
haematids) 1,009 zygotes were counted.
(5) In July to August I succeeded in infecting 22 out of
28 healthy sparrows, and some other birds, by the
bites of infected mosquitos [1898, 1905].
This work was speedily confirmed by R. Koch [1899], by
C. W. Daniels [1899], and, subsequently, by many others.
I completed my work on human malaria in 1899 in Sierra
Leone [1899, 1900] ; but in the meantime Bignami, Bastianelli
and Grassi had already observed that the human parasites have
the same life-history [1898- 1899.] Since then the life-cycle of
the parasites in mosquitos has been studied by many workers
(section 6).
17. Experimental Mosquito Inoculations. — We should
begin by referring briefly to the early studies which showed
that malaria cannot be communicated by marsh water. After
the efforts of Salisbury in 1866, Balestra in 1869, Safford and
Bartlett, Archer, Bargellini, Klebs and Tommasi - Crudeli —
well summarised in the paper of the last named [1879] — to
incriminate various organisms as the cause of the disease,
several Italians carried out good researches on the effect of
drinking water. Celli failed in infecting six people by water
brought from the Pontine Marshes [1886] ; and Brancaleone
and Marino performed similar experiments. The work of
Agenore Zeri [1890] was very complete. He gave water from
^ Very roughly computed.
78 OBSERVATIONS AND EXPERIMENTS [Sect.
the Pontine marshes and elsewhere to nine persons to drink
in doses between 3 and i"5 litres a day for five to twenty days
each. To sixteen others he administered the water in the
form of inhaled spray ; and to five others by rectal injection.
All the experiments were negative. Yet they should have
succeeded if we suppose that the plasmodia live in such water
and infect either by the respiratory or digestive passages —
unless we assume that they died in the water during transit
to Rome, where the experiments were conducted.
In 1895-1896 I made twenty-two experiments with a view
to infecting healthy persons with drinking water in which