REPRINT FROM 
THE SOUTHERN MEDICAL JOURNAL 
FEBRUARY, 1913, PAGES 80-89 
CONCERNING THE PATHOGENESIS 
OF RELAPSES IN MALARIAL/ 
FEVERS* \J 
fact that one of the most debated and ob- 
scure questions in the pathology of malaria 
is precisely that which concerns the genesis 
of relapse; these, as every one knows, are 
found in all kinds of malarial infections, some- 
times separated by brief intervals of apyrexia, 
sometimes by long periods of latency. 
By DR. AMICO BIGNAMI, M.D., 
Professor of Pathology, University of Rome. 
Translated from the Proceedings of the Society for 
the Study of Malaria, Rome, Vol XI, 1910. 
Translated by W. M. JAMES, M.D., 
Ancon Hospital, Canal Zone. 
It is also known that relapses may happen 
one after the other with a certain regularity. 
For in sick persons who take quinine only in 
sufficient quantity to cause a cessation of the 
fever, and who then suspend the use of the 
drug, it is especially observed that relapses re- 
turn at intervals a little short of two weeks; in- 
tervals, as I have noted formerly, that approxi- 
mate the medium duration of the period of 
incubation of the original infection. Again, 
it is not unusual to observe malarial fevers 
that relapse at intervals of about a month. But 
as far as I am aware the truth is less generally 
known about those fevers in which, after a 
long period of latency, relapses occur at cer- 
tain seasons, so that it seems as though such 
relapses follow a definite law, for only recently 
this type of malarial recurrence has received 
attention. For instance, it is not uncommon to 
witness tertian malaria relapse in the spring, 
after remaining latent throughout the winter; 
and there are also estival fevers (estivo-au- 
tumnal infection, due to P. falciparum)* that, 
after remaining entirely dormant during the 
winter and spring, relapse at the beginning of 
summer. 
As is known, since the researches on the 
cycle of the malarial parasites in anophelene 
mosquitoes, the problem of the treatment of 
malaria has assumed a very great social im- 
portance, considering that the specific treat- 
ment of human illness represents a method 
of social prophylaxis to which is given more 
trust than to any other. 
But anyone who has a knowledge of mala- 
ria knows the difficulties which are not seldom 
encountered in the task of treating obstinately 
relapsing infections. It is not unusual to ob- 
serve sick persons who, after a long series of 
relapses, have become so - skeptical in regard 
to the efficacy of quinine that they refuse to 
continue taking the remedy. 
And inasmuch as various facts bring me to 
the belief that the relative resistance of re- 
lapsing malarial infections to the valuable 
drug may be in intimate relation with the path- 
ogenic mechanism of such infections, I think 
it is of advantage, on account of the practical 
importance of my argument, to explain certain 
considerations bearing on these facts,, although 
I may not deal in great part with anything 
new. 
For example, I had occasion to observe a 
patient,- who had incurred fever in the sum- 
mer of 1901 in Trinitapoli; after remaining 
entirely well throughout the winter and spring 
of 1902, he relapsed on the 25th of June o.? 
that year with a grave malarial attack, durir./ 
It is almost useless to call attention to the 
*Read by title at the annual meeting of the South- 
ern Medical Association, Jacksonville, pla.. JJov. 
12-14, 1912, 
translator’s parenthesis. 80 
SOUTHERN MEDICAL JOURNAL 
which asexual estivo-autumnal parasites were 
found in the blood, but no crescents. Of 
course, during' the entire period of latency he 
had not exposed himself to the possibility of 
incurring a new infection. Nor would it be 
difficult for me to refer to other cases sim- 
ilarly well observed. 
epidemiological viewpoint. This point, and 
others, are questionable, and it is not essential 
to my purpose to go to the bottom of the mat- 
ter, so that I limit myself to this brief notice. 
As for the genesis of relapse, it is necessary 
to recognize that it is not yet known precisely 
in what forms the malarial parasites are found 
in the intervals of apyrexia between the feb- 
rile accesses, or to what biological property of 
these parasites may be attributed the fact that 
there are relapses of the fever. 
For some time various students of the fac- 
tors concerned in malarial infections have sup- 
posed they could affirm that these estivo-au- 
tumnal relapses in the beginning of summer, 
after long latency, are due to a regular phe- 
nomenon that is manifested in a great number 
of sick persons, so much so that these ob- 
servers believe these relapses may be due to 
accumulations of gametes from which anophe- 
les are infected, thus producing again estivo- 
autumnal infections. In this way the new 
epidemic year is begun*. I cannot say, from 
my experience, if these facts to which I have 
just alluded possess very much importance 
from the epidemiological viewpoint, for, in 
truth, in malarial localities, it is very difficult 
to distinguish between a relapse and a rein- 
fection in the inhabitants of these, and all 
criteria that have been suggested for the in- 
terpretation of the matter seem to me to be 
very arbitrary. The clinical course, for ex- 
ample, upon which some depend, is not to me 
a sure criterion; it is true that as a rule pri- 
mary infections are graver, lasting longer than 
the attacks of relapse, but this happens in per- 
sons who hitherto have not had fever, while 
in a patient formerly a malarial subject a new 
infection cannot by any character be told-from 
a relapse. 
All the hypotheses of the various authorities 
who admit that in man the gametes can mul- 
tiply by means of parthenogenesis are worthy 
of being noted here. Although such a proposi- 
tion may have been listened to in general with 
favor (some, for instance, believe thqt the epi- 
demic year, at the onset of summer, begins 
with a group of relapses determined in old 
malarial cases by a “springtime parthenogen- 
etic reproduction,” as they say, of gametes), I 
maintain that such an hypothesis not only lacks 
a firm base of facts, but does not even lend 
itself to a satisfactory explanation of relapses. 
The opinion that by the parthenogenesis of 
gametes relapses may be explained has as a positive 
foundation solely the observation of Schaudinn. (i) 
He, at the beginning of a relapse in a case of tertian 
malaria, saw and picture 1 a series of modifications in 
the macrogametes (female sexual parasites), which 
he thought he could interpret as similar to the 
forms of asexual multiplication. He reproduced in 
a plate the various forms that he found, placing 
them as in an ordinary developmental cycle. Then 
he adds that he has seen in other cases also some 
similar forms, but it is a fact that only once, and in a 
single patient, the whole series of forms in question 
has followed at the beginning of a relapse* Not- 
withstanding this, he, after he had given a most 
accurate description in his report, expressed the 
conviction that relapses after long intervals owe 
their origin to macrogametes, which live a long time, 
and have the power, according to him, of undergoing 
a reversion to the form of schizonts (asexual para- 
sites). 
While I can, then, from my own experience 
affirm the occurrence of a relapse after a long 
period of latency, and at the beginning of the 
epidemic year, I cannot say if this happens 
with that regularity which would make the 
fact useful. If this be true, very great im- 
portance could be attributed to it from the 
Although the publication of Schaudinn was put 
out in 1913, the process that he describes has not 
had even the most infrequent and insufficient con- 
firmation by new observations * The unconfirmed 
opinion based on that report has been listened to 
with favor, as though it were a datum of fact at 
this time unassailable. 
*The Italian school refers to the period of the 
annual increase and decline of malaria as the “epi- 
demic year.”—Translator’s note. 
I cite the observations of some Dutch authors, 
the only ones, as far as I know, who have also 
seen the forms described by Schaudinn. 
Dr. G. I. Vajr der Hilst Karrewij (2) has taken BIGNAMI and JAMES: PATHOGENESIS OF RELAPSES IN MALARIAL FEVERS. 
81 
up again the study of the disputed point, not having 
found other publications since those of Schaudinn. 
He in one case only of tertian malaria has found 
a series of forms that suggest to him a cycle of 
evolution in the macrogametes, precisely at the onset 
of an attack, and he describes the forms that he 
saw in the same manner as did Schaudinn. We have 
to do, then, with a simple confirmation of the ob- 
servations of the latter, whose designs, it may be 
noted, are neater and demonstrate the points bet- 
ter than those that accompany the report of Kar- 
rewij. It should be noted that the patient with 
the tertian malaria who was the subject of Kar- 
rewij’s observations already had had several attacks 
of fever when that one unexpectedly occurred at the 
beginning of which Karrewij found the forms de- 
scribed as demonstrating the parthenogenesis of the 
gametes. 
to the pyrogenous cycle. Therefore, the observation 
of Karrewij is not important concerning the origin 
of relapse, in the strict sense of the word, but would 
also lead to the belief that in the ordinary sequence 
of attacks the gametes might reproduce themselves 
either entirely or in company with the other forms 
of the parasites.* 
Nor can I agree with Karrewij when he states 
that parthenogenetic division has been observed sev- 
eral times in crescents, and cites as confirmation the 
observations of Grassi, Mannenberg and Ziemann; 
these observations in my opinion, refer solely to iso- 
lated and incomplete reports, which hint at a trans- 
verse division of crescents, and thev lack entirely 
value of demonstration in respect to the question 
which at present concerns us. 
Similar observations to those of Karrewij in ter- 
tian malaria have been made, in the Dutch East 
Indies, by G. J. Merz and M. Bluml (2). There is 
this that is new in the results of these authors: in 
six preparations of blood from five persons sick 
with tertian malaria, they found forms that they in- 
terpret macrogametes in asexual division, and at the 
same time schizonts in division were also present. 
It is worthy of note that they had to do these cases 
with very heavy infections; so heavy were these 
that the authors found regularly double infection of 
the erythrocyte, more than once four tertian para- 
sites in the same red blood cell, and in one as many 
as six schizonts. Schizonts in division were most 
plentiful, from 140 to 160 in a single preparation, 
nor were double infections of erythrocytes with 
gametes and schizonts lacking. 
Now. to diagnose macrogametes in division, and 
to distinguish such from the numerous schizonts 
that were found in division at the same time in the 
preparations, the authors above mentioned relied on 
the description given by Schaudinn, and admitted 
without further proof that the distinctive character- 
istics of, macrogametes in division had been previ- 
ously ascertained and definitely postulated. 
This simultaneous occurrence of macrogametes and 
schizonts in division, together with the fact that they 
were not able to state definitely in two of their cases 
whether a relapse or a reinfection were present, 
but rather had to admit the possibility of the latter 
supposition, naturally caused Merz and Bluml to 
think that the division of the macrogametes might 
not be the sole cause of the onset of relapse, as 
Schaudinn thought, but that to such division had 
been given too great value and broadness of meaning. 
But now, without following these authors in their 
attempts to give a satisfactory interpretation of the 
phenomenon, I shall content myself with noting that 
they have not seen the series of forms in question at 
the beginning of a relapse, and that, relying on the 
single observation of Schaudinn, they admit the re- 
lation between relapses and the multiplication of 
gametes. The same completeness, which constitutes 
the new and interesting data in their report, takes 
away, in respect to the question of relapse, its demon- 
strative value. 
Now, it is evident that, to explain the cause oi 
relapse, we would expect to find the said forms at 
the beginning of the first attack of the relapse itself, 
while everything tends to the belief that the following 
febrile attacks in a relapse are produced, as a rule, 
by the regular multiplication of the forms pertaining 
*An excellent account of Schaudinn’s work, with 
reproductions of his plates, is given in English by 
Deaderick, Practical Study of Malaria, 1909, p. 124, 
et seq. In the Journal of the Roval Army Medi- 
cal Corps for December, 1909, Major W. S. Har- 
rison gives an account of a similar phenomenon ob- 
served in the gametes in a case of relapse in ter- 
tian malaria, and his illustrations, which were made 
before he saw those of Schaudinn, are practically 
identical with the latter’s, and with similar forms 
not infrequently seen here by me in tertian and 
quartan infections. Maj. Harrison does not commit 
himself, however, to a definite statement that his 
forms are undergoing parthenogenesis. It is also of 
interest to note that Captain C. F. Craig, U. S. Army 
Medical Corps, interpreted similar forms shown by 
me to him as the result of conjugating parasites. 
My personal opinion at the present time is that the 
forms I have observed are due to the atypical sporu- 
lation frequently seen in anemic blood, such as is 
common in those who suffer from relapse, but I am 
not prepared to make a definite statement at pres- 
ent. This information is appended solely for the 
guidance of those interested, and to confirm the 
statement that the forms described by Schaudinn 
actually occur, not in any way as a comment or a 
criticism on the views of Bignami, Schaudinn and 
others on the subject.—W. M. J. 
*Dr. Bignami evidently is not familiar with the 
observation of Major Harrison, which should receive 
the credit due the careful statement of fact by an 
experienced and unprejudiced observer.—W. M. J. 
*That is, Dr. Bignami questions whether the at- 
tack observed by Karrewij were really a relapse, for 
it followed unexpectedly other attacks of fever. Now. 
if this parthenogenesis actually has explanatory value 
in this instance, this value does not pertain to the 
cause of relapse, but merely shows that in the course 
of a malarial attack the phenomenon was observed. 
In other words, here the phenomenon means no more 
than ordinary asexual multiplication would mean, 
for there is no proof that it was part of a true re- 
lapse. (Translator’s note.) 
The observations of H. M. Neeb (3) are even less 
conclusive than those that I have mentioned. He 
refers in his work to having seen in tertian malaria 
some'forms similar to those described by Schaudinn, 
and adds drawings and a description of three forms 
of parasites which he interprets as crescents in par- 
thenogenesis. He found these in two preparations 
from a patient ill with tropical fever, but does not 82 
SOUTHERN MEDICAL JOURNAL 
state how long the fever had lasted. It is, however, 
true, that the opinions expressed by various observ- 
ers who examined Neeb’s specimens were not in 
agreement as to two of the forms, although Pro- 
wazek interpreted them as parthenogenesis fo~ms of 
crescents; Le Dantec showed the similarity of these 
same forms to the ordinary schizogony of estivo- 
autumnal parasites, and was reserved in his judg- 
ments. Others, of the Institute of Tropical Diseases 
in Hamburg, expressed the opinion that the forms 
were macrogametocytes (male crescents) in which 
the chromatin had already divided in the phase pre- 
ceding the formation of the microgametes (flagella). 
As for the third form in question, Neeb himself 
admits that he cannot give a precise opinion.* 
are lacking, and that these should be carefully 
followed through, using staining methods best 
adapted, especially for estivo-autumnal ga- 
metes, which, as is well known, have morpho- 
logical characteristics better differentiated and 
more easily distinguished than are those of the 
gametes of the other species of malarial para- 
sites.* 
There are very noteworthy facts, as to par- 
thenogenetic reproduction, in other parasites; 
but, although analogy can be a guide in re- 
search, in this instance we cannot value it as 
a base for an hypothesis, when direct research 
in a well-known group of parasites does not 
furnish us with sufficient data to corroborate 
analogous findings in other groups. That the 
hypothesis (parthenogenesis) does not furnish 
an adequate basis of fact for the present con- 
clusions, especially those for the estivo-autum- 
nal species, is plain from the observations 
made many years ago by Bastianelli and my- 
self on the behavior of crescents in human 
blood, observations thAt our recent researches 
have confirmed. So that, although it is ad- 
mitted such a thing as the parthenogenetic re- 
production of crescents in man may be possi- 
ble, this hypothesis does not in any way help 
the interpretation of the cause of relapse, as 
is shown by the data just presented. 
The above facts, if I mistake not, are very 
far from being sufficient to convince us that 
relapses are due to schizogony of the macro- 
gametes. They treat isolated observations 
which may, in some respects, demonstrate the 
possibility of parthenogenesis, but they do 
not permit us to affirm that such a process 
happens regularly at the beginning of a re- 
lapse. In fact, the proof of the constancy of 
such occurrence, and of the regular produc- 
tion of the phenomena in exact correspondence 
with the first access of relapse at long inter- 
vals, is lacking. Now it is not out of place 
to record that many students of malaria have 
patiently sought the phase of multiplication of 
crescents in the beginning of relapses, without 
success in demonstrating such a fact. Fur- 
ther, such researches have been made by Bas- 
tianelli and myself since the biological signifi- 
cance of crescents was first known; that is to 
say, when it seemed necessary that the phase 
of multiplication of crescents ought to exist 
in the blood of man. If all this is considered 
I believe that before firmly maintaining that 
Schaudinn is correct in his interpretation of 
the genesis of relapse,* we should take up 
new methodical researches, which at present 
Nothwithstanding what is urged in favor 
of parthenogenesis as a cause of relapse, there 
are not infrequently recurrences of estivo-au- 
tumnal fever, at the beginning of which it is 
not possible to find crescents, even though 
splenic puncture be done, as has been noted 
in other works. In several instances, in the 
intervals of apyrexia between one relapse and 
the other, in persons who had chronic malaria, 
I have made examinations of the splenic juice 
without success in finding a crescent. On the 
*ln the Journal of Tropical Medicine and Hygiene, 
Volume XIII, No. 7, April 1, 1910, under the title of 
“The Parthenogenesis of the Female Crescent Body,” 
Dr. Neeb gives in full detail the account referred to 
by Dr. Bignami, and also a plate showing the three 
forms in question, with tertian macrogametes in par- 
thenogenesis also. Although Dr. Neeb had not seen 
the criticism of Dr. Bignami, as the two publications 
are of about the same date, he takes up in this 
article in great detail an explanation of the ob- 
jections urged against his views by Dr. Bignami. 
(Translator’s note.) 
*1 assert that this reserve should be maintained, 
although Ruge Handbuch der pathog. Microorganis- 
men, Heraus von Kolle und Wassermen, Ergan- 
zungsband, Zweites H., page 416) considers the ques- 
tion of the pathogenesis of relapse now cleared up by 
the observation of Schaudinn on tertian malaria. 
(Author’s note.) 
*Such researches have been taken up this year in 
my laboratory. (Author’s note.) BIGNAMI and JAMES: PATHOGENESIS OF RELAPSES IN MALARIAL FEVERS. 
83 
other hand, in quartan malaria, in which re- 
lapses often happen from month to month, ga- 
metes are extremely scarce, as has been shown 
by the negative results that have occurred re- 
peatedly when it has been tried to. infect 
anopheles mosquitoes with quartan parasites. 
Now it seems little likely that in such instances 
the cause of the continuance of the infection is 
due to forms of the parasites that occur very 
infrequently. 
the action of the remedy. Analogous exam- 
ples are furnished in other infections, such as 
syphilis, in which a part of the virus escapes 
the specific cure, and by the cause of the later 
manifestations in the disease known as sleep- 
ing sickness, etc. Similarly the genesis of re- 
lapses at intervals rather short and more or 
less regular that present themselves frequently 
in those sick persons that are not treated ade- 
quately may be determined. As noted above, 
the period that intervenes between one group 
of febrile attacks and another sometimes has 
a duration that approaches that of the incuba- 
tion period of the primary infection, and one 
may suppose that in the interval between these 
attacks there arises a progressive multiplica- 
tion of the few residual parasites, until the 
quantity necessary for the production of the 
febrile attack is reached. 
According to observed facts, it can be ad- 
mitted that a portion of relapses are in con- 
nection with the recrudescence of pathogenetic 
reactivity of schizonts that carry on regularly 
their life cycle for a more or less lengthy pe- 
riod, without giving rise to fever. This is 
easily observed in quartan parasites, in whom 
the life cycle of the parasites can be followed 
in the finger blood to sporulation, and also 
through various generations, without the pro- 
duction of corresponding febrile attacks. In 
another work, in speaking of immunity, I have 
noted this fact, and I proposed to interpret it 
by admitting that the patients in question had 
acquired a transitory immunity against the 
fever producing activities of the hemosporidia. 
When this immunity is suspended, especially 
after some such occasional cause as chill or 
overwork, relapses follow. 
And there are other relapses, which come 
on after a more or less lengthy period of laten- 
cy, which can be thought to have the same 
genesis. Indeed, there is nothing to compel 
us to admit that the residual parasites, which 
survive the action of quinine, and pass reg- 
ularly and typically through their life cycle, 
ought to increase in a progressive manner by 
their multiplication. As is commonly known, 
quartan and tertian infections are seen, which, 
when not treated, go on monotonously for 
weeks and months without showing exacerba- 
tions, even not rarely diminishing in intensity 
of clinical symptoms, while not only does the 
number of parasites show no increase, but also' 
may diminish in proportion to the lessening of 
the clinical symptoms. This may be explained1 
by stating that not all of the young forms re- 
sulting from multiplication go on through a 
regular cycle of development. From these 
data we may suppose that a minimum quan- 
tity of parasites escapes the action of the spe- 
cific remedy, and these follow their accustomed 
life cycle, without increasing in number, or 
perhaps without arriving at the limit of the 
quantity necessary to give fever until a long 
time has elapsed. Increase in number, with) 
Facts similar to these cited, such as the pres- 
ence of parasites in the blood without accom- 
panying febrile phenomena, have been ob- 
served recently by various authors, especially 
in the races resistant against malaria. 
In such instances it cannot be doubted but 
that relapses may be due to the parasites of 
the pyrogenous cycle, which have been living 
in the blood without developing manifest path- 
ogenic activity, such as the production of a 
febrile attack, on account of the particular 
condition of the patient at the time. 
In considering the continued development of 
schizonts under such conditions, another group 
may be thought of; that which goes on in its 
cycle when cinchonization is not sufficiently 
prolonged and intense, such parasites escape SOUTHERN MEDICAL JOURNAL 
sapid and progressive multiplication of the 
parasites can occur when the patient suffers 
from some debilitating cause that is the ob- 
vious occasion of the return of the fever. If 
this viewpoint be accepted the genesis of most 
relapses would be substantially identical with 
that to which I have just referred. In other 
'words, it may be that in the intervals between 
relapses the usual forms of the pyrogenous 
cycle are found in the peripheral blood; or it 
may be that they cannot be found, yet relapses 
could always be due to the presence of such 
ncsidual parasites, which, in the greater num- 
ber of cases, are too few to be found in the 
regular examination. 
knowledge that the sooner after the manifesta- 
tion of fever treatment is begun the more 
easily the physician can control the infection; 
while infections that have run for.some time 
are more rebellious to treatment. 
Nor is it easy to understand, granted that 
relapses are due to the mechanism to which I 
have referred above, the relapses due to dif- 
ferent species of the parasites. For example, 
cases are not rare, when, after a series of 
estivo-autumnal relapses during the autumn 
and winter and apparently cured, in the spring 
a relapse of ordinary tertian occurs under cir- 
cumstances of environment that make it possi- 
ble to exclude a reinfection with this parasite. 
Why have the parasites of tertian fever re- 
sisted the action of the remedy that has con- 
quered even the estivo-autumnal parasites, if 
the former occurred in the blood in the well- 
known forms of the pyrogenic cycle? 
But, although due consideration be granted 
to the foregoing data, there are yet certain 
facts for which a satisfactory explanation has 
act yet been given. Thus it is not easy to un- 
lierstand why, if, in the intervals of apyrexia, 
quinine is administered every day and in large 
doses, still, in a certain number of cases, re- 
lapses occur. I repeat, this is not easily un- 
derstood, if it is admitted that in the blood in 
minimum number there are the same forms 
that develop during the febrile periods, and 
that in these it is not possible to demonstrate 
any biological change, unless we wish to sup- 
pose that during the periods of latency the par- 
asites are more resistant to quinine, and fur- 
ther, that during the fever certain modifica- 
tions occur, by which the parasites may be 
made more sensible to the action of the drug, 
which facts certainly cannot be denied a priori. 
These consideration's, and others analogous 
to them, caused me some time ago to formu- 
late an hypothesis that should depend on a 
morphological basis. According to this some 
spores (monogenic sporozoites) might be de- 
posited in the internal viscera, where, making 
a membrane for themselves, they could change 
into resisting forms and could provide for a 
continuance of the infection. 
It is well known that not all of the parasites 
that result from sporulation at the beginning 
of a febrile attack go on through the devel- 
opmental cycle. In fact, and this is especially 
demonstrated in quartan infections, if all of 
the merozoites resulting from multiplication of 
the parasites should develop regularly the 
number of parasites in successive attacks 
would increase in a definite proportion, which 
is not so. Some of these merozoites and also 
entire fission forms are deposited in the inter- 
nal viscera, especially in the spleen and in the 
' bone marrow, where, and this rests the hy- 
pothesis, they may be able to convert them- 
selves into resistant forms. 
More than once I have administered the sul- 
phate of quinine in doses of a gramme a day, 
and even in larger doses, to persons who had 
chronic malaria, and I have seen a relapse 
occur, with estivo-autumnal parasites in the 
peripheral blood a few days after the with- 
drawal of the remedy. On the other hand, I 
bare found out that, in cases of experimental 
malaria, which were energetically treated after 
the first access of fever, relapses were reduced 
to a minimum, and sometimes entirely sup- 
pressed. Moreover, it is a matter of common 
This hypothesis was adopted, in my opinion, 
to explain not only the facts previously re- BIGNAMI and JAMES; PATHOGENESIS OF RELAPSES IN MALARIAL FEVERS. 
ferred to, but also particularly the fact that 
relapses are less probable and less numerous 
in direct proportion to the number of febrile 
attacks that occurred before the exhibition 
of a rigorous and methodical quinine treat- 
ment. 
had cases in which it could be demonstrated 
after fourteen days. This observation is of 
importance, because it gives us a possibility 
of explaining by this resistance the negative 
results that occur in the treatment of sleep- 
ing sickness, notwithstanding the administra- 
tion of the remedy for a long while. 
But inasmuch as more accurate researches 
undertaken whenever the opportunity offered, 
especially on the spleen and bone marrow, in 
cases of chronic malaria, have not given me a 
positive result; that is to say, such researches 
have failed to demonstrate the supposed re- 
sisting forms as morphologically differentiated, 
nor have others had better success, it is now 
my opinion that the said hypothesis ought to 
be abandoned, at least provisionally,* the more 
so since it is possible to substitute for it an- 
other that has as a bqsis the support of anal- 
ogy. I refer to the observations made in the 
past few years in the school of Ehrlich con- 
cerning the behavior of trypanosomes when 
acted upon by various remedies. 
Once acquired, this property of resistance 
can remain unchanged for long periods. Thus, 
the strain resistant against arsanil (arsanil 
fast) has been passed 300 times through nor- 
mal animals, which requires about 700 days, 
and despite this long time it has preserved in- 
tact its resistance; that is to say, the resistance 
is hereditary. 
Ehrlich has carried the strain resistant 
against atoxyl (atoxyl fast) through more 
than 125 changes without observing any dimi- 
nution in its powers of resisting the drug. 
Also of importance is the fact that the re- 
sistance of these types of strains is specific. 
So that the strain resistant against fuchsin 
is not resistant against atoxyl and trypan-red 
and vice-versa. The resistance is lost if chem- 
icals other than those of a particular group 
are used. 
As is known, in the Institute of Frankfort 
(4), it has been demonstrated that the insuc- 
cess of the protracted treatment of trypanoso- 
miasis over a long time, and with various 
chemical agents, depends upon this fact; that 
there is formed little by little varieties of try- 
panosomes resistant against the said agents. 
Thus Ehrlich, with Browning and Rohl, has 
obtained a strain of trypanosomes resistant 
against fuchsin and against a series of other 
toxic substances (tri-pheny 1-methane staining 
substances), a strain resistant against trypan- 
red and allied substances—trypan-blue and 
trypan-violet—and finally, a strain resistant 
against arsanil. 
Nor are facts analogous to the preceding 
lacking. 
Thus Franke, in Ehrlich’s laboratory, has 
found that there exists types of strains of par- 
asites resistant against the protective sub- 
stances formed during the course of an infec- 
tion. 
Levaditi has observed the same fact with 
regard to the spirilla of relapsing fever. 
To the same group of facts belong the ob- 
servations of Effront, who many years ago 
succeeded in obtaining protozoa resistant to 
hydrofluoric acid, and biologically endowed 
with properties different from those of the 
normal protozoa; and also he showed that 
these protozoa preserved through many gen- 
erations this specific resistance to poison, ac- 
quired by adaption. 
In rats resistance against atoxyl is observed 
as a rule after a long time, but Ehrlich has 
*lt. would be useful to study anew the question, 
applying to the examination of the blood-making 
organs of patients with relapsing malaria, who die 
from intercurrent diseases such as pneumonia, all 
the new methods introduced in the last few years in 
histological technique and in the recent study of 
protozoa. It is noted, in view of the necessity of 
such study, that I, apropos of my old hypothesis, do 
not express myself as abandoning it decisively. 
(Author’s note.) 
It is a question, then, according,to Ehrlich, 
of a general law. This is of the greatest im- 86 
SOUTHERN MEDICAL JOURNAL 
portance because of the fact that the acquired 
modification (resistance or immunity)* results 
from hereditary properties. 
physicians who practice in malarial communi- 
ties. And it is on account of this resistance 
that not seldom patients refuse to continue 
taking quinine, because they do not feel in 
a more manifest manner the beneficial effects 
of the drug. Thus they prefer to have re- 
course to the patent medicines which inundate 
the market and find ready believers in their 
virtues; especially when the name does not 
indicate clearly the quinine content;, so that 
the thoughtless do not realize that, under a 
different label, they are continuing to take 
the valuable alkaloid.* 
Ehrlich knows of one case communicated 
by Professor Plimmer, with respect to 
a strain of trypanosomes from a patient with 
sleeping- sickness, who had been treated for a 
long time with arsanil, which strain, when ex- 
perimentally introduced into animals, showed 
itself very resistant to that substance (arsanil 
fast). 
I shall add this fact, shown by the re- 
searches of Morgenroth and Halberstaedter 
(5), that there is a similar connection between 
quinine and trypanosomes. These authors, 
who sought to demonstrate by research if 
quinine would exercise a prophylactic action 
in experimental infections with trypanosomes, 
were of the opinion that they had demonstrated 
that the drug had such an action (the quinine 
acted on the trypanosomes by inhibiting their 
reproductive activity) and they admitted the 
possibility that, in latent trypanosomiasis, there 
can be established a kind of habituation of the 
organisms to quinine, (a certain quinine fast 
property of the trypanosomes). 
I have already stated the results of my ex- 
perience. Not only did the administration of 
quinine by mouth every day in large doses 
fail, in some cases, to eliminate subsequent 
relapse, but the same insuccess can follow 
energetic treatment by hypodermic injections. 
Not to limit myself to the citation of my own 
experiences, I shall record, for example, a 
case described by Torti and Angelini (6), who 
in this instance injected hypodermically every 
day a gramme of quinine for fifteen 
days; then gave the remedy by mouth 
for about a month, and, notwithstand- 
ing this, observed a relapse. They then 
gave hypodermic injections for fifteen days 
more (half a gramme a day), and the day after 
the suspension of the remedy, they observed 
fever with the finding of parasites in the peri- 
pheral blood. 
I have cited at length the results of the above 
studies in order to set forth what seems to be 
justified in the actual state of our present 
knowledge, a similar hypothesis to explain the 
obstinate resistance to quinine that is presented 
in relapsing malaria, especially in the clinical 
cases of chronic malarial infection. 
But it would be useless to cite further in- 
dividual observations, so well is known the 
resistance which not rarely cases of chronic 
malaria offer, whether or not febrile manifes- 
tations are shown, to energetic and continued 
quinine treatment. 
Such resistance is common knowledge of 
translator’s parenthesis. 
Although the authorities mentioned, as occasion 
has offered, in their experimental researches have 
obtained strains of maximum resistance, we must 
not expect, according to Ehrlich, that the same grade 
of resistance in the course of a drug treatment will 
be obtained in man as is obtained in animals, for in 
man strains of medium resistance (half fast) will 
follow habituation of parasites to a drug; under the 
action of atoxyl in suitable doses, trypanosomes be- 
come scarce, but after a certain time they reappear, 
whence the difficulty of treating these cases. 
I have already noted the facility with which 
cases of experimental infection from anophe- 
les can be controlled, if, as soon as the fever 
*Evidently the sale of “sure cures” for fever and 
chills, which are guaranteed not to contain quinine, 
is not confined to the southern part of the United 
States. One of these was analyzed some years 
ago by me. The label stated that it was guaranteed 
not to contain quinine, but none the less five grains 
of the drug to the dose was found in the prepara- 
tion.—W. M. J. 
The experience that we possess in regard to such 
cases (those in which such “half fast” parasites have 
been transferred from man to animals)* is very 
scanty, 
translator’s parenthesis. BIGNAMI and JAMES: PATHOGENESIS OF RELAPSES IN MALARIAL FEVERS. 
87 
is manifest and the parasites appear in the 
blood prompt and continued treatment is in- 
stituted. From the facts of which I have 
knowledge although they are not numerous, 
I am of the impression that infections brought 
about by injection of malarial blood do not 
yield so easily. This difference perhaps could 
depend on the fact that in this latter instance 
the injected parasites were already habituated 
in the first human host to the action of qui- 
nine, to which, in the schizont stage, they had 
already become resistant. 
cera secondary to the parasitic invasion, and 
at autopsy no parasites are found, or perhaps 
a few forms after accurate examination (7). 
The conclusion that follows from all this 
has not to do, certainly, with confidence in 
the efficacy of quinine treatment, as every 
one knows that by persistence in proper treat- 
ment the infection can be conquered; but it 
concerns the treatment of malarial patients as 
rapidly as possible, intensifying our efforts 
at the beginning of the malady, inasmuch as 
a complete and rapid cure is the more probable 
in proportion to the promptness of the admin- 
istration of the remedy.* 
All these data can be interpreted by the 
hypothesis that I shall propose as most in con- 
formity with our actual knowledge. Thus, I 
admit that certain malarial parasites under 
the action of quinine, in some cases, are select- 
ed to form resistant strains, whence the dif- 
ficulty of a radical cure in such fevers that 
relapse obstinately. It is not possible to say 
certainly, with any approximation, to what 
extent this can be verified. But resistant 
cases, although rare, are evidently those which 
should be most considered in regard.to prophy- 
lactic measures, because it is these which are 
largely responsible for the persistance of in- 
fection and its continued spread by such cases 
that are able to be up and around. 
And it is almost useless to add that the for- 
mation of strains resistant or semi-resistant 
(half fast) to quinine is a matter that does not 
admit of experimental proof, such as has been 
shown with trypanosomes. Human malaria 
not being transmissible to animals, it would 
be necessary to inoculate a healthy person 
with the blood from a resistant and relapsing 
case, in order to see if the same biological 
properties of the parasites would be recogniz- 
able in the inoculated person. But for obvious 
reasons, this is not practicable, nor is the 
solidity of the hypothesis affected thereby, so 
many are the observations that sustain it. 
There are also facts which cause me to 
think that there may be some strains of para- 
sites endowed orginally with great resistance 
to quinine. For example, several times March- 
iafava and I have seen at autopsy cases of 
pernicious malaria very rich indeed in para- 
sites accumulated in the vessels of the central 
nervous system, the spleen, the liver, the bone 
marrow, etc., in spite of an energetic quinine 
treatment for more than two days. Since 
these were recent infections, in these cases it 
does not seem admissable that the resistant 
strain, so to speak, was selected in consequence 
of the use of the alkaloid. With these may be 
contrasted those pernicious cases in which the 
quinine used in large amounts brings about 
the complete destruction of the parasites; not- 
withstanding which death supervenes, seem- 
ingly in consequence of alterations in the vis- 
It seems to me possible to infer in due 
course concerning the genesis of relapses: 
1. That the data presented hitherto do not 
permit, as far as our present knowledge is of 
avail, that the reports of relapses due to per- 
sistence of the macrogametes are partheno- 
genetic multiplication of these can be affirmed 
with certainty. 
2. That in all probability relapses, whether 
at short or long intervals, or whether sepa- 
rated by lengthy periods of latency, should 
be considered from a single viewpoint: that is 
to say, as having the same genesis, depending 
on the persistence of the pyrogenous cycle. 
one can come to practically the same 
conclusion, if one admits that the genesis of relapses 
is due to parthenogenesis of the macrogametes. In- 
deed, the peculiar resistance of these forms to the 
action of quinine is common knowledge. (Author’s 
note.) SOUTHERN MEDICAL JOURNAL 
In one group of relpases the parasitic ma- 
terial that maintains the infection is repre- 
sented by a minimum quantity of forms of 
the ordinary fever producing cycle, often 
recognizable by an accurate microscopical ex- 
amination, at least at some time in the course 
of the infection, which forms for a long time 
cannot attain the quantity or the virulence 
necessary to cause fever. Especially in those 
cases in which a series of relapses occur av 
longer or shorter intervals without quinine 
treatment, one should keep in mind the possi- 
bility that after a series of febrile attacks the 
organism acquires a certain immunity in re- 
spect to the pyrogenic action of the parasites; 
which immunity being transitory, as happens 
in other infections, it is attenuated or ceases 
after a certain period of apyrexia; whence 
the onset of relapse. 
in trying to explain all the facts regarding re- 
lapses, and especially the inefficacy of quinine 
treatment during long periods of latency ac- 
companied by perfect health, and also the 
relation that exists on the one hand between 
the frequency and the obstinacy of relapses, 
and the number of febrile attacks that occur 
without cure or with only an incomplete thera- 
peutic success on the other. 
If the facts that I have demonstrated are 
admitted, so that it is conceded that occasional- 
ly there occur strains truly resistant to quinine, 
it is reasonable to think that similarly there 
are found with a certain frequency in chronic 
cases of malaria strains of parasites endowed 
with a medium resistance against the alkaloid, 
analogous to what Ehrlich believes to happen 
with the trypanosomes in sleeping sickness 
in respect to arsenical preparations; and 
though in such malarial cases treatment not 
sufficiently energetic and protracted will bring 
about a practical absence of parasites from 
the blood, it will not avoid a return of the 
fever and parasites after a longer or shorter 
time. 
But there is also a group of relapses, in 
which the material that maintains the infection 
during the period of latency, is represented 
by forms resistant to quinine, due to a process 
of selection under the action of the alkaloid, 
as occasion offers; it is not necessary to sup- 
pose that such forms differ morphologically 
from others as I, myself, more than once,* 
have also thought. 
Note.—The construction of sentences in Italian 
differs so _ from English composition that 
in many instances it has been necessary to recast 
entire paragraphs. I have, however, tried to follow 
as faithfully as possible the style and expression of 
Dr. Bignami, and any lack of clearness or fault of 
rhetoric should be attributed to the shortcomings of 
the translator, and not to the author, whose paper in 
the original is a model of clearness and good style.— 
W. M. J. 
Such modifications in the biological proper- 
ties of the parasites are admitted by me, on 
account of the difficulty that is encountered 
*1 was formerly of the opinion that all forms of 
the parasites, except, of course, the gametes, were 
equally affected by the action of quinine when the 
drug was properly administered, and so expressed 
myself in a paper on quartan malaria. But since 
reading Dr. Bignami’s article, I have made a more 
careful study, using quinine in varying doses, and I 
can confirm Dr. Bignami’s statement, that there are 
forms of the ordinary asexual cycle that are resist- 
ant to quinine, and do not differ morphologically 
from the normal asexual parasites. If quinine be 
given, say in tertian infections, in doses of three 
grains three times a day, many of the parasites can 
be observed undergoing the changes accurately de- 
scribed by Captain C. F. Craig as occwring under 
the influence of the drug, but many more do not 
show such changes. In proportion as the dosage is 
increased, fewer normal parasites are found, but 
prolonged search will nearly always reveal such nor- 
mal parasites, and these, as long as they escape the 
action of quinine, certainly could renew the infec- 
tion, as Dr. Bignami believes.—W. M. J. 
REFERENCES. 
1. J. Schaudinn: Studien über Krankheitserre- 
gende Protozoen. See the chapter, Ruckbildung und 
Schizogonie der Markrogameten bei einem Recidiv. 
Arbeiten und dem Kaiserl. Gesundheitsamte, 1903. 
pages 230 et seq. 
2. Geneeskundig Trijdschritt voor Nederlandsch- 
Indie, 1908. 
3. Geneeeskundig Tijdschritt voor Nederlandsch- 
Indie, 1909. 
4. Ehrlich: Chemotherapeutische Trypanosomen- 
Stndien, Liepzig, 1909. 
5. Zur Kenntniss der Chininwirkung. Berk klin. 
Woch, 1910, n. 14. 
6. Infezione malarica cronica con i sintomi della 
sclerosis a placche. Reform Merica, 1899. 
7. See Marcbiafava e Bignami, L’infez.ione ma- 
larica, 1902. (This work, which is bevord anv ques- 
tion the most complete published on malaria and its 
complications, is printed in English in the Ninteenth BIGNAMI and JAMES; PATHOGENESIS OF RELAPSES IN MALARIAL FEVERS. 
Volume of the Twentieth Century Practice of Medi- 
cine. New York, William Wood & Co. I earnestly 
recommend anyone interested in the study of malaria 
to consult this volume before advancing any per- 
sonal observations. I speak from personal experi- 
ence.—W. M. J.)