Note: This article first appeared in
the journal Medical Record, November
I take up a recent book,1 which mirrors
accurately enough current opinion, and there I read, "Quinine
is the one specific for all kinds of malarial fevers as it absolutely
destroys the malarial parasites." This
is the general teaching of the schools, and when one first begins tropical
practice; one relies upon quinine as a certain cure for malaria. Some
ten years ago, experience led me to doubt this infallibility. In Hong
Kong about that time, malaria was the chief cause of sickness among
the troops. As I remember, the admission rate to hospital for malaria
was about 2,400 per thousand. (The number 2,400 is correct. A startling
number--the equivalent of every man in garrison being a patient in
hospital nearly two and a half times every year!) Quinine in various
forms, orally and hypodermically, in different courses of treatment
was tried, but no
method could be relied upon to obviate a relapse. During my service
in Hong Kong, I should have had no difficulty in producing many cases
showing records of seven or eight relapses. These relapse cases have
been a matter of concern because of the ensuing inefficiency, and recently
with the troops in India, efforts have been made to systematize the
quinine treatment, to ensure that quinine is taken in sufficient doses
and that the treatment is spread over a sufficiently long time. These
measures are complete enough as the following details will show: (1)
No case of fever is diagnosed as malarial until the parasite has been
recovered from the blood; (2) No case of malaria leaves hospital until
the peripheral blood is negative, showing no parasites; (3) After leaving
hospital, all malaria patients attend for further treatment on a "malaria
register": (a) benign cases receive quinine sulphate in acid solution,
gr. x, daily for one week and, afterwards, three times weekly until
four months of quinine treatment has been completed, and (b) malignant
cases receive quinine in the same form, gr. x daily for one month and,
afterwards, thrice weekly for three months longer. And yet relapses
occur. Patients return to hospital deaf from cinchonism, ill with fever,
and showing parasites in their peripheral blood.
I think the impression is very general that benign cases are cured
easily and relapses occur rarely. Here in Upper Burma, there seems
little distinction between benign and malignant cases as regards their
curability under quinine. Relapses seem as frequent in the one infection
as in the other, the only difference being in the cachexia, which is
persistent and progressive in bad cases of malignant infection. Major
Lelean, R.A.M.C., writing in the Journal of
the Army Medical Corps (November 1911), has had the
same experience in the 7th Division in India. I
quote his figures
as they show the importance of the subject: "Statistics have been
kept which show the relapses occurring among a total of 1,053 malarial
patients who attended hospital at Meerut for three months subsequent
to their discharge. During that period, they received 15 grains of
quinine on two days per week. The drug was administered in solution
and in the presence of an assistant surgeon, who kept a roster of these
men and strictly enforced their regular attendance. We do not know
what the mean daily strength was exactly, but it must have been approximately
so for the 18 months during which the results were kept. In that period,
there were 734 recurrences among these men, i.e., at the rate of 489
per year. It is, of course, obvious that this is but an approximate
calculation, but it shows a per mille per annum attack rate amongst
these men of no less than 2,876, which affords a considerable margin
for error without losing its startling character." And continuing,
he reiterates in slightly different form the question I have already
suggested, "Within comparatively recent years it has been taught
that the action of quinine upon malarial parasites was so certain that
quinine could be relied upon for clinical diagnosis. Was that teaching
correct?" I think not.
Quinine has its sphere of usefulness, but it is an empirical remedy – a
fundamental fact we have forgotten because the remedy is so time-honored.
In the foregoing, I have used the word "relapse" in the
ordinary medical acceptation of the term as applied to any disease – a
recurrence. Colonel R. H. Firth, in the Journal
of the Army Medical Corps (February 1913),
in speaking of apyrexial malaria wishes a distinction to be drawn between relapse
and recrudescence. By recrudescence of infection, he speaks of a recurrence
of the fever due to increased schizogony of the parasite after a period of
apyrexia. By relapse of infection, he indicates a recurrence of the fever due
to a reversion to schizogony after the establishment of sexual forms in the
blood. Professor Minchin,2 in his Introduction
to the Study of the Protozoa,
the 'incubation' period of the disease, schizogony alone occurs in all probability,
but when the numbers of the parasite are sufficient to affect the health of
the host, the reaction of the host against the parasite probably stimulates
the production of the propagative phases, and Schaudinn has described the changes
of the trophozoites which become sporonts."
In the light of the recent work3 of my friend, Dr. John Beard, on the occurrence
of dextrorotatory albumins in organic nature and the part played by ferments
in the protection of the animal body, all these things find a ready explanation.
Schizogony of the parasite produces the clinical disturbance we call fever,
the sexual forms are harmless, and the asexual growth of the parasite, as is
the common feature with all asexual growths, can proceed to an unlimited number
of generations or cell-divisions until checked by the natural protective ferments
of the animal body. Just as the trophoblast is checked in its growth by the
ferments of the developing embryo (Beard), so the natural protective ferments
of the host react against the asexual phase of the parasite, and sexual forms
begin to appear. The varying degree of immunity, the degree to which the malaria
remains dormant, is a measure of these natural protective ferments. In a like
manner, as these ferments are insufficient to destroy the asexual forms, the
disease recurs. There is no essential pathological difference between the cases
termed "relapse" and those called "recrudescence." Clinically,
there is a difference only as to the time that has passed since infection.
Before leaving this portion of the subject, reference should be made to the
recent publication by Prof. Emil Abderhalden in his study, "Protective
Ferments of the Animal Organism." In this work, the author has gone a
long way in the same direction as Dr. Beard's researches have led him.
In 1907, it was foretold by Dr. Beard that the parasites of malaria would be
readily destroyed by the enzyme trypsin, and the scientific principles involved
have been enunciated by him in papers published in 1907 and 1913.3,4 It may
be of interest to cite one scientific conclusion from his recent memoir. In
this, Beard writes: "Since the organisms underlying the chief tropical
diseases, such as malignant malaria, trypanosomiasis, sleeping sickness, yellow
fever, relapsing fever, kalaazar, etc., are, so far as these attack human beings,
asexual generations, it follows that the natural means of destroying the organisms
of such tropical diseases and of curing the patients are the use in combination
of the powerful pancreatic ferments, trypsin, and amylopsin."
Not until January, 1913, did the opportunity come to me of putting these principles
into practice in cases of tropical disease and of seeing whether, under treatment
by ferments, these relapses in malaria were preventable. As a test for this
enzyme-treatment, out of about 100 patients, the cases of severe infection
and those showing relapses were selected. Clinically, the results are most
marked, the change in the patient within a few hours remarkable, and the benefit
permanent. As circumstances have arisen that have interrupted this work, and
as I do not know when I can carry the observations further, I think that these
clinical results demonstrating the utility of the pancreatic ferments in the
severer forms of malarial infection should be recorded.
For a discussion of the nomenclature of the organisms of malaria, reference
may be made to: Doflein, F., Lehrbuch der Protozoenkunde,
3te Auflage, Jena, 1911, pp. 774-788. Following him and adopting Plasmodium
as the generic
name, the two forms dealt with in the following are Laverania malariae, the
organism of malignant tertian malaria, and Plosmodium vivax, that of benign
The method of treatment has been by intramuscular injections of the enzymes,
trypsin and amylopsin. My acknowledgments are due to Messrs. Fairchild Brothers & Foster
for the injections employed in the following cases. Both ferments are supplied
in glass-ampoules holding about one cubic centimeter. The injection trypsin
has a digestive value of 1,250 Roberts units, and it is the most potent preparation
of trypsin made. The injection amylopsin is of maximum potency and contains
500 Roberts amylolytic units. The preparations are sterile and stable. I have
kept some of these ampoules for nine months in Central India without appreciable
loss of strength. Before injection, the contents of each ampoule should be
diluted with normal saline 1:5. Latterly, I have found, when using these ferments
other diseases, that by using two
needles, which should be as fine as possible, the pain which often follows
injections of trypsin may be avoided. The one needle is used to take up the
injection into the syringe, the second one, which in this way has no trypsin
upon it, to make the actual
injection. My usual practice is to take up the contents of one ampoule of trypsin
and of one ampoule of amylopsin in a 10 c.c. syringe, and then fill the syringe
with sterile normal saline. This amount I usually give as a single dose. Baetzner,9
using the same preparations in surgical tuberculosis, gives his injections
hypodermically, but I prefer to give the injections intramuscularly and select
the buttock, finding that patients suffer the least inconvenience in this way.
Using ordinary surgical technique in giving these injections, I have made some
hundreds after this fashion and no harm has ensued. The ferments diffuse slowly
from the tissue into which they are injected, and some local edema remains
for 12 to 24 hours, when it disappears. The local pain is little more than
due to the needle
prick. The effect of the trypsin on the normal tissues at the site of injection
is practically nil.
But the general effect, as seen in the cerebral type of case, is marked. The
headache vanishes, the patient's restlessness ceases, the skin becomes moist,
temperature falls, the patient's aspect is changed totally in a few
hours, and he feels fresh and looks bright. As a rule, a single injection is
sufficient to clear the peripheral blood of parasites. But in severe infections,
I think that three injections given at intervals of about four days, are necessary
to effect a cure. My previous experience6 in the use of ferments in malignant
disease has lead me to repeat the injections until the injections themselves
cause a rise in the patient's temperature. This I elsewhere called a "trypsin
reaction." When this happens, I know that the patient is fully under the
influence of the treatment. Usually this occurs in malaria with the third injection,
and having proceeded so far, the worst cases I have to deal with have remained
free from relapse.
The cases cited here were all those of British infantry soldiers.
Three natives (Gurkhas) were also treated, but my notes of these cases are
too fragmentary for inclusion.
I: Private C., No. 9,457.---Malignant tertian malaria with
Contracted malaria in Maymyo, Burma, November, 1912.
5, 1912--Admitted to hospital. Temperature 101º+ F. Malignant
tertian rings found in peripheral blood. Quinine gr. x thrice
6, 1912--Morning temperature 103º F,evening temperature
Hematuria appeared. Quinine stopped. Arsenic given.
7 and 8, 1912--Temperature normal, but hematuria continuing.
1912--Apparent recovery. Discharged from hospital, but ordered
to attend daily and to receive a daily dose of gr. x of quinine
Relapse--January 11, 1913--Readmitted to hospital.
Evening temperature 100º F. Malignant tertian rings and
crescents found in peripheral blood. Quinine gr.x given thrice
to 16--Evening temperature 100º F to 102º F. each evening.
January 17--Quinine treatment stopped. First injection of trypsin
and amylopsin. Evening temperature: 100º F.
temperature 101ºF. Blood shows crescents.
temperature 101.6º F.
January 23--Evening temperature 96º F.
January 24--Second injection of trypsin and amylopsin. Six hours
after this injection the patient's temperature rose to 100º F,
but the peripheral blood showed no parasites.
January 25 and
26--Blood negative. No symptoms.
January 31--Third injection of trypsin and amylopsin. Discharged
The patient was seen by me on March 16, April 27,
31, 1913, and he has had no further symptoms.
II: Private G, No. 9,876---Malignant malaria with relapse.
Contracted malaria in August, 1912 and was treated in hospital from
August 22 to September 2, 1912, malignant tertian rings being found
in the peripheral blood. The first relapse occurred in December,
1912. Patient in hospital from December 13 to 19, 1912, when again
malignant tertian rigs were found. Patient had been continuously
under quinine treatment from August 22, 1912, to January 2, 1913---the
regulation four months' course of treatment.
Second relapse took place in January, 1913, patient being admitted
to hospital on January 29. He was deaf from cinchonism, the blood-smears
were repeatedly negative, showing no parasites, but the patient's
temperature each evening rose to about 100º F. He was discharged
from hospital on February 11 and ordered to attend daily for further
Third relapse---On March 2, 1913, patient was attending for his daily
dose of quinine, when he appeared to me to look so ill that I detained
him in hospital. His evening temperature was 99.2º F and blood
March 3--Admitted to hospital, complaining
of pains all over, worst in bones and joints.
March 4--blood showed
malignant tertian rings.
In the evening, the temperature rose to 103º F, and patient
became delirious, showing cerebral symptoms.
March 5--Very severe
headache. First injection of trypsin and amylopsin.
March 6-- Headache
gone. Feels well. Temperature in evening 99.6º F.
headache or other signs. Second injection of trypsin and amylopsin
March 9--Temperature normal, neither signs nor symptoms, blood
March 12---Continuing normal without symptoms. Third injection
of trypsin and amylopsin given. This was followed by a rise of temperature
to 102.4º F. Blood-smear negative.
March 13--Blood-smears again taken; no parasites found. Leucocyte
count: Polynuclear 50%, large mononuclear 17.3%., lymphocytes 24.7%,
The changes in the large mono-nuclear and eosinophile white blood
cells are noteworthy.
March 16--Discharged to duty April 16, and
19, the patient was seen by me. No further symptoms.
III: Lance Corporal J, No, 8,459---Contracted malaria in October,
1912. Was treated in hospital between October 25 and 30, 1912, benign
tertian rings being found in the blood. The quinine treatment was
continued from October, 1912, to February 28, 1913, i.e., a four
On March 8, 1913, patient had a typical attack of ague in barracks
and was not seen by a medical doctor.
On March 10, 1913, patient was brought to
hospital with temperature or 104.2º F., and malignant tertian
rings were found in the blood.
March 12---First injection of trypsin
and amylopsin was given.
March 15---Second injection was given.
March 18--Third injection
March 23---Discharged to duty.
Up to June 16, 1913, patient
has had no relapse and no further symptoms.
Query: was this case
a mixed infection of benign and malignant malaria, or a fresh infection
of malignant malaria while the patient was taking quinine?
IV: Private T, No. 9,141--Benign tertian malaria. States he
first had malaria in Rangoon some two years ago and that he has been
stationed in Mandalay since June, 1912, arriving in Maymyo, Burma,
on March 8, 1913.While in Mandalay, he had five relapses of malaria.
1913—Detained with severe ague. Temperature 103.8º F.
Benign tertian rings and gametes in peripheral blood.
to hospital. Evening temperature 103.8º F.
March 15--First injection
of trypsin and amylopsin.
March 18.--Second injection. Blood negative.
March 22--Third injection.
March 25--Discharged to duty.
Up to June 16, 1913, no relapse and
no further symptoms.
V: Lance Corporal G, No. 6,638--Benign tertian malaria. Contracted
malaria in December 1912. Was treated in hospital December 28, 1912,
to January 5, 1913.
Relapse on March 14, 1913. Temperature 102º F.
Blood-smear showed benign tertian rings and gametes.
March 18--First injection of trypsin and
March 19.--Evening temperature 102º F (due to yesterday's injection).
March.--Temperature normal; blood negative.
March 22--Temperature normal.
Second injection of trypsin and amylopsin.
March 25: Discharged to
Up to June 16, 1913, no relapse and no further symptoms.
VI: Private S, No. 8,561--Malignant tertian malaria. Contracted
malaria in January,1913. Was in hospital from January 31 to February
14, suffering from a severe attack; since that time, he has been
taking quinine regularly.
March 4--Arrived in Maymyo, attending three
times a week for quinine.
March 15--Reported sick with a temperature
of 102.4º F.
Malignant tertian rings found in peripheral blood.
in the evening.
March 18--First injection of trypsin and amylopsin.
March 19--Temperature normal.
March 22--Second injection of trypsin
March 27--Discharged to duty.
Up to June 16, 1913,
VII: Private S, No. 9,600--Benign tertian malaria, in which
quinine seemed to give no benefit. Contracted malaria in September,
1912. States that he has had three relapses out of hospital. Returned
from maneuvers on March 6, 1913.
March 21--Reported sick. Temperature
102.4ºF. Benign tertian gametes found. Quinine gr. v. four-hourly
March 24--Temperature, morning 101.2ºF, evening 101.6ºF.
March 23--Temperature, morning 100ºF, evening,
gr. x thrice daily.
March 24--Temperature, morning 99.6ºF, evening
100ºF. Continue quinine.
March 25-29--Temperature normal. Continue
March 30--Evening temperature 100ºF. Severe head-ache
March 31--First injection of trypsin and amylopsin.
Evening temperature 100.2º F.
April 1-4--Temperature normal; no
April 5--Second injection of trypsin and amylopsin.
8--Discharged to duty.
Up to June 16, 1913, no relapse and no further
After nine days of quinine treatment in this case the parasites were
still able to produce fever, severe headache, and joint pains, all
of which vanished after one injection of the ferments, trypsin and
VIII: Private W, No. 9,402--Benign tertian malaria. Contracted
malaria in September, 1912, being treated in hospital from October
11, 1912. Completed a four months course of quinine treatment in
On March 27, 1913, reported sick, with a
temperature of 102º F,
benign tertian rings being found.
On April 1 and 5, he received injections
of trypsin and amylopsin.
On April 10, he returned to duty, since when
he has had no further symptoms.
IX: Lance Corporal F, No. 9,327--Benign tertian malaria. Contracted
malaria in October, 1912, being treated in hospital from November
1 to 12
1912 and continuing the quinine treatment out of hospital
the middle of January, 1913.
On March 24, 1913, reported sick, temperature 104.8º F, and
benign tertian rings were found.
On April 1 and 5, he received injections of trypsin and amylopsin,
the second injection causing a rise of temperature to 100º F.
On April 10, he returned to duty and has since had no further relapse.
X: Private T, No. 8,014--Malignant tertian malaria. First
admission, severe double infection.
May 19, 1913--Headache and colic.
Temperature 102.2ºF. Quinine treatment begun.
tertian rings found in peripheral blood.
May 21--Temperature, morning
103.6º F, evening
102.4º F. Headache severe.
May 22--Temperature 104º F and
May 23, 101ºF and 100º F.
May 24, 99.4º F and 100.4º F.
May 25, 99.2º F
and 99.2º F. May 26, 98.6º F and 100º F. Quinine treatment
stopped. First injection of trypsin and amylopsin. Compared with the
eight days of treatment with quinine the progress made after one single
injection of trypsin and amylopsin is marked.
May 27--Better and brighter.
Evening temperature 98.6º F.
May 28 to
June 3--Temperature normal. No further symptoms.
XI: Private T, No. 9,660--Mixed infection with debility. Patient
a tall lank phthinoid subject. Contracted malaria in January, 1913.
March 16--Admitted to hospital with pneumonia of right base.
March 22--Temperature 101º F. Blood examination showed numerous
rings and malignant tertian rings also. Quinine treatment begun.
April 8--Discharged from Hospital, but continuing the quinine treatment
as an out-patient.
Relapse--April 15, 1913--Admitted to hospital. Temperature 103.8º F.
Malignant tertian rings in great numbers.
April 16 First injection of trypsin and amylopsin.
temperature 100.6º F.
April 18--Temperature normal.
morning 98.6º F, evening 100º F. Second injection of trypsin
April 28--Temperature continuing normal. Blood negative. Third injection
of trypsin and amylopsin.
May 3--Returned to duty.
Seen June 15,
1913. No relapse and no further symptoms.
XII: Private H, No. 9,535--Malignant tertian malaria with
cerebral symptoms. First admission. Severe cerebral type of case
and double infection.
May 12, 1913--Detained. Temperature 102º F
at noon. 104º F at 3 PM. Blood-smear negative.
morning 101.6º F,
evening 104º F.
May 14, 100º F and 102.4º F.
and 105º F.
May 16, 98º F and 103º F.
May 18--Malignant tertian rings
found. Quinine treatment ordered.
May 19--Transferred to my care. Headache very severe. Restless. Continuing
the quinine treatment.
May 20--Headache and restlessness more marked,
and patient became comatose. First injection of trypsin and amylopsin.
May 21--Headache gone. Patient looks fresh and eyes bright. Temperature
now 99º F. All symptoms vanished.
May 26--Second injection of
trypsin and amylopsin.
June 5--Discharged from hospital to duty.
"If a doctrine be challenged," said
Pasteur, "it happens
seldom that its truth or falsehood cannot be established by some
crucial test. Even a single experiment will often suffice either to
refute or to consolidate the doctrine."7 Again, the great investigator,
Emil Fischer, set up the doctrine of "lock and key" regarding
the action of ferments by two
experiments, and two only. The first experiment was to observe the
fact, the second to confirm it.8 In the foregoing pages, twelve experiments
are set set forth, and every single one of these confirmed the scientific
conclusions, which lead to their being made. For, as Carl Ernst von
Baer wrote long ago, "That which always repeats itself cannot
be conditioned by chance or passing caprice, but must depend upon
F.W. Lamballe, MB
8 Barnton Terrace
1. Ball, Eustace Reynolds. Outfit and equipment. 1912, loc. cit. p.47.
2. Minchin, E.A.: Introduction to the Study
of the Protozoa, 1912
loc.cit. p. 361.
3. Beard, J.: "On the Occurrence of Dextrorotatory Albumins in Organic
Centralblatt. Vol. XXXIII, pp.150-170, 1913. Also in MEDICAL
March 29, 1913.
4. Idem: "The Interlude of Cancer," MEDICAL
5. Abderhalden, Emil: Schutzfermente des tierischen
6. Beard J.: The Enzyme Treatment of Cancer, London, 1911, loc.cit.
pp. 185 and 209.
7. Valley-Radot, Rene: La Vie de Pasteur, Paris, 1901.
8. Fischer, Emil: "Bedeutung der Stereochemie fur die Physiologie," in
Zeitschr. f. physiol. Chemie, Vol. XXVI,
1898-99, p. 81.
9. Baetzner, W.: "The Trypsin Treatment of Surgical Tuberculosis," The
Practitioner, January, 1913, pp. 203-219.
10. Baer, Carl Ernst von: Reden, Vol. I, 2te Auflage, 1886, p.