A report on hemoglobinuric fever in the Canal Zone;

ISTHMIAN CeNAL COMMISSION

A REPORT

ON

HEMOGLOBINURIC FEVER

IN THE

CANAL ZONE.

A STUDY OF ITS

BIOLOGY: AND TREATMENT*

W. E. DEEKS, M. A M. D.,
-Chief of Medical Clinic, Ancon Hospital, C, Z.
AND
W. 19.AMiE S- M. D.,
Phvaician, Ancon Hompital, C. Z.

LISW9ED BY THE EiPARTMENT OF SANITATION.

trants 9.'s EPARTMENT
Mzurr 110or, C. Z.

LETTER OF TRANSMITTAL.

CoL. W. C. GORGAS, Medical Corps, U. S. Army,
Chief Sanitary Officer, Isthmian Canal Commission,
Ancon, C. Z.
Sir:
SWe have the honor to submit herewith the report of our
investigation into Hemoglobinuric Fever in the Canal Zone and its
Etiology and Treatment; also a Synopsis of the Cases (rom which
our data were derived, AppendixA; and a Discussion of the Various
.Hypotheses as.to the Etiology of the Disease, based on our findings
S and the literature, Appendix-B.
The conclusions reached by us are the result of deductions from"
i. 'or study, and were not determined by any preconceived opinions.

S.: ..... Very respectfully,
W. E. DEEKS,
W. M. JAMES.
S. coNO. HOSPITAL, Canal Zone, April 2. 1911.

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INTRODUCTION.

In recent years there has been much discussion in regard to the
etiology and treatment of hemoglobinuric fever, and most of the
authorities agree.that these are as yet unsolved problems in tropical
medicine. The authors of this paper herewith submit evidence that
bears on these problems, derived from an analysis of 230 cases of
hemoglobinuric fever which occurred in Ancon Hospital. Many of
these cases have been reported at other times by various physicians
in the service of the Isthmian Canal Commission, particularly by
Gorgas,' Brem,2 and Connor,3 and many of the conclusions reached by
Connor in his careful study of the cases that occurred under his personal
supervision, we have been able to confirm, as a result of our analysis
.of all of the cases that were treated in this hospital. However, we now
present for the first time an extended study of the entire number of
cases, and of collateral data as well.
That no misconception of the evidence presented may arise, we
consider it well to state explicitly our view of the interpretation of the
term "hemoglobinuric fever." It is well known that hemoglobin may
appear in minute quantities in the urine, so that it can be detected by
the guiacol-turpentine test, in several affections-notably scarlet
fever, syphilis, estivo-autumnal malaria, septicemia due to the strep-
toocFus pyogenes, and other diseases. In fact, any disease which
..produces a powerful hemolytic factor leads to a hemoglobinemia which
may result in more or less hemoglobinuria.
e Our conception of the disease cannot be expressed better than in
the following excerpt from Marchiafava and Bignami.'
"The hemioglobinuric attack is a syndrome which is encountered
Snot rarely, especially in hot climates, in the course of a malarial infec-
S tion. Te& chief symptom of the attack is the emission of urine contain-
ing alumin and hemoglobin in greater or lesser quantity.
S"All or nearly all authors place hemoglobinuria among the per-
. .... :fcious fevers. We maintain, however, that a special place should
.. S;i~ers ed for hemoglobinuria among the clinical forms of the malarial
Ij-;i ti.... The pernicious fevers are grave estivo-autumnal malarial
"i .: ..the principal cause of which is to be found in the deteriora-
tiin:. .. bb.od through the action of the very great number of para-
': it .U.'i*M t of which is easily demonstrable in the majority of
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tween the intensity of the infection and the gravity: of the symptom .
is usually quite evident. Hemoglobinuria, on the other hand, is.a .
phenomenon which may be manifested during the course of an active ii>!
infection as well as in one which has spent its course; it is intimately.
related to malaria, but there is no direct casual relation between this
phenomenon and the malarial parasites, such as there is, for example, "
between the coma of a pernicious attack and the $arasitic invasion of
the capillary vessels of the brain. Nor do we believe that we can class
together, as some have done, hemorrhagic malarial infections in "
general and hemoglobinuria. Indeed, cutaneous or mucous-membrane :
hemorrhage (nasal, intestinal, and the like) constitutes a symptom .*
which may accompany grave malarial infections, while hemoglobinuria
may develop in malarial subjects under the most varied conditions,
as will appear in the course of our study. We may also add that,
while the pathogenesis of the pernicious attacks has been in great
measure cleared up by the recent parasitological investigations, the
same cannot be said of hemoglobinuria, the pathogenesis of which is
still not only obscure, but is also certainly more complex." .
We have included in our analysis only those cases that in our opinion
manifested the characteristic blackwater due to hemoglobinuria, with ii
the presence of the granular detritus and the hemoglobin casts peculiar '..":
to the disease when a microscopical examination of the urine was made. ,i
The onset of the blackwater is sudden and paroxysmal, a d almost
always is associated with a chill and more or less severe constitutional.
disturbances, such as fever, vomitingfabdominal distress, liver pains,
and the appearance of jaundice more or less severe.
The resulting anemia depends upon the amount of blood destruction,
and the prognosis upon the severity of the above-mentioned symptoins ,
in conjunction with the kidney lesions. These latter vary from sliht.. :!
irritation to almost complete destruction of the epithelial tissues, tus ,
leading to suppression. This condition, which almost always is fatal,.
will be referred to later.
A close relationshipj.between malaria and hemoglobinuric fevr 'has.
long .been suspected, but whether that relationship is etiooca or: ::
accidental has been a mooted point.. The searches of Chistp rs
and Bentleys into thisproblem hav.p gne far toward etablitshFi' :
strong presumptive evidence Ain avr 4 .m~.4 a.a sh.h.peae
disposing cause of hemoglob z#;pi.evr, -e w..
-admit that every considedatilpotz l u
specificity of some.:hitherto

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7

At present, opinion as to the etiology of hemoglobinuric fever is
divided between those who hold that malaria is directly or indirectly
the prime factor, and those who assert that some organism related to
the piroplasmata is responsible. Also, the relationship of hemoglo-
binuria to the administration of quinine has been, and still is, a poiht
at issue. The data that we have collected will throw lighten all these
propositions.
A review of the literature of hemoglobinuric fever shows that many
of the arguments advanced in favor of the different etiological
hypotheses lack the confirmation of extended observation. A large
number of cases has been recorded, but no single series of these has
been observed over a prolonged period under control conditions.
The concurrence of malaria and hemoglobinuric fever among a cer-
tain class in a givtn locality has also been noted frequently, but there
are few, if any, observations extending over a period of years that
embrace all classes of people who reside in the same locality. The
eppidemiology of concurrent malaria and hemoglobinuric fever has been
studied, but there has been no evidence adduced as to the relationship
between hemoglobinuric fever and other concurrent diseases; and
while it has been possible to compare the seasonal relationship between
malaria and hemoglobinuria, there is no evidence bearing on a similar
Relationship between these two, and other diseases endemic in the same
locality. In nearly all cases of hemoglobinuric fever there is a history
of previous "fever," and such fever for the most part has been assumed
,to be malaria. In regions where malaria is epidemic, it is probable
i :ht such an assumption has been correct, but positive evidence of
:'h, :I s correctness has been lacking.
The conditions on the Canal Zone are such as to furnish data of
considerablel e reliability as a basis for an investigation into all these
S factors concerned in the etiology of hemoglobinuric fever. For over
i. years many individuals of three distinct races have been working
: ;ii to:;.:i l; a;untry in which malaria is endemic at all seasons of the year, and
:" I:.. I h.. uiwjtamer appears as an.epidemic. But although this disease is
p..; i:' ". .:~nsible for a very large proportion of the sick rate, others occur in
S. :::. :i, bersFii'e sufficient to form a reliable basis for a comparison of all their
o:.g. cal factors with those of malaria and hemoglobinuric fever.
.: .... i.:.!. .i:: 'percefitage of all diseases is under hospital supervision, and
.;i .h.: ::':spIal records of previous admissions can often be substi-
: :::i:::;,,;ii;i.i h and empirical experience. We do not claim
...;*di o~is 'eas been correctly made, and for reasons which
b aiparent, the hospital records are not. altogether
AbfunU t4 in re rd to the limatic, epidemiological,

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believe to be substantially accurate, and certainly, as far as we have "
been able to ascertain, more complete than those hitherto reported
from any one locality in a given period.
In undertaking this study of the factors concerned in the etiology of
hemoglobinuric fever, we have been neither guided nor governed by.. .:
any preconceived hypothesis. Our'object has been solely to collect
data, and to find if any definite conclusions could be induced from them.' :
That:.these data are reliable, a study of the following charts and
tables will show. There is a substantial uniformity in the results
that have been obtained. When it is considered that these results
depend upon observations and diagnoses made by many physicians in
the period from January, 1905, to September, 1910, the uniformity
that is manifested at all times is in itself a proof of the correctness of
the data.
We do not believe that any mistakes were made in the diagnosis:of
the 230 cases of hemoglobinuric fever in this series. While it is true
that a microscopical exariination of the urine was not made in every
case, in the cases in which such a urinary examination was made, the
characteristic findings in hemoglobinuria were always present. More-
over, every fatal case, so far as we have been able to ascertain was
correctly diagnosed before death, as the autopsy findings subsequently ::
proved.
* In order to make this study, as complete as possible, we. shall dis-
cuss the subject of our paper under the following heads, a considera-
tion of which we believe to be.necessary to a comprehension of the
factors that enter into the problem of the etiology of *hemoglobinutic
fever in the Canal.Zone: -
1. The influence of the topography of the Canal Zone on the
prevalence of malaria.
I.I. The racial distribution of the employees of the Canal CommisY z .
sion and their manner of.living. :
III.. The prevalence of malaria in the Canal Zone.
IV. The distribution of malaria among the employees of the Comf.y:'.
mission.
V. The relationship between malaria and hemoglobinuric fever'. Wi' -:TI
VI. Length .of residence in a malarial country asaa fa ctord i i.I
etiology of hemoglobinuric fever, ... ...' ,A.;;!
VII. An. hypothesis as. to the etiology of. ltmogleBi*i
-the part played by quinine ip the production of 4.; ip1&*W
Treatment of the malady. t S

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9

I.
THE INFLUENCE ON THE TOPOGRAPHY OF THE CANAL ZONE ON THE
PREVALENCE OF MALARIA:
The Canal Zone is a strip of land ten miles wide and forty-five miles
long; the width being a distance of five miles on each side of the line
of the Canal; the length, the line of the Canal from the Atla'ntic to the
Pacific. The Chagres River joins the line of the Canal at a right
angle about two thirds of the distance from the Atlantic to the Pacific,
and follows this line'to five miles from the Atlantic, where the river
diverges, and empties into the ocean about six miles from the Atlantic
end of the Canal. At the north end of the Canal is the city of Colon;
at the south end, the city of Panama. Over the entire Canal Zone,
and these two cities, the Government of the United States has the right
of sanitary regulation.
The coast on the Atlantic side of the Canal Zone is made up of low
alluvial flats, with many swamps and lagoons that extend inland for
several miles. On the Pacific side the land is more elevated, but the
high tides that prevail there make swamps whenever an inlet is afforded.
In the interior are numerous hills and valleys, and through many of
the.latter tributaries of the Chagres make their way. In the valleys
where there are no rivers, the heavy rainfall that prevails during
most of.the year produces pools and swamps, which are fed during the
'interval between rains by countless springs. Over all the country,
when not removed by the hand of man, is a dense growth of jungle,
whose heavy shade keeps the ground moist; and the tangled roots of
theii&bundant vegetation favor the retention of the surface water in
littlaponds.
Before the Government of the United States took possession of this
territory, the "Isthmus," as is commonly known, was a synonym for
the. habitat of all varieties of pernicious malaria, and yellow fever was
a poteat.factor-in the mortality rate. Hemoglobinuric fever was com-
rnoma.ndfatal among aliens and was known to the residents as ."Chagres
i. fever although sometimes this term wasapplied also to the cerebral
form'-f;pernicious malaria. It does not appear that other diseases
w: more common than elsewhere in the tropics. What is of impor-
t an ..,,i'i.:eis:.that the topography of the Canal Zone, and the prevailing
: id d ml.. stological conditions in it, have made the country in the past an
bt* :e:ing ground for the insect hosts of malaria and yellow fever;
" iiu:iiiS re. solely by the most rigid enforcement of. sanitary
S i'i.thesi diseases be kept to a minimum.- *
Seit sanitation, in estery sense that the word implies, *

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the former unhealthiness of the Canal Zone has been abated. greatjy.
We say abated, for the conditions.that cause unhealthiness are iate ,t, ii
and need no more than a relaxation of sanitary vigilance to bring abqot.i-
a return to former conditions. Places that favor the accumulation,.i .'Il:i
filth and the propagation of mosquitoes have been eliminated frpm the :,,,
cities of Panama and Colon; along the line of the Canal the jungle has
been cleared; the pools and swamps in and about the Zone towns have
been drained, and these towns are kept dean and dry; and an effect .::'
water supply and a sewerage system have been installed throughout thl
entire Canal Zone, and in the cities of Panama and Colon. The effici-
ency of such measures in promoting the health of the entire population
natives as well as aliensis amply shown by a comparison of the present ,
rates of mortality and sickness with those of the past, and also with
those of more favorably located communities.
Notwithstanding the improved conditions of sanitation, malaria
.still manifests itself, and is decidedly the prevailing factor in the sick
rate. .This is due to conditions under which many of the laborers
live' the constant need of new drainage, owing to the progress of the
.work; and the filling of the artificial lakes that are to become part of
the waterway. It is our purpose to treat with the intimate relation
which obtains between the prevalence of this malaria and that, of ..
hemoglobinuric fever; and to adduce the data which we have collected,
to demonstrate whether the latter disease is dependent on malgirias.. '
a predisposing factor, or if it be of independent origin.

4 i .. ..
THE RACIAL DISTRIBUTION OF THE EMPLOYEES OF THE CANAIJif- rli
MISSION AND THEIR MANNER OF LIVING. 'i
Since the American occupation of the Canal ,Zne its inhabitant -"
may be divided into two groups: the one composed of those .who wo rk
for the Isthmian Canal Commission (referred to herafter ,a the..Com- .,
mission); the other made up of natives of the country,. wih suiq imini-
grants as have been attracted by the increase .i. business.:. ..U~~e ...th
number and racial distribution of the persons included in the it.. grTQP
are based the data set forth subsequently. This group comnprie t)ee: Ie
distinct races: the American, which is Aglo-Saxon in originr.i
European, made up iiostly of Spanish a.ndJtalianJlborers wi
siderable preponderance of Spaniards;, and..the6 I
coming in greater part, from .the islands .q( JawM ,.
SThe numerical ratio between these ;.ce. ti t X

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this country of the individuals who comprise them, and the relative
susceptibility of each race to disease must be kept constantly in mind,
for these factors render complicated any attempt to compile reliable
statistics that pertain to the total distribution of disease in this country.
Two sets of figures are necessary, the one showing the total disease for
Small races, the other, totals for the separate races. And as far as pos-
sible, such figures have been obtained. The second group, that of
natives and non-employees, is of importance only in so far as it acts
* as a means of conveyance of disease to the first; the prevalence of
disease in it dbes not effect to any appreciable extent the figures used
Sin the subsequent tables and charts.
These three races are natives of localities' where, broadly speaking,
malaria does not prevail to any great degree. The Italians are mostly
from the north of Italy: the Spaniards from the north of Spain; and
; Jamaica is not badly infected with malaria, while Barbados is said to
:: be free from endemic cases. Such immunity against malaria, as is
present during the earlier part of a residence here, is therefore racial
and not acquired. How much of such immunity exists will be shown
later. It is sufficient at present to say that Americans and Europeans
are alike susceptible to the disease, while the negro possesses a partial
racial immunity.
The same general conditions of sanitation, such as drainage, water
supply, sites from which grass and underbrush are removed, and in-
spection of..quarters by the Department of Sanitation, obtain equally
among the three races. But it is impossible to equalize the racial
appreciation of such important individual sanitary measures as care of
screening, predisposition to cleanliness, prophylactic use of quinine,
and personal regard for health. These latter vary greatly among the
races, and are directly responsible for the prevalence of malaria in
proportion to racial susceptibility to the disease.
S The American employees of the Commission are the skilled mechan-
ics, clerks, foremen, responsible railroad employees, civil engineers,
: physicians,and.nurses, and otherswho fill the many positions connected
W; ith the executive, constructive, and administrative functions of the
S "Canal building. Since Januatry, 1906, almost without exception, they
; a;;i;?e lived in houses provided by the Commission. These houses are
eq,, ..;:i.pped with screen doors, screened windows and verandahs, and are
*.i ::;iikept by their inhabitants, any defects in the screening or the
S I g beint reported promptly. Among these employees the use
~t he at thkrst &aset of feveris universal, and prompt consulta-
Sthieaearesot Commission physician is the rule. Each employee
.i..'. vacation, with pay, for twelve months' service, and

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If a bachelor is too ill to work he is sent to the Commission hospital at
Ancon or Colon, and most married men, who, by reason of sickness,.
are unfit for duty, also avail themselves of the hospital service. A
sanitarium for convalescent patients is 'maintained in the malaria-
free island of Taboga, in the Gulf of Panama. The Americans do not .
frequent at night the native quarters in the Zone towns; do not expose
themselves unnecessarily to malarial infection; and of their own initi-
* ative aid greatly in preserving their health and in keeping sanitary
regulations. Classed with Americans, who are also stalled '"gold"
employees, aie those white men of other nationalities who hold positions .
entitling them to similar quarters and treatment.
Those of the European laborers who so desire live in well kept and
carefully screened barracks, and for families, screened quarters are
provided. But no amount of advice seems to be effective in securing
among them individual prophylaxis against disease. Every sanitary::
regulation needs to be rigidly enforced. They often prefer to sleep in
hammocks or even on the ground under their quarters or in other places.
They mingle freely at night with the natives, and cannot be kept ..
indoors. As a race they are not addicted to strong liquor, but we .
are informed by Mr. LePrince, the Chief Sanitary Inspector, that an
increase in malaria among them is always accompanied by an excessive
consumption of rum, and very inferior rum, in the belief that the drink
is an efficient medicine. They are indifferent to personal hygiene, and
equally indifferent to their state of health until illness compels them
to seek aid.
As elsewhere in the world, the enforcement of sanitation among the.
negroes is a gigantic task. A small percentage, only of this race live:
in the free quarters'provided by the Commission. The rest either;
prefer cheap lodging houses, where they huddle together at night like, :
so many sheep, or else they live in straw-thatched hats after the man '"
ner of the natives. The European laborer, though he mingles with.:;
the natives, does not live with them, but the negro lives:and sleeps in:'
their houses, exposing himself constantly to the endemic- malasial'
infection there prevalent. As long as he has a roof over his head andi
a yam or two to eat he is content, and. hisideal of personal hygiene-
is on a par with his conception.of marital fidelity. ;
The conditions under which the three races .ive should be .9td
carefully, for they have a direct -bearing on the distribution of-.
and hemoglobinuric fever. It will be. shownLhat s if m..
frequent among the negroes, despite, th i" .ms "
acquire it, than among either of the other :

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shown also that hemoglobinuric fever prevails among all races in
direct proportion to the amount of malaria among them.
Chart No. 1 shows the total number of employees by thousands per
month from January, 1905, to September, 1910, and the same for
individual races as far as it was possible to obtain the latter figures.

III.
THE PREVALENCE OF MALARIA IN THE CANAL ZONE.

The data used in the compilation of these statistics relating to the
prevalence of malaria in the Canal Zone are taken from the monthly
and the annual reports of the Department of Sanitation, and from the
records of Ancon Hospital. In some of the tables there is a slight
discrepancy between the figures credited to Ancon Hospital in the
monthly and annual reports, and the figures shown by the ward regis-
ters of the hospital for the same time. This discrepancy is not of a
nature to affect any conclusions drawn from the figures given, and is
less than 1 per cent of the total malaria.
While we were able to ascertain the figures for the prevalence of
malaria as a whole, and its prevalence in Ancon Hospital, we were not
able to examine personally the records in all of the cases of hemoglo-
binuric fever reported on the Isthmus. For this reason we have taken
the records of Ancon Hospital as a basis for comparison, and have ascer-
tained how far the admissions for malaria into this hospital constitute
a true index to the prevalence of malaria on the Isthmus; because a
larger percentage of cases of hemoglobinuric fever than of malaria is
sent to Ancon Hospital.
A routine examination of the blood is made whenever a patient is
admitted to the medical side of Ancon Hospital. In malaria the diag-
nosis is made: (a) if the parasites are found: and (b), when the para-
sites are absent, if the physical signs and the clinical symptoms, with
the course of the disease, justify the diagnosis. When the parasites
are found, the diagnosis is made according to the species of parasite
present, and such cases are hereinafter described as "positive malarial
cases." These positive cases are divided into "estivo-autumnal,"
and tertiann" malaria. When the parasites are absent, the diagnosis
is "clinical malaria," and such cases are hereinafter referred to by that
nale,. Mixed infections of estivo-autumnal and tertian malaria,which
dbastitute between 1 and 2 per cent of the positive bloods, are credited
d t'd h tari'etas one case. The number of quartan infections is too
i naitqie considered.

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15

Table I shows the number of cases of malaria per annum dis-
charged from Ancon Hospital from January, 1905, to September, 1910.
The records of the hospital show discharges per month, not admissions;
r but since the average stay of a malaria patient is seven days, the table
Sis approximately correct if it is also used to denote admissions. In
column 2 (a) of this table are the figures showing the total number of
cases per annum, discharged with a diagnosis of malaria; in (b), the
number of these cases that were positive. In column 3, the percentage
S of each variety of malaria is given. In column 4 are the percentages of
estivo-autumnal and of tertian malaria in the positive cases. In column
5 are estimated percentages of these two varieties as applied to the
total number of cases.
The average percentage of estivo-autumnal malaria as shown in the
S positive cases, is 74. We believe that this is too low, if taken as the
percentage of this variety in all cases of malaria. The true percentage
of estivo-autumnal infection is at least 80. An explanation of the
figures in this table will show why we regard the latter figure as pre-
ferable.
The average proportion of positive to clinical malaria is 58:42. i
SForty-two per cent of clinical cases may seem too high, and possibly
Suggests that many cases diagnosed as clinical malaria might have been
due to other causes. We do not deny that occasionally such a mistake
Might have been made, but we do not believe that the error was com-
mon. There are several very good reasons why the percentage of
clinical malaria is not lower. Among the Americans admitted to the
hospital the percentage of clinical malaria is always very high, as will
.4 : be shown later, for the reason that but few of these patients are ad-
mitted until they have tried to cure themselves with quinine at home.
Prior to admission, a very considerable proportion of Europeans and
negroes had been from one to four days in the sick camps, and while
there had received liberal doses of quinine. In many of the cases but
: :;:;'":a; : blood examination was made; for at times, in some of the medical
:; ".. awards, as many as forty patients a day were admitted, and unless a
:patient was seriously ill, there was not time to make a more extended
b:::,:,:,..-lood examination. If all'of these facts are considered, a rate of
Vi er cent of positive bloods is a very good average.
iii ......:... :iOne. of the objections urged against a diagnosis of clinical malaria
- '.:i .. ji 'hat in some of the cases so diagnosed no fever is present after
sik. Daily we see patients in whose blood either estivo-autum-
",lT d ian parasites are found, and who have no rise in temperature
6t2 If: it h tch patieAnts:f iler subsequent to admission
SltaInIy inilmar' absence of fever, in patients whose bloods

::: .::... .. ....... : :. . ............... ..............
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infection, is no bar to a diagnosis of malaria.
It is in these clinical cases that a relatively larger -percentage of
estivo-autumnal malaria obtains than in the positive. In estivo-
.autumnal malaria there is frequently a time in the cycle of the para- "
sites when none of them are present in the peripheral blood.* Often
there is fever when no parasites can be found. The young estivo-autum-
nal parasite does not stain as readily as does the tertian, is 'smaller,
and so is more easily overlooked. In tertain malaria the parasite is
always present in the peripheral blood when there is fever, the gain-
etes are more abundant, and are easily found. Also, tertian malaria
is more amenable to quinine, and tends more frequently to spontaneous
cure, so that there are relatively fewer admissions due to it than to ..
estivo-autumnal malaria in the clinical cases. For these reasons, in
estimating the percentage of the two varieties of malaria, we have .
added 10 per cent to the estivo-autumnal percentage in the positive
cases, and have calculated the percentage of estivo-autumnal malaria
in the clinical cases in the augmented proportion. This gives the'esti-
Smated proportion, averaged for five and one-half years, of estivo-
autumnal to tertian malaria as 78:22; Table I, column 5. This
percentage of 78 we regard as a minimum, and, as we have stated pre-
viously, the true proportion of the two varieties is about 80:20.
That the figures given in Table I are approximately accurate is
demonstrated by the comparatively small variation among them.
The data on which these figures are based extend over a period of nearly
six years. The diagnoses and blood examinations were made by many "*i
different physicians. Since 1906 we have depended on Wright's and
Hastings' stains for blood work; at times the quality of these staiis
has not been good, and often the slides were examined by men who ll
had not acquired a very definite knowledge of the parasites. In the
year 1907, in which the variation in the percentages in Table 1'S
from the arithmetical average was greatest, the percentage ofInala'il. .
cases admitted to Ancon Hospital, compared with that of tie total:.,,
malaria in the.Canal Zone, was smallest. This means thati. :: :,i
malarial patients as were admitted for that year had been treated -with .
quinine before admission; a circumstance that always increases "the
positive tertian percentage and-lowers the positive estivo-.aium Ml,
because as a rule only those tertian cases who are quite ill coiinei athe *i
hospital. Including this year (1907) the greatest vaatioii ':ti-- ,.

'This statement refers to our routine examination, -ot to 'thie: "i ii::bi:
method. j

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positive bloods between any two years is but 18 per cent; not a large
figure when all factors bearing on the finding of parasites are con-
sidered.
Chart No. 2 shows the prevalence and seasonal variation of malaria
as based on the discharges per month from Ancon Hospital from Jan-
uary, 1905, to September 1, 1910; and calculated to the number per
thousand of employees in each month, as shown in Chart No. 1. As
has been stated, the figures are approximately correct if used as an
index to the admission rate also. This chart exhibits the intensity of
malaria as shown by the number of patients admitted to Ancon
Hospital. It is necessary to compare this intensity with that of the
total malaria in the Canal Zone, in order to ascertain how far Chart
No. 2 may be regarded as an index of the total prevalence of
malaria. Table II shows the number of cases of all diseases admitted
tdo all Zone hospitals and sick camps, and the percentage of these
admitted to Ancon Hospital; the number of all cases admitted to the
Zone hospitals alone, and the percentage of these admitted to Ancon
Hospital; and the number of these cases diagnosed as malaria in
the Zone hospitals, with the percentage of such cases admitted to
Ancon Hospital.
TABLE II.-Showing the total number of cases of all diseases admitted to all of the Comnission harospats
and sick camps per year; the total number of cases of all diseases per year admrnted to the Commnssion
hospilals: the total number of cases of malaria admitted to all of the Commission hospitals; and the per-
centage of each of the foregoing admitted per year to A neon Hospital. This table shows how far the admis-
sions fr malaria and other diseases into A4con Hospital is an index to the prevalence of malaria and
aoter diseases on the Isthmus. The increasing number and percentage of cases of malaria and other
diseases into Amen Hospital should be noted carefully.

Totalof otalof Number Number Percent
all ale cases per Percent- of cases r these age of
aditead Numberl Percent-] year in
l Number age of ll peryear cases hee
year hospital diag- cases
to the cases as mission of these cases nosed a that diag-
Year. ho pitals admitLed admitted hospitals admitted admitted malaria were d as
and sick per year Iper ear eiive to Ancon per year in the diag- malaria
amp o L con to cn o e Hospial. a Anconi Commis- o ain Ancn

1906........ 30,490 12.535 41 .. .. .. .. ...... 7.561 34.7
1907....... 58.521 14,237 24.3 32.063 14.237 44 16.429 6,505 40
1908........ 53,755 15.880 29.3 27.251 15.880 58.3 12.290 8.192 66.6
1909........ 46,593 18.750 40.2 27.184 18.750 68 10.071 8.837 87.6

Table III shows the annual number per thousand of employees
admitted with malaria to all hospitals, and the percentage of these
admitted to Ancon Hospital. We were able to procure more data
for the compilation of Table III than for Table II. Table III shows
that the greatest prevalence of malaria was in 1906, when 821 per
thousand of all employees were admitted to the Zone hospitals. The
percentage of admissions of total malaria into Ancon Hospital, as

: i "' ." .-
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-;' ..........
... .. .. .. ... ..

shown in able 111, snouli De Kept careiuny m mina in exammn g
Chart No. 2.
TABLE 11I.-Showing the annual average of ke Ital number of employees of the Commission per woar;
the nu mber of admissions due Io malaria per tkou nad of this annual average to all Commisaiom heaispi ..r.
she veaou annual percentages of the maximum rae per thousand of admissions ,wkich maximum ocred
in 196,. the number of ddmissons due to malaria pertloisand of he annual average lo Arao Hospilat"
and the perrentage of these admissions of the total malarial admissions.

Per cpnt of the .
Number of ad- Per cent per Number of ad- totl numb er
missions per year of the maisioas per -. cases o:
Average num- thousand per 1906 maximum thousand per .malaria per
Year bek employees year, due to of admissions year. due to thOusand em-
per year. malaria, into per thousand malaria, into pl.oy -
all hospitals. in al hospitals. Ancon Hospital year. admitted
Hospital
1905 .. 13.331 514 61 339 65
1906.. ... 26,500 821 100 285 54.2 4
1907 ... 39,343 424 52 165 40
1908......... 43.890 282 34 186 66
1909.. 47,167 215 26 187 87

We have not added to the figures and curves in Chart No. 2 the: .
difference between the number of cases of malaria admitted to Ancon
Hospital and the total number of cases of malaria, in order to show
graphically the variation of the malaria rate for the Canal Zone;
because a larger percentage of -malarial cases is admitted to Ancon
Hospital when the malaria rate is high than when it is low: for example,
in 1907, 40 per cent of the malarial cases in the Zone hospitals was
admitted to Ancon; but it is probable that a lower percentage than
40 was admitted in March, April, and May, and a higher in July,
August, September, and October.
Chart No. 2, and Tables II and III, show that since 1906 malaria,. 1.
has steadily declined in prevalence. A well marked seasonal variationF;
is plainly evident. This variation is somewhat exaggerated by the. ::
increased percentage of admissions when the malarial rate for the Zone6; ,
is high, and the decreased percentage when the rate is low. Thie.; J. i:i
seasonal variations correspond exactly to the duration of the wet and: ''
of the dry seasons, the curve being high in the former and low in the j:;:.
latter.'.
This seasonal variation is due in a very great degree to the fluctua- :: .
tions in the amount of estivo-autumnal malaria. The difference,: .'ii
between the curve of the total malaria and that of positive cases, in:..
Chart No. 2, represents the amount of clinical malaria. At least.:i:
80 per cent of this clinical malaria is estivo-autumnal, and if this'i '::iiilB
80 per cent were added to the curve representing the prevalence ofi:'
estivo-autumnal malaria shown by the positive blood examinatio .is% l
the seasonal variation in this kind of malaria would be much
evident than the chart indicates. Even if the positive aBe on ly. .
S. . .... .. .. ...: .
: ... ..: .

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...... ..... .. .. :. i.. i .. .::. !i i ;.".. '^.. ,ii .: ., ..:........."

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19

considered, it will be seen that the estivo-autumnal curve corresponds
very closely to that of the total malaria. While the seasonal variation
of tertian malaria is synchronous with that of estivo-autumnal, at no
time, except in 1907, does the former influence the curve of total
malaria as does the latter.
Chart No. 3 shows the monthly rainfall on the Canal Zone from
January 1, 1905, to September 1, 1910. The average annual rainfall
from 1905 to 1909, inclusive, is also shown, so that a comparison of the
rainfall of any year, with the average rainfall may be had. If Chart
No. 2 is compared with Chart No. 3 it will be seen at once that the
increase and decrease in the prevalence of malaria corresponds almost
exactly with the increase and decrease in the rainfall. It is of great
interest to determine how far this climatological factor is instrumental
in determining seasonal variations in malaria.

In our opinion this seasonal variation of malaria is due more to
relapses than to primary infections or to re-infections. If it were due
to primary infections or to re-infections, then the number of anopheles
mosquitoes should increase synchronously with the increase in rainfall
and the increase in the malaria rate and should decline in a similar
manner. Mr. Le Prince, the Chief Sanitary Inspector, has informed us
S that the increase in malaria of each year always antedates by several"
weeks any appreciable increase in the number of anopheles mosqui-
toes. While it is not easy in countries where malaria is endemic
throughout the year to discriminate a relapse from a re-infecton,
SMr. Le Prince's observation demonstrates that a very considerable
S amount of the June and July malaria must be due to relapses.
Estivo-autumnal malaria is very prone to relapse. Once acquired
it is not easily eradicated, and there are many factors that predispose
i.. to relapse at a time when a person who has acquired the infection is
exposed to inclement weather. A relapse in malaria means that para-
sites are present in theta system and an immunitas non sterilisans has
been established. Temporary immunity can be interrupted by a
seri. of conditions; some of which are active throughout the year, and
s~inrme seasonal.
I:; Ofthe causes that prevail throughout the year which may interrupt
S a tepaporary immunity, probably the most potent here is syphilis. In
uE.ntated syphilis, patients will return repeatedly with malarial re-
iii" lapses and tQ- effect a cure the administration of specific treatment is
S.... asne:: : sa: as th. administration of quinine.
l ; By rea,':on its depressing influence, influenza is also an important
.....faiq. i th'iproduction of malarial relapse. It is not unusual to

..iii,, :: ". .. '.r. :

M ... .......... .... iii.. ii.i;;. % ,.4i..ii.i.ii....: ".; ... . ...

i77

and for parasites to be found when a careful search at the time of i
admission failed to reveal them.
Injury, an operation, the administration of an anesthetic, childbirth,
any severe shock, all of which depress the patient, may interrupt the
temporary immunity established in latent malaria, and an acute
exacerbation of the latter may ensue.
Muscular fatigue has long been known to be an important means of
precipitating a malarial chill. The explanation has been given that
an accumulation of sarcolactic acid is formed in the tissues by excessive
exercise, and that this accumulation interferes with the action of the
protective alexins and opsonins which act best in a slightly akaline
medium. The interference with the same protective agents by the
excessive use of alcohol may be considered as a factor in producing
relapses.
Among the seasonal factors that cause relapses, climatic change is
S most important. It is a very common experience to find an acute
exacerbation when a person who has temporary immunity journeys
from the tropics to a northern country, and vice versa. Probably thie
same cause that operates in- this instance is in the Canal Zone the most
frequent in producing relapses after exposure to wet and to cold.
SThese factors, exposure to wet and to cold, are considered by the
S Italian writers to be of thegreatest importance. In the beginning of our
rainy season, and throughout it, the laborers are frequently thoroughly
wetted, and being far from their quarters, have no opportunity to.
change their clothing, and many of them would not change it if they
had the opportunity. Hence there is a chilling of the body, and a
temporary lowering of resistance, which brings about a malarial exacer-
bation. Whether such a relapse is due to a direct lowering of the
phagocytic power of the leucocytes in their passage through the super-
ficial capillaries, by lowering the temperature of the leucocytes, as has
.been suggested by some writers; or whether it*is due to centripetal ",l
influences which affect the nerve centers that preside over nutrition :'I
and cell metabolism, thus inhibiting the elaboration of protective
agencies in the body, and cellular food supply, it is difficult to state.
Any of the above named causes for relapse will be made more efficient
by the climatological factors that prevail at the beginning of the w.t : '";::::: ..
season; and any cause will be less effective .i the mild weather tat :
prevails in the dry season. .
It is because estivo-autumnalmalari isinore prone to pee .
is tertian, and because it persists n.rfe tenaciously w hi : o* sqI' I
that the amount of the former is so murchgreafte. !A t,

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K 21

season has advanced sufficiently to furnish suitable breeding places,
the increased number of anopheles will account for a part of the in-
crease in the malarial rate. But even this increased number of mos-
quitoes does not explain why estivo-autumnal malaria should increase
actually and relatively more than tertian, unless the former is more
susceptible to propagation. The same conditions which favor the
spread of the one variety, favor also that of the other; is, then, estivo-
autumnal malaria more readily disseminated?
Dr. S.T. Darling" has noted that the gametes of estivo-autumnal
parasites remain for a longer time in the peripheral circulation than
? do those of tertian, in both cinchonized and untreated persons. He
has also found that actually more zygotes develop in anopheles fed on
blood which contains crescents, than in those fed on blood containing
Stertian gametes, when the number of gametes in the blood in each in-
stance is taken into consideration. Darling has also shown that
Anopheles albivanus is the principal carrier of malaria in the-Canal
Zone. He fed eighty-eight anopheles on blood that contained cres-
cents. Of these, seventeen were A. malefaclor, none of which were
infected. Of the remaining seventy-one, zygotes were found in 50
per cent, nearly all in A. albimanus. Twelve anopheles were fed on
blood that contained tertian gametes, and 50 per cent of these were
infected, all A. albimanus. Of forty-two A. albimanus fed on blood
.. that contained crescents, twenty-nine, or 70 per cent, were in-
fected. Several of these were .dissected between twenty-four and
fifty-eight hours after infection, and it may be that the ookinets
or the young zygotes were not found. Of seven A. albimanus fed on
blood containing tertain gametes, six, or 85.6 per cent, were infected.
iFrom this, it is evident that A. albimanus, the principal carrier of
malaria, is susceptible to infection equally with either tertian or with
estivo-autumnal gametes.
Now, while it is true that crescents remain for a longer time in the
peripheral blood than do the gametes of tertian malaria, the latter are
relatively more abundant. It is but seldom that gametes are not
present in the blood of patients admitted with tertian malaria, while
crescents are not found in most estivo-autumnal infections on admis-
sion. We have observed that in infections with tertian malaria which
either aig cutibated or.rilapsed while the patients were in the wards,
gametes were present, thus proving that these have been developed
by the time that the clinical symptoms had manifested themitelves.
.. In' imar insitans, in estivo-autumnal infections, and also in estivo-
S i ktum fectos that were permitted to run without quinine, the
S|a|lit dnopt:pear until several days after the onset of the fever.

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than those pertaining to the number of gametes in the peripheral blood
of infected individuals, and other than the susceptibility of anopheles
mosquitoes to infection from such blood, must be adduced to explain
the increased prevalence of estivo-autumnal malaria in the rainy
season. As Chart No. 2 shows, the annual increase occurs too sud-
denly tp be accounted for entirely by an augmentation in the number
of anopheles, although this augmentation undoubtedly contributes
to the increase, and certainly is a considerable factor in maintaining
it through the wet season. But the decrease is as sudden and marked
as is the increase, and it is unreasonable to suppose that the very
great number of anopheles accumulated during the wet season, perishes
as rapidly as the malaria rate falls when the rains cease.
Undoubtedly the climatological changes, as shown in Chart No. 3,
are very important influences in the marked seasonal variation in the
malaria rate, and this variation-is to a considerable degree independent
of the agencies concerned in the transmission of malaria. These
climatological factors are effective in that they influence the causes
which determine relapses, and so produce the preponderance of estivo-
atumnal malaria in the wet season. The importance of the preponder-
ance of estivo-autumnal malaria in the determination of hemoglo-
binuric fever will be discussed subsequently.

SUMMARY.

Malaria prevailed extensively in the Canal Zone in 1905 and 1906,
and since then has been steadily diminishing in frequency.
There is a well marked seasonal variation in the malaria curve, and
this variation is largely dependent on climatological influences.
Relapses are more frequent in estivo-autumnal malaria than in
tertian, and the relapses contribute to a considerable extent to the
seasonal variation in malaria.
Climatological influences determine to a great degree the number of
relapses, and more malaria is due to relapses than to primary infections
or to re-infections.
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A-A, Total manlarla.
'-B, PoSitive cases.

I II 1 1 J3..I I 1 1 1 1 1 Id I I 1 I I.- 5. L.I^L-LL. r.T I 1 I II
RACIAL FPaEALENGE OF MA.LA.UA 1iN AICaon7 HOSPITAL.

The fliguvi refer to the monthly rat ep thouslnad; t Ah .race.

0-0, Estivoautumnal malaria
D-D. Tertian malaria.
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IV.

THE DISTRIBUTION OF MALARIA AMONG THE EMPLOYEES OF THE
COMMISSION.

If all the inhabitants of a given locality were equally susceptible to
malaria, or if malaria prevailed to the same extent among all classes,
the total malaria rate could be used as an index applying to all races
and persons. We have indicated previously the different conditions
of residence, personal regard for health, and individual respect for
sanitation that obtain among the three races employed by the Commis-
sion. It is of importance to ascertain how far these conditions are
responsible for the prevalence of malaria among these three races.
Chart No. 4 represents the prevalence of malaria among the Euro-
pean laborers, the negroes, and the Americans, for the period from Jan-
uary, 1908, to September 1, 1910, as shown by the number of discharges
per month from Ancon Hospital in proportion to the number of persons
employed of each race. It has not been possible to obtain similar
figures for the preceding years. Chart No. 4 is drawn to the same scale
as is No. 2, and the figures and lines in the former represent the same
varieties of malaria in the same proportion as in the latter. Table
IV, A, B, and C, sets forth the same data as are represented in Table
I for the total malaria, but applied in Table IV to the separate races.
A comparison of Chart No. 4 with Chart No. 1 demonstrates that in
the period designated by the former, the number of Americans and
Europeans was about the same, while that of the negroes was from
seven to eight times greater.

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In 1905, as shown in Table III, the admission rate to all hospitals
from malaria was 514 per thousand, of which 65 per cent was admit-
ted to Ancon Hospital. Owing to the exposure to which they were
subjected, malaria must have prevailed very extensively among the
Americans at that time.
The few Europeans on the Isthmus also suffered severely, and heavy
infections were common among the negroes, as an examination of the
ward registers proved. The July epidemic of that year affected
Americans in great numbers. Beyond the fact that malaria was
universally prevalent in all three races in 1905, as shown by the
admission rate and the ward registers, we were unable to get more
e:wt.. data
In 1906, the Americans were better protected than in the preceding
:. :eat, and their degth rate from malaria was 1.33 per thousand, as com-
pe... d witf 7.8 per thousand among the negroes. In this year the
:ima i ratin of. European laborers began, and this class must have be-
c e. vily infected with malaria.
I' '. 9 7, re wa4.a deathii rate among Americans of only one-third
oRE .rt^ of 19g04 h a nalked decrease in the prevalence of malaria
....... ..,
... ..::: ~i i i. . ..
f.. ..." ."." ....
. .. .. ..
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b

25
Although it was not possible to obtain data showing the relative
amount of malaria prior to 1908, we are able to give some figures that
enabled us to approximate closely this amount. Col. W. C. Gorgas,
M. D., U. S. A., Chief Sanitary Officer, and Head of the Department of
Sanitation, whose well known work in tropical sanitation has quali-
fied him as an authority on the prevalence of tropical diseases, has told
us that in his opinion the death rate per thousand from malaria is a
very reliable index of the prevalence of the disease. We were able to
ascertain this death rate for the period 1906-1909, and it is given in
Table V.. A comparison of the death rate in 1908-1909 with the preva-
lence of malaria in that time, as shown in Chart No. 4, shows that
Col. Gorgas' hypothesis is substantially accurate.
TABLE-V.-Showing the annual average of each race of employees, he number of deaths from malaria
in each race, and the deal rate in each race, per thousand per year. due to malaria.
Americans. Europeans. Negroes.
Number Death Annual Number Death Annual Number Death
Year. Annual of deaths rate pen average of deaths rate per average of deaths rate per
average per year thousandd of em- per year thousand of em- per year thousand
of em- from per year ployees. from er yea I ployees. from peryear
ployee. malaria. from I malaria.alaria malaria rom
malaria. malaria. malaria.
1906........ 5.464 7 1.33 2.000 ? I 26,500 211 7.8
1907........ 6706 3 .44 4.000 30 -7.5 28.634 146 5.11
1908........ 6,572 4 .60 5.811 25 4.25 31.507 25 .77
1909......... 6056 0 0 5,606 14 2.38 35.505 25 .70

malaria was severe also among the negroes.
In 1908 and 1909, the admission, rate per thousand from malaria to
all Zone hospitals fell to less than one-third of the same rate in 1906.
The marked falling off in the death rate among negroes and Americans
in these years agrees with the decrease in the admission rate. Com-
pare Tables III and V. The death rate among the European laborers
in this time also diminished, but was always much higher than in the
other two races. Chart No. 4, when compared with Table Vrdemon-
strates the preponderance of malaria among the Europeans.
The racial prevalence of malaria, as is evident from the foregoing
observations, has varied greatly since 1905. In 1905 and 1906 there
was a very considerable amount of malaria among the Americans, and
since that time this amount has greatly diminished, In 1905-
1907 the negroes were heavily infected but since January, 1908, have
suffered but little. Malaria has prevailed extensively among the
Europeans at all times, but has lessened in the last two years.
Chart No. 4 shows distinctly this preponderance of malaria among
the Europeans and demonstrates most clearly the value of individual
prophylaxis against the disease. The relative immunity of the negro
is apparent. Notwithstanding the unfavorable conditions under which
this race lies, and although in number it far exceeds the other two, a
in it in recent years the malaria rate is lowest. Especial attention
should be given to the comparison of the prevalence of malaria in the
Europeans and Americans. Both of these races are equally suscep-
tible to the disease, but the higher regard for sanitary measures in the
one keeps its malaria rate far below that of the other.
The seasonal variation. of malarial due to relapse is well shown in .i
Chart No. 4. It is manifested most clearly among the Europeans anid ;
is not so evident among the Americans. It will be observed that the: . :''
curves of the prevalence of malaria among the Americansaremuch m~ore ::.
irregular than those of the other two races. This supports the hypo-.,.:..
thesis which we have advanced; that the seasonal' variation is due: ":;
largely to relapses. Since among the Americans malaria not only *is.. ..
more easily eradicated, but is also under better control, there are fewer, F
relapses and more primary fevers, which latter occur morelnregularly ...i
than do the former. .. ... !ii
Among the Europeans and the negroes, the advent of the wet.seasw~ ::o:. ..::: i
is productive -of causes that predispose to relapses. an4the beginning' .sii.il
the dry season removes.the principal.of. thesecac~ase.-... mIr
and chilling. The sudden and marked rise in thfe int ':":"
.. ... .. . ..: .:.

i

27

the Europeans, and, to a lesser degree among the negroes, needs other
explanation than that of primary fevers or re-infections.
It was stated in the consideration of Chart No. 2, that the seasonal
increase in malaria is mostly due to an augmentation in the estivo-
autumnal variety. In the curves of malaria among the Europeans and
negroes in Chart- No. 4, this increased estivo-autumnal rate is well
shown. If the statement is accepted, that by far the greatest part
of clinical malaria is due to estivo-autumnal infection, most of the
seasonal increase among the Americans is due also to the latter.
A study of Table IV reveals several important factors in the distri-
bution of malaria among the races. That the disease is milder among
Americans than among Europeans and negroes is seen by a comparison
of the percentage in the positive bloods in Table IV. It is a truth that
in any race admitted to the hospitals, relative and acquired immunity
being excepted, the greater the percentage of positive bloods, the
greater is the severity of malaria. For not many patients of any race
are admitted unless they were unable to cure the disease by outside
treatment, or until a neglected fever had acquired severe proportions.
Among the Americans, as we have pointed out, the use of quinine at
the onset of the fever is almost universal; and an attack of malaria
promptly treated at the time when the prodromal symptoms or the
primary paroxysm are manifested, is not likely to be severe. Also,
many Americans treated outside of the hospital for malaria a'nd cured,
were later admitted that they might be sent to Taboga, as a rule of
the Commission requires that all such persons shall first be admitted
Sto Ancon or to Colon Hospital. For these reasons, it is not surpris-
ing to find so small a percentage of positive bloods among the
Americans.
The percentage of positive bloods among the Europeans and negroes
is about the same. But owing to the relative immunity of the latter
Against malaria the disease is severe among the former. This is an
important fact and will be discussed in detail in consideration of the
relationship of malaria to hemoglobinuric fever. In the dry season
patients of these two races are treated in the dispensaries and sick
camps and only those who"are unable to work are sent to Ancon or
Colon Hoepital. After the wet season has set in the sick camps will
notfaccommilateall who are ill and many patients are sent in directly
A nd without treatment. Individual use of quinine is not common
among these to aces, and often the sick will not apply for aid until
afterseveral paroxysms of fever. In the bloods of such patients
-pan pAsitesare read ily found, and malaria among them, being untreated,
: i sevAere, eo ialyr t amonagl the. Europeans,.

..: ........
;; ::: i': ap n nytoe h~r nbet okaesn oAcno
;,i_: Coloa Hos~~~~~~~~~tal i:. fe h e eao a e nth ikcmswl

malaria is lowest among the Americans, highest among the negroes, '
and about a mean between the two among the Europeans. Very
probably the proportion of primary infections with each species in all
three races is about the same, but such infections are less likely to re-
lapse among the Americans, owing to a more prolonged exhibition of
quinine. And the percentage of tertain malaria, as compared with that
of estivo-autumnal, is higher in primary infections than in relapses.
Charts No. 2 and 4 show that the amount of tertain malaria in the
dry season, when primary infections or re-infections are more common
than are relapses, is always relatively higher when compared with the .
amount of estivo-autumnal than in the rainy months. The negro
not only has a considerable relative immunity, but in him tertai -
malaria tends more readily to a spontaneous cure. Nor does he suffer
much from the febrile paroxysm of this variety. We have seen
frequently such paroxysms in members of this race who did not.
appear to suffer much discomfort. So that relatively few negroes with
certain malaria apply for treatment; and very often such as do apply
are not ill enough to be sent to the hospitals.

SUMMARY.
Malaria prevails among the employees of the Commission in direct
proportion to exposure to infection and susceptibility to disease.
In 1905 and 1906 all three races were exposed to malaidal infection,
and suffered in proportion.
Since January, 1907, and probably from the middle of 1906 Americans I'
have been less and less exposed to malarial infection, with a consequent .'
diminution in the malaria rate among them.
At all times the European laborers have been exposed to malari 4i ',. i
infection, and; since this race is very susceptible, have suffered heavily. .. i
The negro is exposed the most of the three races. It has a relati e
immunity against malaria, which in tinies of severe prevalence of "the:
disease, as in 1905-1907, inclusive, keeps this race :frbm, decirtim '::'i
and when the disease is not expensive, enables it to:eaxhibi t a.co'p"raS-.i
tively low malarial rate.
The seasonal variation, due to relapse ismore maked i ....:ri ::::
of the Europeans and negroes than id that of the Akmeri si"f i '
The tertian variety is not an"important factor in.: he ia 4isi. 44
bution of malaria among the Europeans and .ieg.roes .... ....

S ... .... .. v" :: ": : ".". : : ':: "':'

.. ." .. .

:29

V.

THE RELATIONSHIP BETWEEN MALARIAL AND HEMOGLOBINURIC FEVER.

The reader is referred to writings of. Christophers and Bentley,
Stephens,7 Manson,8 Deaderick," Marchiafava and Bignami, Craig,9
Daniels,'o and others for a discussion of the geographical distribution
of"hemoglobinuric fever,and the relationship between this distribution
and that of malaria.* It is evident from their researches that hemoglo-
binuric fever is epidemic only in the countries where malaria also is
endemic. It is true that occasional cases of hemoglobinuric fever
present themselves at times in localities free from malaria, also it is
argued that there are regions where severe malaria abounds, from
which the other disease is absent; but in the former instance a history
of previous residence in a malarial district can invariably be obtained,
while even if the latter proposition be true, it does not invalidate the
premise that hemoglobinuric fever is nowhere endemic except in
malarial countries. Every year evidence is accumulating to prove
that the disease prevails in regions which were previously thought to
be free from its presence; and at this time the problem of its absence
from malarial countries is, at least, subject to further research before
a definite affirmative statement can be made.
In any country where malaria is endemic throughout the year, and
at certain seasons epidemic, sooner or later the disease will be acquired
by nearly all persons exposed to it, except those who are immune. It
is obvious, then, that in hemoglobinuric fever or in any other disease,
which is also endemic in such countries, a history of prior or coincident
malaria will often be obtained.
To what extent such a history affects the etiology of hemoglobinuric
fever, and to what extent it affects that of other diseases, are problems
that must be determined before any opinion can be given upon the
Influence of malaria as a causative factor in the eventuation of hemo-
globinuric fever. If it be demonstrated that prior or coincident
malaria is associated with hemoglobinuric fever in a constant and
definite manner, and that such association is lacking between malaria
and other diseases, then it must be admitted that malarial infection
is a necessary element in the production of hemoglobinuric fever.
SWe shall discuss the possibilities of this association under the follow-
if:g heads:

ii!i'; *A complete account of the geographical distribution of hemogolobinuric fever,
,' an of. the elatioaship between this disease and malaria in countries other than
th' Canal Zone will be found in Appendix B, at the end of this paper.

f..l.' ...
........ .... .. ..... ... ... "..................." .. ..." .... "

iii

30

1. A comparison of the epidemiology of malaria with that of hemo-
globinuric fever.
2. A comparison of the epidemiology of malaria with that of the .
principal infectious diseases prevailing in the Canal Zone.
3. Malaria as a predisposing cause of hemoglobinuric fever.
4. Malaria as an exciting cause of hemoglobinuric fever.
5. The species of malarial parasite which is concerned in the pro-
duction of hemoglobinuric fever.
A COMPARISON OF THE EPIDEMIOLOGY OF MALARIA WITH THAT OF i
HEMOGLOBINURIC" FEVER.
From July, 1904, to September, 1910, there were approximately
83,000 admissions to Ancon Hospital. Forty thousand nine hundred,
and twenty-eight, or slightly less than 50 per cent of these were ll
diagnosed as malaria, the rest were admitted for other medical diseases,
or to the surgical side of the hospital. In the same period the number
of patients admitted with hemoglobinuric fever or its after effects or ..
who developed it after admission, was 232. This number is a minimum,
for some cases diagnosed as hemoglobinuric fever were not accepted
by us on account of insufficient data on the charts. We have used the
charts and histories of 230 of these cases to obtain our data, and for
convenience of reference have divided the cases as follows:
Class 1. Those with a history of hemoglobinuric fever prior to ad-
mission, but in whom no hemoglobinuria was manifested subsequently.
Class II. Those with hemoglobinuria at the time of admission.
Class III. Those in whom hemoglobinuria developed after adinijs-
sion.
In Class I there were 15 cases; in Class II, 113 cases, and inf Class
III, 102 cases.
Of great importance for epidemiological comparison are the cases in .
Class III. Ninety-eight of these were admitted with either positive
or clinical malaria. The other four were admitted to the surgical
side. In three of these latter a well defined malarial paroxysm pr.- .
ceded the onset of the hemoglobinuria, while in the fourth, in whichith're': .
was a history of much previous malaria, the hemoglobinuria, fqllow
the experimental use of quinine. Since in this class, in which obsr-
vations of the entire course of the disease could beimade nrifodbfavorably, ::
hemoglobinuric fever developed in connection withinglaria only, an4 ,
no other malady, it is most probable that malarial inf action is largti
concerned with the etiology of hemoglobir~ric fewer. If a
this connection should be shown in the comparative epideziolq
the two diseases. . :

.. .. ... ..
. .... ... !ilL..s

M i jib;" ".'
"U "A:lll'==.l" -E""[:''[['

.79I

.75.'
.74 -- - p to M:-

.78 - - --

A,., ~ ,,,,,,,,

.68
.67;

Chart No. 5 shows the prevalence of hemoglobinuric fever from Jan-
uary 1, 1905, to September, 1910. It is based on the admissions of the
cases into Ancon Hospital, and is drawn to the scale of one one-hun-
dredth of a case per thousand of employees per month. There are
two epidemic cycles in the prevalence of the disease, one beginning in
June, 1905, and ending in May, 1907; the other beginning in October,
1908, and ending in July, 1909, followed by a much lessened prevalence.
Chart No. 5 should be compared with Chart No. 2, and Table No. I I.
It will be seen that the first epidemic cycle coincided with the period
of the greatest prevalence of malaria. This was in July, 1905, and the
summer months of 1906. The second cycle coincided closely with the
prevalence of malaria in 1908-1909, inclusive, beginning and ending
somewhat later than the malarial epidemic at that time. Table VI
shows the seasonal prevalence of malaria and hemoglobinuric fever,
with the percentage of cases of each disease according to the season.
TABLE VI.-Showing she seasonal average o u ach of the d eases indlcalud. ThAi able is basud on the
number of the diseases as they occurred from January, 190i, 1 o Januury, 1910.

Seans. Hemolo- a. Lobar Typhoid
Seasons. binurc Malaria. pneumonia ever
I ever. I I
Dry season. February-April. ... .... 26.J *17.18 *209 22.8
Beginning of wet season. May-July. .. 17.5 23.76 32.0 35.5
Middle of wet season. August-Oclober. .1 20.7 30.17 t23.1 t26.9
End of wet season. November-January .. 34.7 28.7 16.9 16 7
'Marcb, 1907. figures missing.
tAugust. 1906. figures missing.
The malaria rate is lowest during the dry season, and increases to the
middle third of the wet season, when it remains stationary, while that
of hemoglobinuric fever is lowest at the beginning of the wet season,
and highest at the end. Both diseases have approximately the same
period of greatest intensity, toward the end of the wet season. This
comparison will be treated more fully when we take up malaria as a
predisposing cause of hemoglobinuric fever; it is used at present to
show that there is a seasonal factor-namely, the period of greatest
intensity, common to both diseases.
*It will be observed, by reference to Table III, that malaria has been
declining steadily in prevalence since 1906. If this disease is an im-
portant -factor in the etiology of hemoglobinuric fever, one may well
ask the reason for the increase in the latter at a time when the annual
malaria rate has fallen from 821 to 282 per thousand.
Chart No. 5 represents the occurrence of hemoglobinuric fever as a
whole. In a consideration of the comparative epidemiology of the two
diseases, it is necessary to show, if possible, that malaria was associated

. .II

...
4 i i l iii. ,:! i .. ".,..

SThe intensity of malarial infection in the period 1905-09, inclusive,
has been given in a previous section of this paper. It will be remem-
bgred that Americans were exposed most in 1905 and 1906, the period
of greatest exposure to infection being the wet season of 1905, and the
first part of 1906. The negro was also heavily exposed in 1905 and. .
1906, and somewhat-less in 1907, after which time comparatively
little malaria, has prevailed among that race. But at all times the
Europeans have suffered severely from malaria.
Table VII shows the annual rate per thousand of cases of hpmoglo-
binuric fever among the three races. It is based on the admissions
into Ancon Hospital, and the annual average per thousand of each
race. This latter could be obtained with reasonable- accuracy, for the
negroes and Americans for all years. We estimated the annual aver-
age of European laborers for 1905 at 1,000, for 1906, at 2,000. These
figures are probably somewhat high. In 1907, 47.3 per cent of all
cases diagnosed as hemoglobinuric fever was admitted to Ancon
Hospital; in 1908, 44.5 per cent, and in 1909, 81.6 per cent. : i
TABLE VII.-Based on the number of admissions due to kemoglobinuric faer into Anon r osRpita, end
the number of cases of thai disease which developed in the hospital from January, 1905,to September, 1910,
and showing the in cidence of the disease per thousand in each race according to the annual average of ech
race, as shown in Table 'V.

Race.
1905. 1906. 1907. 1908. 1909.
(Number of cases of hemoslobinuric (ever per
thousand per year.)
S In Americans .................................. 3.30 1.9 .70. .39 4 .
In Europeans.................................. 5.00 5.5 1.25 5.88 1.36
In negroes ............... .................... .33 .59 .18 0. .2

Table VII shows plainly that in the first epidemic cycle.the occur-
rence of hemoglobinuric fever among the Americans and EuropeOans ..i
was very nearly in proportion to that of malaria. This propoi in ,; i
is materially less in the negro than in the other two races, and the '' :
reasons for this relative immunity against hemoglobinuric fever as..:
Swell as malaria will be discussed later. Table VIII giyes in detail the :
number of cases of hemoglobinuric fever in Ancon Hospital from JuIl
1904, to September, 1910, showing the nationality and length of esi :
dence in months of 'each case. It will be. observed that in the f-i.ra:.
epidemic cycle there was a distribution of hemoglobinuric fever atibig
all three races. In the second epidemic cycle this.distributii4'. '
almost entirely among European laborers. ,In. fIt wt.i ,l V 4%
cent of the cass admitted to Ancin Hospitami. i t ,
in 1909, 80.5 per cent. The great pepoidera .

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i

european laDorers aurng Lme time 01 ne second eplaemic cycle is
shown in Chart No. 4. Since in 1905-07, inclusive, hemoglobinuric .
fever occurred among all races at a time when all members of these
races were exposed to malaria, and since in 1908-09, inclusive, malaria
pirvailed extensively only among the Europeans; it follows that -in
the second epidemic cycle malaria was associated with hemoglobinuric
fever in the same manner as in the first-that is, the latter prevailed in
proportion to thd prevalence of malaria. This is also shown by the
fact that at all times the large amount of malaria among the Europeans
has been associated with a preponderance of hemoglobinuric fever in
that race; compare Table V and Chart No. 4 with Table VII. It
should be remembered that in 1907 the very large increase of European .:.
laborers tended to lessen decidedly the rate per thousand of hemoglo-
binuric fever in that year.
The same epidemiological factors in malaria and hemoglbbinuric
fever in the first epidemic cycle were: a seasonal prevalence that,;:
reached its greatest intensity at the same time as that of malaria;'.
the occurrence of hemoglobinuric fever as a whole in definite pro-
portion to that of malaria as a whole; and the incidence of the one
disease in proportion to the incidence of the other among the different .
races. In the second epidemic cycle these factors are the same. The
seasonal prevalence of hemoglobinuric fever in 1908-09 bears the same
relation to the seasonal prevalence of malaria in that time, as was
shown in 1905-07. The Europeans, at the time of the second cycle,
'were the race most subject to malaria, -and hemoglobinuric fever pre-
vailed mostly in that race. And at this time Americans and negroes
were but little affected with malaria and but little with hemoglo-
binuric fever.
It is evident from the foregoing statements that there are similar
factors in the epidemiology of the two diseases and that these factors
are constant. Each disease has the same period of maximum intensity.
Hemoglobinuria as a whole prevails directly in proportion to the occur-
rence of malaria as a whole when this occurrence is analyzed. Although
in the time of the second epidemic cycle the total malaria rate was
diminishing, the rate among the European laborers was very high, and
it was in this class that nearly all of the hemoglobinuric fever occurred.
A COMPARISON OF THE EPIDEMIOLOGY OF MALARIA WITH THAT OTE.....
PRINCIPAL INFECTIOUS DISEASES OF THE CANAL kONE
It has been stated that in any country in which malaria isbn; '.;
endemic and epidemic, a history of prior or coincident .malariAz :. -.
other diseases will very often be obtained. It hasb een aiwa ii .. -

... ...' ....
... ... ..... ..............
::. W .,i..:::" '; ':,.i,:F ;;iii;,~ ii"
".: ..'.VE[E !!.h E[[EE :[ "Ef :
... ,:" ", .;.,':: A
.. ... . :: I' :: :j ::E:[[".EE :.. E E.[
:'... ,, :::;!: !':i'!:i i! ii i~

35

preceding section that there is a definite epidemiological relationship
between malaria and hemoglobinuric fever. It may well be asserted
That since these two diseases prevail for the most part in unhealthy
seasons, when chilling and wetting of the body predispose to their
occurrence, a similar seasonal prevalence will be found in other en-
demic infectious diseases; moreover, a like relationship to malaria
may also be found in them.
We have demonstrated in those cases in which hemoglobinuric
fever developed after admission to the hospital that a positive or
clinical malaria preceded the onset of the hemoglobinuria. The prin-
cipal endemic infectious diseases, other than malaria are: typhoid
[ever, lobar pneumonia, amoebic dysentery, and pulmonary tubercu-
losis. From 1905 to 1909, both inclusive, 1,043 cases of typhoid fever,
1,283 of lobar pneumonia, 360 of amoebic dystentery, and 487 of pul-
monary tuberculosis were admitted to Ancon Hospital. In addition
there were many thousand cases of other affections, medical and
surgical, admitted during the same period. With the exception
of the four cases previously noted that occurred on the surgical
side, not one case of hemoglobinuric fever developed among the
42,000 admissions due to causes other than malaria. It is plain, then,
that other diseases do not predispose to hemoglobinuric fever as does
malaria.
These other diseases may be complicated with prior or coincident
malaria, but not to the extent that hemoglobinuric fever is so compli-
cated.* Taking only those cases of hemoglobinuric fever in which
positive malarial infections were found; in Class II, patients admitted
with hemoglobinuric fever, 23 per cent of the blood examinations
were positive, and in Class III, patients in whom hemoglobinuria
developed after admission, 61 per cent. In no other disease are such
high percentages of positive bloods obtained. It has not been possible
for Us to examine all the charts of cases of the four diseases mentioned,
I: not to ascertain the proportion of the surgical cases complicated
Switch malaria; but the data that we could obtain makes it probable
:: that not over 10 per cent of all other medical and surgical cases'were
admitted with coincident malaria or developed the disease while in the
hospital. So that other diseases prevalent in the Canal Zone are not by
anyineans complicated with active malaria to the extent that hemo-
Sglobinuric fever is so complicated.
The comparative epidemiology of malaria and hemoglobinuric fever
dem-onstrated: that each disease has the same seasonal period of

Mw T n;e qll z trted more ftll M in Appendix B.
WE

.. .... . ..

. .. ...

36

maximum intensity; that hemoglobinuric fever as a whole prevails
in proportion to the occurrence of malaria as a whole; that hemoglo-
binuric fever obtains among a race in proportion to the susceptibility
of that race to malarial infection, and the amount of such infection;
and it may be noted here that hemoglobinuric fever is in proportion
also to the amount of previous malarial infection. It is now of import-
ance to ascertain if a similar comparison of malaria with other diseases
will show the same results.
Chart No. 6 demonstrates the prevalence of typhoid fever, lobar
pneumonia, amoebic dysentery and pulmonary tuberculosis, as shown
by the discharges and deaths from and in Ancon Hospital from Jan-
uary, 1905, to September 1, 1910. It is drawn to a scale of one-tenth
of a case per thousand of employees for each month. In thecurve
representing typhoid fever, the discharges and deaths have been ante-
dated one month, in order to approximate more closely the time of
onset. In lobar pneumonia, which has a high death rate, but in cases
of which the average duration in the hospital is three weeks, the curve
represents discharges and deaths per month. Amoebic dysentery and
pulmonary tuberculosis are of uncertain duration, not only prior to
admission, but subsequently as well. In both of these diseases it is ....
hopeless to try to represent the time of onset, and the best that can be.
done is to show their prevalence as represented by discharges and
deaths per month.
As a considerably greater propotion of the total number of cases of
these diseases than of malaria is admitted, the curves of typhoid fever
and lobar pneumonia represent very accurately the seasonal prevalence
of the two.
A comparison of Chart No. 6 with Chart No. 2 shows at once that
while there appears to be dome resemblance between the seasonal
prevalence of malaria and that of lobar pneumonia, the regularity of the
seasonal prevalence in the former is lacking in the latter. Lobar .. :
pneumonia shows its greatest increase in 1906, at a time of the year :
somewhat later than the greatest prevalence of malaria. After 1907
the occurrence of the former is lessened and irregular, while that .of
the latter, although diminished, maintains its seasonal regularity. In
'Table VI is given the percentage of cases of lobar pneumonia according .. ::
to seasonal prevalence. This is lowest in the dry season, reaches:, ::i
its maximum at the beginning of the wet season, and then declines
So that the period of maximum intensity in lobar pneumonia is ear ir
than in malaria. Moreover, the periods of increase in the prep l "iite
of lobar pneumonia last but a few months. at the iost, Mand rqpa .IS
irregular intervals, while those of malaria are very dini
.... ........

..: ..! ": ": : ". .::.... :". ::om

"" : ;... .. ':;: ...- i:. ."" ,, .. : . .."**. .."j;....::,...... .... .. .......

8.60
2.60

21.55 1 1 t . . . . .pE
2.50
2.45

..2.40l
2.35,*

2.25
2.20
2.15
2.10-

2.W --T7I
2;x~ 0s 0~
1.90
1.85
1.80
1.75
1.70
1.65 - -
1.60
1.55 -V
1.50
1.45
1.40 -
1.35 -
1.30 - -
1.25
1.20
1.15
1.10 -
1.05
1.00
.95 ,--
.90. .....
.85.
.80 ------

.75

.70

.55
.50 vA
.45 -T -T
.40

.25
.15rr x

BlakI r 'pyuUOUEL
Data Bac, ufilO" Y ubl'tt(As
~tRed. TyphQ14 feveri
f Doted ed, moebdysetW7
Ar

and in time of recurrence. Although there is a resemblance in the
total amounts and seasonal prevalence of both diseases in 1905-07,
inclusive, this resemblance is wanting subsequently. The same sani-
tary measures that have lessened the frequency of malaria have lessened
also that of lobar pneumonia; but it should be remembered that in
1908-09, inclusive, hemoglobinuric fever prevailed in proportion to the
distribution of malaria, while there is no resemblance whatever between
this distribution and that of lobar pneumonia in the same period.
If lobar pneumonia affects a race in proportion to the amount of
malaria in that race, Europeans would show a higher percentage of
cases of the former than would negroes or Americans. As it is, the
negro is by far the most susceptible to pneumonia, while the European
is affected somewhat more than the American.
The amount of previous infection with malaria has nothing whatever
to do with the occurrence of lobar pneumonia. The greatest amount of
previous malaria is in the Europeans, of pneumonia, in the negroes.
The latter disease manifests itself at all times, and patients who have
nut been ill previously make up a considerable proportion of the cases.
A comparison of Chart No. 2 with Chart No. 6 shows. as in lobar
pneumonia, an apparent resemblance of the seasonal prevalence of
typhoid fever to that of malaria. But Table VI demonstrates that
the seasonal prevalence of the two diseases is not the same. Like
lobar pneumonia, typhoid fever prevails most at the beginning of the
wet season. It is, however, least frequent at the end of the wet season.
There is no regularity in the curve of typhoid fever, and its apices
occur at indefinite intervals.
* Nor does the total amount of typhoid fever agree at all with that of
malaria. In 1905-06, inclusive, when the prevalence of malaria was
greatest, that of typhoid fever was least, except in 1910. When
the malaria rate was falling in 1910, that of typhoid fever was rising,
and subsequently has been irregular.
Typhoid fever prevails in about equal proportions among all three
races. Perhaps the disease obtains slightly more among the Europeans
and negroes, but there is no great difference. Like lobar pneu-
monia, it occurs equally among those who have had malaria and
those who have not had it.
No seasonal prevalence can be established for amoebic dysentery and
pulmonary tuberculosis. As would be expected in such chronic
affections, the seasonal occurrence is very irregular. Both diseases
affect negroes most and Americans least. Among the natives of the
Canal Zone, a race in which we have seen but one case of hemo-
globinuric fever, they are of frequent occurrence.
*A

S .. ... .......... ........

not, ana one should endeavor to trace a positive connection between
malaria and any one of them, such as has been traced between malaria
and hemoglobinuric fever, the attempt would not result in any definite
findings. For while there are times when these diseases occur in pro-
portion to the prevalence of malaria, the contrary is as often true.
Active malaria is seldom present in their clinical course.* A history
of previous malaria is frequently present, but as often can be excluded. :
There is not in any distribution of these diseases, total or racial,"the 'i
orderly sequence of cause and effect that is shown in the comparison.
of the epidemiology of malaria with that of hemoglobinuric fever; in
which comparison the total, racial, and seasonal prevalence of the latter
was found to correspond with that of the former. .
For these reasons we maintain that there is no definite relationship
between the epidemiology of malaria and that of other-diseases preva-
lent in the Canal Zone.

MALARIA AS A PREDISPOSING CAUSE OF HEMOGLOBINURIC FEVER,

If malaria be a predisposing cause of hemoglobinuric fever, a history
of prior infection with the former should be found in all or nearly all
cases of the latter; and hemoglobinuric fever should prevail, as a whole,
in proportion to the total amount of previous malarial infection, and
should obtain in any particular race of people according to the extent
of previous malarial infection in that race.
From the histories of the 230 cases of hemoglobinuric fever we have
compiled the following data relative to previous malarial infection.
As an examination of the hospital records subsequently demonstrated,
these histories were fairly accurate. They may be analyzed in two i
ways; previous admissions, without statements by the patients as to .
the nature of the former diagnosis, and previous admissions which the
patients stated were due to malaria. ,
In 215 of these cases the hospital records were searched in order to
ascertain the diagnoses of the previousahdmissions. This was a very i,;:
difficult task, as most of the patients were European and negro labor- :
ers, whose names were frequently misspelled, and for this'reason their
previous admissions could not be found in our card index. Moreover, .
not all previous hospital admissions recorded oni the charts were to 'i; ....i......ii
Ancon Hospital. Yet we were able to identify positively the previous.
admissions of seventy-five patients. Table IX'gives the result of our
S. findings. Seventy-one of the 'Aventy-five patients, or 94.6 per cnt,.
*E xc p-. t:. .. 1... :. :..;*:" .7."" '"d*
*Except in amoebic dysentery. S.e Appendix B, .i

.. ...: .. :........

..... ... .
,,.::.::;' : .:;, :., '" :""=::: =::: ..i.t".=

:4

*,iii
Ir

showed one or more previous admissions due to malaria. Of these,
forty-seven, or 66.4 per cent, were positive. Forty-one of these
positive infections were estivo-autumnal, five were tertian, and one was
a quartan. So that 87.2 per cent, of the positive bloods, and, if the
same ratio be applied to the diagnosis of clinical malaria, 87.2 per cent
of this previous malaria was due to estivo-autumnal infection. It
should be noted that the percentage of positive bloods in these prior
admissions was above the average.
TABLE IX.-This table shows the number of eases of hernoglobssurir fever in dhich wie u.e *able to
verify the previo s admissions by means of the hospital records. Senenty-fie iases were found to
have been preNiously in the hospital, and the findings in these premvous admissionrs are getl an t he
table. This table shows only whether the presous admlsiLons were postlrre or n reltie for malarra.
and does nos include previous admissions due to hermoglobinsric fever Prior multipie admissions
for malaria are counted rnly once, and the numbers of the multiple admissions are given elsewhere.
The obert of the tabe it to show, as far as possible, the per cent and kind of malaria in the previous
admissions.
Number of cases in which pnor admissions were verified . ... 75
Number of these diagnosed as malaria in the prior admissions 7
Percentage of verified prior admissions diagnosed as malaria. ..... .. 94 6
Number of verified prior admissions in which the blood was positive 47
Percentage of these positive ... 66.4
Number of estivo-autumnal infections in the verified prior admissions .. .. 41
Percentage of estivo-autumnal infections in the posits.'e bloods . 8 2
Number of tertian infections in the verified prior admissions 5
Percentage ofteitian infections in the positive bloods 1 I
Number of quartan nfecuons m the verified prior admission. ... I.
Percentageofquartan infections in the positive bloods. . 1.4
Number of clinical malarial infections in the verified prior admisnons .. 24
Percentage of these clinical infections . ... 33.6
Since the cases whose prior admissions were thus ascertained com-
prised one-third of the number examined, and were not purposely
selected, but occurred at more or less regular intervals in the series,
there is no reason to doubt that the previous admissions which we could
not confirm would show the same per cent, 94.6, of malarial diagnoses.
In no disease other than hemoglobiniric fever is there so large a per-
centage of prior admissions due to malaria. Not even in malaria
itself, with its numerous re-infections and relapses, is this percentage
so high. It is plain then, that a very large number, at least 90 per
cent, of previous admissions of patients prior to the hemoglobinuric
.attack was due to malaria.
Table X gives an analysis of the statements on the charts in regard
to previous admissions or previous attacks of malaria.* In this table
a "prior attack of malaria" means that the attack occurred sometime
prior to admission. In those cases in which no history of a previous
admission or of a prior attack of malaria could be obtained, there is
evidence to show, as we shall explain, that an attack of malaria pre-
ceded the onset of the hemoglobinuria, either outside or while the
lk A. patient vas in the hospital. And such an attack we shall consider as
; a predisposing cause, for we do not claim that every case of hemoglo-
Sbinuric fever develops only after repeated infections with malaria.

Not all of these statements are accurate, but in the aggregate they are sub-
stantially as"

. ... . ... ..::..

5 a.i:mll :: :ll :.".. :
1n'1 it'.:5::, ,:':" : *" :
h rt ; :: .

'I ADlaL. A.--.nou' Hme rl p1dings aso prefli'iU0 nospuiat aalssions or r Or a jtr o Jerr, aou S laRr1
from Ike hirlories of the palsents who had rhmoglobinric frer. M

Number Percentage
Class f cases. of cases in Remarks.
each class. r
Denied previous malaria.. 6 2.60 Of these, three. or 50 per cent,were admitted with
positive infections. Two had hemogiobinuria
before admission, and one had clinical malaria.
No record of previous ad- 24 10.43 Of these, fourtee. or 58.3 per cent were admitted
missions or prior febrile with positive infections. The others had hemno-
attacks. globinuriabeforeadmission. or clinical malaria
I on admission.
Chars were marked 'No 1 739 This may mean that there were no admisionsto
previous admissions" or Ancon or other hospitals, but does not exclude
"No prior febrile at- admissions to dispensaries or sick camps .iand
tacks.' there may have been lever without treatment
or hospital admissions.
One previous Hospital ad- 6 5 28.26 Forty-six cases gave histories of one previous
mission or one prior at- hospital admission. Nineteen cases gave his.
tack of fever. stories of one prior attack of fever.
Two previous hospital ad- I 34 14.78 Twenty-two cases gave histories of two previous
missions or two prior hospitaladmissions. Twelve cases gave his-
attacks of fever. stories of two prior attacks of fever.
Three previous hospital 23 10.00 Nine cases gave histories of three previous hospi-
admissionsor three prior tal admissions. Fourteen cases gave histories
attacks of fever. of three prior attacks of fever.
Four previous hospital ad- 18 7.82 Eightcases gave histories of four previous hospital
missions or four prior at- admissions Ten cases gave histories of four
tacks of fever. pnor attacks of fever.
Overfourprevioushospital 43 18.43 Twenty-two cases gave histories of over four
admissions or over four i I previoushospital admissions. Ttenty-oiecase
prior attacks of fever I gave histories of over fourprior attacks of lever
'This table was made before the case reports were verified as to previous admissions. The few dis-
crepencies between the table and the case reports are due to errors in the history.
Six patients denied a history of previous malaria. Parasites were
found on admission in the bloods of three of these: two others were
admitted with hemoglobinuria, a condition, that as we shall show,.
makes the finding of parasites very difficult, and the.sixth patient was
admitted with a well-marked clinical malaria, in him the hemoglo-
binuria did not develop until later. Now, we have demonstrated that
in every instance in which hemoglobinuric fever developed while the
patient was under observation in the hospital, the onset of the disease'
was preceded shortly before by an attack of positive or clinical malaria. :..- .
There were 102 such cases, and it is no more than reasonable to suppose.
that a similar malarial attack preceded the hemoglobintria in those ..::.. ::::
patients who were admitted with the latter disease. So- that in node :..l'..*.:!
of the six cases in which a history of previous malaria was denied can the
existence of a malarial attack prior to the hemoglobinuria be excluded'; ..
and in four of these there was positive evidence of such an attack. .. : l
In those cases in which there were no records on the charts as to pre-
vious admissions or prior malaria, the blood was positive in fourteen, .. ....i
or 58 per cent. All others were admitted with either A clinical.malariis. : 7 7
which preceded the hemoglobinuria, or with, the latter ..already:': :i':il
developed.
The same is true of the seventeen eases that had noiiistory bof;ll .l
vious hospital admissions; either positive br diaical n'i t air
the hemoglobliuria, or the latter was present Aa
.:.
Ph .......... .

*. .... ...

-** -. .. -' -"

41

The remainder of the cases in Table X are those in which one or more
prior hospital admissions or prior malarial attacks were designated in
the histories. The same reasons as given above apply to that small
proportion of these cases in which the previous admissions might not
have been due to malaria, in order to show in these a malarial attack
that preceded the onset of hemoglobinuria. A summary of the table
shows that the cases may be divided into two groups; in one of which
there was no history or record of previous admissions or prior febrile
attacks; in the other, a history or record of one or more of each of
these. In both groups an attack of malaria that closely preceded the
hemoglobinuria can be shown for many of the cases and safely inferred
for the remainder. The large number of cases in which there were
multiple previous admissions or prior febrile attacks is worthy of con-
sideration. In every instance in which three or more of the previous
admissions could be verified, two of these were always due to malaria,'
and very often all of them. In our summary of the 230 cases of hemo-
globinuric fever in Appendix A at the end of this paper, these prior
admissions, when found, are included in the case reports. There is,
then, in practically every one of these rases a definite history of a
malarial attack at some time prior to the onset of the hemoglobinuria.
In no case is there reason to exclude such a history. So great an amount
of previous malarial infection is not to be found in the histories of cases
8f other diseases, not even in malaria itself. as has been noted, and is
ample-proof that malaria is in some way a predisposing cause of hemo-
globinuric fever*
We shall now consider the premise, that if the malaria is such a pre-
disposing cause, hemoglobinuric fever should prevail in any particular
race in proportion to the amount of previous malarial infection in that
race. When considered as applying to a race as a whole, previous
malarial infection occurs in two ways. In time of severe prevalence of
malaria, such as in 1905 and .1906, a race may acquire a greater amount
of infection than in a period of several years when the malarial rate is
Slow., Consequently previous malarial infection is in proportion to the
:.:. prigr prevalence 6f'malaria; and a great amount may be acquired in a
short while,, or an extended length of time may be necessary to
obtain it.
The universal and severe prevalence of malaria in 1905 and 1906
has already been described, and the fact noted that hemoglobinuric
fever obtained not only as a whole in proportion to this prevalence, -
Sbut i:.al.i0in, proportion to the racial distribution of malaria, among the
li:.;::: .:Ae ns. and: Europeans. It has also. been shown that since 1907
he pmportio

.. . .., ::! .. .

pea s nLU Ucie [tidbt aiilUlig L111 l tL-AItiill. IL idaUIt A.l ,I glVen T
the length of residence prior to the onset of hemoglobinuric fever in our
series of cases. It will be seen that in 1905 and 1906 the time necessary :
for the development of the disease was much shorter, as a rule, than
subsequently. Since 1907 the few cases in Americans have occurred
in those who have been a year or more on the Canal Zone. It is esti-
mated at this time (September, 1910) that not over 15 per cent of
the Americans now employed have been on the Isthmus over four
years. In the last three years but little malaria, comparatively speak-
ing, has prevailed in this race; and, as the table shows, but little hemo-
globinuric fever also.
It will be noted that in 1908 nearly all of the cases of hemoglobinuric
fever in the Europeans occurred in those who had been between one
and two years in this country. And in 1909 and 1910 most of the
.cases occurred in those who had been here between one and three
years. That is, the disease has prevailed chiefly in those who arrived
in the latter part of 1906 and in 1907. In these years, as has been .
explained, there was a continual immigration of those laborers. Ma- :
laria has been very prevalent among them since 1907, but not as severe
as in 1905 and 1906. So that it has taken a longer time to acquire ..
the necessary amount of previous infection.
In analyzing the cases which occurred in 1905 and 1906, it was found, :
with two exceptions, that every case gave a history of previous malaria:
In the two cases excepted, there was a positive malarial infection in
one, and the other was admitted with hemoglobinurda. So that in
times of great prevalence of malaria repeated attacks of thatdisease
occur at short intervals, and most of the cases of-hemoglobinuric fever
that occurred in this period were in persons who had been less than a
year in the Canal Zone.
The prevalence of malaria among the -negroes in 1905-06 was dis-
proportionate to the occurrence of hemoglobinuric fever. Table V
shows that in 1906 and 1907 the death rate from malaria in this race
was very high, and that in 1908 and 1909 it fell to a very low point. .
Table VII demonstrates that at no time has the rate-per thousand for
hemoglolbinuric fever been so high in proportion to the malaria rte ...
as in the white races, and that for some reason hemoglobinuric fever. ."
does not follow malaria in the negro to any great extent.
Now, while it is true that the negro is relatively immune-to malaria,
he is very prone to pernicious attacks of the disease.. Not many of .
the Americans or of the European laborers will allow a malarial atta ck .
to continue without treatment for any length of time.. Butn the 4ner
a malarial paroxysm or two is often followed by a so-calltd spohtaneOU
,

S..... ...

"

S43

cure, due very likely to the calling forth of certain factors that render
him immune. When this relative immunity is once overcome, the
disease, if untreated, proves rapidly fatal. For this reason, in times
of great malarial prevalence, the death rate among the negroes, when
compared with that of other races, is relatively higher than the amount
of infection. Relapses are much less likely to occur in this race than
in the European, as is plainly shown by the small rate per thousand for
malaria of the negro in 1908-10 (See Chart No. 4). And the evidence
hitherto adduced is conclusive as to the importance of relapses in
malaria as a predisposing cause of hemoglobinuric fever. It is plain,
then, that notwithstanding the disproportion between the rates per
thousand of hemoglobinuric fever and malaria, in 1905-06, the relative
immunity of the negro against the latter disease has a parallel in his
relative immunity against the former.
That hemoglobinuric fever prevails in proportion to the amount of
previous malarial infection is evident from a consideration of the pre-
vious arguments. In the section devoted to the comparative epi-
demiology of the two diseases, of the two cycles of hemoglobinuric
fever, the first was shown to follow the general prevalence of malaria
at a time when all races were exposed to this disease; and the second.
to come after prior malarial infection in the only race that was heavily
infected.
One other proof of the necessity of prior malarial infection may be
adduced. The seasonal occurrence of hemoglobinuric fever, shown
in Table VI, follows that of malaria. It is not until malaria has been
prevailing for a few months that the other disease reaches its seasonal
maximum. This is what should be expected of a disease dependent
upon prior infection with another for its etiology. The dependent
disease ought to increase in frequency after the manifestation of the
prior disease; and that this is true, a comparison of the seasonal
prevalence Qf the two diseases show.
SUMMARY.
SPrior to the onset of hemoglobinuric fever in cases that developed
while under observation in the hospital, in every instance there was a
...anifestation of positive or of clinical malaria. In a large proportion
of all cases of hemoglobinuric fever there was a history of previous
hospital admissions, and of these that could be verified, 94.6 per cent
t ere due to malaria.. Most of the patients gave histories of repeated
:: malaria, attacks.
: :piiiir:.. portionn to the prevalence of prior malaria among the races
si..' played by the Commission, and particularly in proportion to their
..... . .. ...
.. .... ... .

susceptibility to malaria and relapses, hemoglobinuric fever developed
subsequently.
The amount of previous malaria, whether recent or remote, deter-
mines the prevalence of hemoglobinuric fever.
From these conclusions, it is very evident that malaria is a predis-
posing factor of great importance in hemoglobinuric fever.
MALARIA AS AN EXCITING CAUSE OF HEMOGLOBINURIC FEVER.
The constant association of an active malarial infection with hemo-
globinuric fever has been noted by many writers on tropical diseases.
Stephens' has collected 23 cases in which the blood was examined on
the day before the onset of hemoglobinuria. Of these, twenty-two,
or 95.6 per cent, showed a positive infection. On the day of the attack
the blood examination showed in sixty-three instances parasites in
thirty-nine, or 61.9 per cent. On the day after the blood was positive
in eleven of sixty-four examinations, or 17.1 per cent. These findings
make it plain that parasites are found for the most part immediately
prior.to the onset of the disease and subsequently lessen in frequency.
Although the percentage of positive bloods in our series of cases
is not as high as in the foregoing, the results obtained from an analysis
of our blood findings are approximately the same. In our cases the.
blood examinations were mostly made as a matter of routine and no
especial attention was paid to the finding of parasites.
We have divided our cases into three Classes for convenience of
reference. Class I-those in which there was hemoglobinuria prior
to admission, but not subsequently; Class II-in which hemoglo-
binuria was present on admission; and Class III-in which it
developed after admission. Since in most cases the blood was exam-
ined only at the time of admission, while the hemoglobinuria occurred
at varying intervals prior.to admission and subsequently, we are unable
to give exact data as to the presence of parasites immediately before,
during, or after the onset of the disease.
In the fifteen cases in Class I the bloods were all negative on admis-
sion. In two patients in this class malaria developed subsequently,
fifteen days after admission in one and twenty days after in the other.
Table XI, a and b, gives in detail the blood findings in Classes II
and III. In Class II there were one hundred and thirteen cases.
The blood examinations were positive in twenty-seven, or 23.8 per
cent of these. A careful study of the histories iarthese cases has c6n- ....
viaced us that too much reliance should not be: placed on the stated
length of time prior to admission that the hemolglobiouriaVoccuxdrr:ed
for, "passing blackwater" one, two, or threedays ma.y m~ ai.th ,:
': '' ::* " : .: X::': .

... ... ...

'V.'

I

45

including or excluding the day of admission. Moreover, many of these
patients were very ill at the time of admission, and histories as to the
duration of the disease might have been inaccurate.
TABLE XI, A and B.-Shows. A.kheresslts of the blood examin nations on admi.sjson in cases of hemoglo-
bitnrit f/eer that developed before admission to the hospital. in which hemoglobinuria Uas present on
admission: and B. Ike results of blood examinations on admission when the hemoglobinuna developed
after admission.
A.
[Result of blood examinations on admission.|

cIes N of No. of Total
Which cases cans nses number I Per.
Admitted to Aco Hospital with hem- esivo- which which Todl of cases centage
globinuris that began- asoumt- teraan the blood number in which of
nal para- parasites was oL he blood positive
aSiswer were ee negative cases. was bloods.
found. found. positive.

The day of admittance before eoLrace into .I
the hospital........................ 5 1 16 22 6 27.2
One day prior to admission ....... 4 3 35 42 7 16.6
Two days prior to admission.... 4 10 14 4 28.5
Three days prior to admission.... ..I ..... .. 4 I 25.0
Four days prior to admission ..... .. 2 2 0 .0
(?) days prior to admission .... ......... 2 20 I 29 I 9 31.0
Totals, and average percentage........ 21 6 86 113 27 230

B
fHemoglobinuria developed.I

*The day of admission after entrance into I
thehospital ........................ 6 .... 8 14 6 42.8
One day after admission............. ... 9 5 14 28 14 50.0
Two days after admission ... ...... 14 2 6 22 16 72.7
Three days after admission ........... 9 3 5 17 17 70.5
Four days after admission ........... 4 2 8 6 75.0
Over tour daysafter admission....... ... 4 2 7 13 6 "46.
Totals, and average percentage.. 46 14 42 102 60 t61.0
'. is not possible to say, in all cases. if the blood was examined beioreor after the onset of hemoglo-
binuria.
fFour bloods not examined prior to the onset of the hemoglobinuria.
It is in Class III, to which we have referred several times, that
the most satisfactory information of the frequency with which malaria
is associated with hemoglobinuric fever may be ascertained. Table
XI, b, gives the percentage of positive bloods at the time of admission,
and shows also the length of time that elapsed before the occurrence
'of hemoglobinuria. The one hundred and two cases in this group were
carefully observed and the data given are quite accurate. In all,
;::. 61 per cent of the blood examinations were found positive, and in
those cases in which negative bloods were found, clinical malaria was
manifested.
S The reasons for the apparently low percentage of positive bloods in
thwetotal. malaria have been explained. These same reasons apply
t t"i:.he .percentage of positive bloods -in Class 'III. The average
f bloood- examinations in malaria was 58 per cent positive; in
......... J.:.%i.n,::: ... : a:.:.nC sI:T"e
... ...

.............. .. .... ....... ... .. .. ...:.
Ii

Class III, this average was 61 percent. There is no reason to doubt
the accuracy of the diagnoses of clinical malaria in this class, and it is
safe to say that a close association with a malarial infection is shown in
all cases in it. Certainly those patients whose bloods were negative
had every other sign and symptom of malaria prior to the onset of
hemoglobinuria, as an examination of the case reports will make plain.
Although it is possible from the data given in thissection, and the pre-
ceding ones, to infer that an active malaria occurs very often immedi-
ately prior to the onset of hemoglobinuria, and a short while before, is
always in evidence, it is not easy to estimate the precise importance
of such malaria as an exciting cause of the disease. There is evidence
to show that in a very few individuals but one attack of malaria pre-
ceded the hemoglobinuria. And at other times hemoglobinuria did
not develop until the patient had taken enough quinine to be cured of
malaria. Such instances, although infrequent, make it improbable
that the malarial attack alone is always the exciting cause, for in most
part such an attack prior to the hemoglobinuria had been preceded by
other malarial manifestations at varying intervals. Our opinion, from
the evidence, is that active malaria, prior to the onset of hemoglo-
binuria, is one of the final determinative factors in the eventuation
of this disease; and in a few instances one malarial attack may act as
both an exciting and predisposing cause. It is certain, however, that
such active malaria is intimately connected with the development of
hemoglobinuric fever, and our data as a rule confirm the opinion of Ste-
phens, "Not only is blackwater dependent on a malarial infection at
some previous time, but the relationship is avery close one, depending
on the actual presence of parasites (or, in our experience, either para-
sites or clinical malaria) immediately prior to the attack. To deny
the significance of these parasites (or of the clinical malaria), as has
been done, seems equivalent to denying the significance of parasites
(or of clinical malaria) in an equivalent number of malarial cases, and
to be contrary to common sense.'" The parentheses are ours.

THE SPECIES OF MALARIA PARASITE THAT IS CONCERNED IN THE PRO-
DUCTION OF HEMOGLOBINURIC FEVER.

In the two hundred and thirty cases of bemogloainuric fever; estivo-.
autumnal parasites were associated sixty-eight times with the disease,
and tertian parasites twenty-one times. The percentage of estiva-
autumnal parasites in the positive bloods was 76.4, that of the tertian
parasites, 23.6. These percentages approximate very clpsel .thu;sel
for the positive bloods in the total malaria" (See Table IL) 4.1; .t'ai;,

. .. . .... . .

. a.
S .. : ... . .. ....

S . .. ....... .

* I

I
.. Eii
..... ..
... ..
:" ii~i
... Y= iii
,. ::'..

:.i.
::~.:7!

":.?iiisl

As

47

It wold appear from this that each species of the parasite is asso-
dated with hemoglobinuric fever in about the same proportion as in
the total malaria. However, it should be remembered that previous
malarial attacks occurred in a large number of patients who had hemo-
globinuria. The percentages of the species of malaria concerned in
the production of these previous attacks, were, as shown in Table IX,
estivo-autumnal, 87.2; tertian, 12.6. (One patient who developed
hemoglobinuria had at the time of onset a tertian infection, and had
been twice before, in the two months preceding his hemoglobinuria,
in the hospital with quartan malaria.) These figures show that estivo-
.autumnal parasites, as an antecedent factor, predispose in considerably
greater proportion to hemoglobinuric fever than do the other species.
When the species of parasite responsible for prior infections is ascer-
tained in individual instances even stronger evidence of the importance
of estivo-autuninal infection may be induced. As far as it was possible
to obtain it, comparison of the species of parasite found on admission
with the species present in prior admissions was made. We have
summarized the results of.this comparison as follows:
1. In twenty-one instances in which the blood examination at the
time of admission for hemoglobinuric fever showed estivo-autumnal
parasites, the blood findings for previous admissions were: estivo-
autumnal parasites, 15; tertian, 2; negative, 4. Percentage of estivo-
. autumnal parasites in the positive bloods, 88.2; of tertian parasites,
11.8. In three instances there were two prior estivo-autumnal
infections.
2. In ten instances in which tertian parasites were found, the blood
findings in the previous admissions were: estivo-autumnal parasites,
6; tertian pa-asites, 1; negative, 2; quartan, 1. Excluding the quar-
tan infection, the percentage of estivo-autumnal parasites in the posi-
tive bloods was 85.7; of tertian, 14.3. There was one former mixed
infection.
S3. In forty-two instances in which the blood was negative on admis-
sion, the findings for previous admissions were: estivo-autumnal
parasites, 21; tertian, 2; negative, all clinical malaria, 17; mixed infec-
:.;tion with tertian and ebtivo-autumnal malaria, 2. Excluding the
mixed infections% the percentage of estivo-autumnal parasites in the
positive bloods was 87; of the tertian, 13. In six of these there were
Stwo'previous infections with estivo-autumnal parasites, and in three,
three- such previous infections.
We were able also to ascertain the blood findings in several admis-
.sions subsequent to the hemoglobinuric attacks. Estivo-autumnal
malaria at the time of the hemnoglobinuria was followed four tifies by

.:. .... ... ..

... ........ .. .".
a... .... .*.........

48

the same variety, but not by tertian malaria. Similar coincident
tertian infections were followed three times by estivo-autumnal malaria,
but not by tertian itself. Admissions for hemoglobinuric fever in ...
which the blood was negative were followed four times by estivo-
autumnal malaria, but not by tertian. One quartan infection
followed a previous hemoglobinuric attack associated with estivo-
autumnal parasites.
Although we were able to make the preceding comparisons in but
one-third of our cases of hemoglobinuric fever, there is no reason to
doubt that the parasites wuuld have been found in the same percentages
had it been possible to get records of the blood findings in all previous
and subsequent admissions. If this is true then the estivo-autumnal
parasite is by far the more important of the two in the production of
hemoglobinuric fever.
There is a very strong probability that many of the patients who
had certain infections at the time of the hemoglobinuria hnay have had
also coincident estivo-autumnal infections. In a series of experiments .
to determine the temperature curves in estivo-autumnal and in tertian :
malaria, we withheld quinine. Fifteen of these experiments were with
what we thought at first to be unmixed terrain infections. Before
the experiments were concluded, in eleven of these tertain infections we ..:,
found either estivo-autumnal schizonts or crescents at some time in the ...
course of the fever. In several, estivo-autumnal infections entirely
replaced the tertian, but we did not observe the converse. It should be
noted that terrain ififection occurred twice only prior to hemoglo-
binuria associated with estivo-autumnal parasites; and once only prior
to similar association with tertian parasites.*
It is not possible to exclude absolutely tertian or quartan malaria in
the etiology of hemoglobinuric fever, either as exciting or predisposing
causes. Case No. 204, a Spanish boy, 9 years of age, died four days
after the onset of a most pernicious hemoglobinuric attack. Up to .
the hour of death, this patient's blood showed the heaviest tertia ti
infection we have ever witnessed; and, although a careful search was
made during life, and in autopsy smears, no estivo-autumnal parasites
were found. This boy had been nine months on the Isthmus and had:
lived three years previously in Cuba. In Case No. 1T, a Germani,' a
well marked triple quartan infection developed on May 3, 1905, after: ,,
the patient had been six weeks on the Isthmus. There was a relapse
of this infection on May 25. On July 15, of the same er, he

*Since this was written, in working with the "thick fihl0 we feqen.tly i
crescent associated with tertian infection : i:
.... ... : .. ..-

... :..." :.,, :
.. .. .. .. ... .... :.. a :=....
..:.-nl;: i :.i .... :::. .. .. .. ..i.:iii

*::*'. ::.. ''
l' WW

49

admitted to Ancon Hospital with tertian parasites in his blood.* On
July 16, hemoglobinuria developed. Although it is not possible in
either of the above cases to exclude an estivo-autumnal infection, they
present evidence that any species of malaria may be present at the time
of hemoglobinuria and may be taken to have etiological significance.
A consideration of the data given above shows that about 87 per
cent of the malarial attacks prior to the onset of hemoglobinuric fever
was due to estivo-autumnal malaria. In the small percentage of
previous malaria due to tertian infection, there is a strong probability
that estivo-autumnal malaria might have been associated with the
milder infection.t In this connection it is well to note the geographical
distribution of hemoglobinuric fever. This disease prevails only in
regions where estivo-autumnal malaria also prevails, and is not endemic
in countries where tertian and quartan malaria only .obtain. The
more intense the prevalence of estivo-autumnal malaria, the greater the
proportion of hemoglobinuric fever, is the rule in countries where the
latter disease is endemic, and our data bear out this observation.
We do not deny the possibility of tertian infection, or of quartan,
as a predisposing cause of hemoglobinuric fever, but the evidence in
favor of these two varieties of malaria is neither so strong nor so con-
vincing as to enable us to attribute to them much etiological im portance.

VI.
LENGTH'F RESIDENCE IN MALARIAL COUNTRY AS A FACTOR IN THE
ETIOLOGY OF HEMOGLOBINURIC FEVER.
Most authorities state that, hemoglobinuric fever attacks in greatest
numbers those who have resided one or two years in a country where
the disease is endemic. Otherwise than as it offers an opportunity for
ithe acquirement of a condition resulting from repeated malarial in-
fections or.relapses, it is not claimed that such length of residence is an
etjolpgicalr factor.
Table XII gives the time of residence in the Canal Zone for the
S226 cases of hemoglobinuric fever in the period from January 1, 1905,
to September 1, 191P. The time of residence for the cases in 1904 is
shown in Table VIII. Such Europeans as were entitled to quarters
similar to those of.Americans are classed with the latter. There were
ery few of these. In the period 1905-07, inclusive, it will be seen
: There i h se doubt as to the correctness of this diagnosis of tertian malaria.
m...L-: .. Yil appear that the quartan relapsed.
.ji on obt investigationss with the "thick film" method, we find crescents in 40 per
We0 In n n p b ttnfctions.

-AIO G ... 'E....UF E VER
...........
: x W! :..~~~~~~~~~~~~~. ...o..r.e.p.,..is.t. limdthtsuhlegh..reieneisa

LLAaL IIIU3L UK LAAC LanCM ULLLU ACU I LA U11IL L11C LIAfL LWCAVt AUUILLL1M UK
residence. For convenience, we shall refer to all cases in this time
as "Group A." In 1908-10, inclusive, most of the cases developed
after twelve months' residence; all cases in this period are referred to
as "Group B."
It is obvious that in Group A, length of residence did not play as an
important part in the production of hemoglohinuric fever as in Group
B. If we assume that the same cause which produced the disease in
the first group produced it also in the second, it will be of interest to.
determine why this cause should operate with comparative rapidity
in one group and slowly in the other.
Table XII shows that in every year a certain proportion of the cases
occurred in the first twelve months.

:, .

"i.:i ,i;

S : .....

A ... ...

;. .. ..:.: .. ...
i::i.:. ..,: :id :n i~,i
L: : .
": :.:.. ":, ".i::! ::i,::~ :::ii ,iiiih;n:i i

*s
a
f

K
-i

I
t
C
B

I.
7&

C
a

Sa
K
C
OB
I!,

x

I":

E;*;.*.. ..i [ -
ii:: . .

I i

51

I r d o e r- .,,i ,,. ,l
I
I ....E. ..

i -,, ,, ., ,,- -

d r m .-. -a .Io
: : I

I
g; __ 1*- '* ". :1\
| ."'-

a |
a Ng

". a
h B |N:N 7 :N I AM

---
II- :: -N T. -
4
s ^ ^ '"" ;=
-- ---------- '* --- -- --
W( 001- N~ - *Q
E

S----- -" _-_ I .....
.. I

41%
. :" ..

"1*"

I

I

and over twelve months of residence is given. No figures are given.
for 1910, as all the data for this year are not yet available. Table
XIII shows that since 1905 the number of cases that developed under
twelve months' residence has gradually decreased, while the number
over that period has steadily increased. A reference to Chart No. 1
partially explains the reasons for this. In 1905 the employees of the
Commission had not been on the Isthmus for a year. We are not
Dealing with a fixed population, but one of changing immigration from
non-malarial countries to a malarial one. It is evident that in 1905'
and 1906 such diseases as occurred, including hemoglobinuric fever,
would necessarily appear in persons who for the most part .had been
less than a year in the Canal Zone. In 1908 and 1909 an average
residence of from two to three years had been established for a .
considerable number of employees, but not all, as there is a constant
immigration and emigration among all three races employed.
TABLE XIll.-Showsing the percenlare of caddS of hnnoglobinuic fever per year ehat had been om Ie
Isthmus under and over twins warthr. Caser whose histories showed a residence of twelvr monkt are
grouped as undtr that time.
1905. 1906. 1907. 1908. 1909,.:
Percentage of cases under twelve months' residence. 84.2 65.8 55.5 .24.3 ..2.5
Percentage of cases over twelve month residence... 15.8 34.2 44.5 75.7 8.5

It will be noted that since 1907 by far the greater number of cases
have developed in European laborers. In 1908, 91.8 per cent, and iti
1909, 80.5 per cent of the hemoglobinuric fever in Ancot-Hospital was
in this class. In the preceding years the disease was distributed far
more equally among the three races. In 1908 and 1'909 the average
length of residence among Europeans was as great'as that ofiiost of
the Americans and many of the negroes, owing to the shifting ofthe '
population in the last two. Why, then, of those who had been ftrm bn
one to two years on the Isthmus, should the Europqans be affected'i ': '..ii
disproportionately? And as, since 1907, there has been a, constantd..;:..
arrival of Americans and negroes to take the places of those who wefe
leaving, why should there not be the same occurrefice of hemoglo-: .: i
binuric fever in the new arrivals as inI1905 and 1906? : :.;a* ii
An examination of the histories of the nineteen cases in 1905, : ank ,:
the thirty-eight in 1906, shows that in 1905, fourteen.r .the'nin n ,
patients. had had prior attacks of fever other than those assci:att& :i
with the hemoglobinuric fever;- and in 1906, thirty-six bf the thi(r. i
eight had been similarly affected.- In these twO y:ea:rs, as iEr
shown, the malarial rate per thousand s ety high ag ....
and in 1905 was especially so .ai8btnth AneAtt S" e.A J

.. .. ..
... .... .................,.... ....... .... .. ............... ......
.. ..:..:., ;,;,;i..', i : ii i
... : ...:" :'% ": ", :IE.I i "':

53

1907, this rate has decreased very noticeably among the Americans
andnegroes, but to a much less degree among the Europeans.
From these data it can be inferred that in 1905 and 1906 repeated
re-infections and relapses were common among the Americans and
negroes, even among those who had been but two or three months in
the country. So that if repeated malarial infections be a primary
cause of hemoglobinuric fever, this cause operated to a far greater
extent and more rapidly in these two races in 1905 and 1906 than sub-
sequently. And it follows, that to be effectual, the cause would need
i a longer time, owing to the greatly decreased malarial rate, in 1907-10,
.inclusive. That such is the truth is evident from the length of resi-
; dence prior to the onset of hemoglobinuria, as shown in Table XII,
Sfor the Americans and negroes in 1908-10.
The effect of the continual exposure to malaria in a given race is
beautifully demonstrated by the examination of the results of such
exposure among the Europeans. In 1905 and 1906 those of this race
S who were resident in the Canal Zone were greatly exposed to malarial
infection, and acquired hemoglobinuric fever in proportion, as shown"in
Table VII. In the latter part of 1906 and throughout 1907 about four
thousand of these laborers arrived on the Isthmus. Although these
new arrivals were exposed to malaria, this exposure was not so great
as that of their predecessors, and owing to the great increase of more
than four hundred per cent in their number, naturally the rate per
thousand for hemoglobinuric fever fell off in 1907 in this race. But
S. with the advent of the wet season of 1908, the malarial rate among
them was increased to a large extent (Chart No. 4). This increase,
as has been explained, was greatly due to relapses in those who had
acquired the infection during the preceding year. And in 1909, some
of those who had escaped hemoglobinuric fever in 1908, had accumu-
lated enough previous malarial infection to develop hemoglobinuria,
while at the same time later arrivals who were more susceptible were
a ..:developing the disease. As a result of this continued exposure to
mala4iM from 1907, in 1909 the hemoglobinuric fever rate per thousand
Reached a maximum. (See Table VII, European rate per thousand in
i. .i 1909), although in this year the malaria rate among the Europeans
al. ower than in 1908 (Chart No. 4).
r Most authorities agree that after a residence of from three to fou*
iiears i ad eerdniic region the hemoglobinuric fever- rate diminishes
At': .. piien (September, 1910) the average residehde of ani employee
is between t*o :arid three. yers:. Owing to the. greatly diminished
Lr i I8R;Iiamong the Aneiican and negioei, we are'unable to sai
:WN a. the ..pese: effect on the frequiendy of hemoglobinuric

. ... ....
,... ... .... ...... ..
b .- "ii"% ::E ::E":":. :Y "":.."::

of these laborers had been on the Isthmus between two and three years,
it would appear that hemoglobinuric fever diminishes in frequency
after that time.
Since 1905-06 very few of this race who were here in those years
have since developed hemoglobinuria.
In determining, then, the effect of length of residence in the devel- *"::
opment of hemoglobinuric fever, two things must be considered: the
effect of this residence in individuals who are less and less liable to
malarial infection; and the effect in those who are continually ex-
posed.* It can be said, that of individuals continually exposed to
malarial attacks, a certain proportion will develop hemoglobinuric
fever with the first few months of residence and a greater proportion
during the second and third years. But when the chances of subse-
quent infection with malaria or relapses due to it are lessened, hemo-
glebinuric fever will prevail in greater proportion in that period when ,
malaria is most prevalent, and will decline in frequency with the
decline in the malaria rate. In our opinion, length of residence is a
factor in the production of hemoglobinuric fever in direct proportion
to the amount of malarial infection acquired in that time.

VII.
AN HYPOTHESIS AS TO THE ETIOLOGY OF HEMOGLOBINURIC FEVER; THE ;
PART PLAYED BY QUININE IN THE PRODUCTION OF THE DISEASE;
AND THE TREATMENT OF THE MALADY. : : .
Sir Patrick Manson, in the latest edition of his "Tropical Disea'ss,
states that one of.the most important problems in tropical medicine : ....::
yet unsolved is that of the etiology of hemoglobinuric fever. This
eminent authority is inclined to the belief that a specific organism as ,.
the cause of the disease, and that such malarial infections as ocu ...
prior to the onset of blackwater are accidental. Christophers, Stephens
and Bentley, whose recent researches into this problem are. mo.st
thorough, believe that every consideration should be given .to -the
possibility of such a specific organism: although these writers do. ot.
find any proof of its occurrence. They believe that prior, mfctioi .::
with estivo-autumnal malaria is the necessary predisposing fac.tor,.a s i.:.
that this prior infection in some manner produces an .lteiij yr ;. ;
is the causative factor in the manifestation of hemO6g ig bda i|
. ... .... . v" s ISE:"".

. .. ...

"IT . ".S"NiE
.. ::, .
:E:E:EEAE
~i.I.. i. !: H ,"
:.E i! .::.. 2. ":: :::.E.: :: ii. : iE ..
..... :, ..A.. :.. .
.. ... rii H5'j !!

55

not our intention to consider in this place the arguments for and
against the various hypotheses of the etiology of the disease, further
than such arguments apply to the data that we have collected. Our
inquiry is limited to the etiology of hemoglobinuric fever in the Canal
Zone, and we shall not say at present how far the conclusions derived
by us will apply to the hemoglobinuric fever of other countries.*
However, all suppositions as to the etiology of hemoglobinuric fever
may be brought together under four hypotheses, as was done by Chris-
tophers and Bentley5, and it is our purpose to apply to these hypo-
theses the results of our analysis of the data which w\e have collected.
These four hypotheses are:
1. That hemoglobinuric fever is the manifestation of an active
malarial infection.
2. That it is the result of quinine poisoning.
3. That it is due to a specific organism.
4. That it is the result of a condition brought about by previous
malarial infection.
1. That hemoglobinuric fever is the manifestation of an active
malarial infection.
In a previous section.we discussed at length the influence of malaria
as an exciting cause of hemoglobinuria. The evidence showed plainly
that all attacks, of the latter disease were preceded at some time
by an active malarial infection. This evidence, however, did not
exclude the fact that in some instances the black-water set in at a
time when the active infection had run its course. It is not reasonable
to suppose that the onset of hemoglobinuria is due to active malaria
. after quinine has been administered from five to twenty-two days in
doses of thirty grains a day, and all acute malarial symptoms have
subsided. Such instances, though uncommon, are of unquestioned
authenticity and have occurred not only in our series, but have been re-
ported as well by other observers. We consider that the evidence
,prei6usly adduced shows beyond question that active rhalarial in-
i:: fection is undoubtedly connected with hemoglobinuric fever in such a
::. inanner that the infection is often an exciting cause, but the instances
:'..cited demonstrate that some other factor undoubtedly must be present
before the hemoglobinurib. is determined. Exceptionally this factor
iiM ybe provoked by pne attack only of malaria, but this happens very
: seldom, soeldoin as to make-possible the belief that in such cases there
S. .iist bmEan. individual idiosyncrasy. '

e Appebir B.
.......'.....'......... ....

...I... ... ... "

LLtC 1UI IJcI AldlpJCZIA I11 CLJUUUL U.J pcI LCLIL UJ Lilt:C ILL ClA ACLU CAU IAJU ZAASLMCI
but 0.25 per cent of the total disease. If acute malarial infection
alone were the cause of hemoglobinuria,.. certainly the latter would '
occur more often than it does, especially when the intimate relation
between the two affections is considered.
Although we admit the importance of acute malaria as an exciting :
factor, it is our opinion that before the eventuation of blackwater can i.. .
be determined some other agent must be present also at the time of
the acute malarial attack. .
2. That hemoglobinuric fever is the result of quinine poisoning. "
Neither in our clinical experience, which embraces a very large.
number of cases other than malaria in which the drug was given, npr
in the experience of other observers under similar circumstances, has
hemoglobinuria followed the administration of quinine to patients who
did not have a history of previous malaria. We shall show that hemo-
globinuria does occur at times when the administration of quinine, and
whatever effect is thereby produced, can be excluded, and there are in .i:
the literature reports of many similar cases. In acute malaria, .
and in persons with a history of previous malaria, as we shall demon- :
state presently, the administration of quinine sometimes determines
hemoglobinuria; but much more often no such effect is produced, and
this fact, together with those just cited, is sufficient proof that quinine
alone is neither the exciting nor the predisposing cause of the disease.
3. That hemoglobinuric fever is due to a.sppcific organism.
The analogy between the clinical symptoms of hemoglobinuria in .
ainmals, in which thediseaseis produced by piroplasmosis,and the clinical . :::
symptoms in man, is responsible for the belief that human hemogl ...
binuria is due to a similar specific organism which is yet undetermined:. .
If such an analogy, which,asStephens has said, "the weary.igvestigator : : .
has only too often wished were true," if such an analogy held good for,.. .. .f
all aspects-of the two kinds of hemoglobinuria, the hypothesis that a" :.i
specific organism is responsible for the production of hemoglobinuric
fever in man should obtain well deserved consideration.. ..But... :.
analogy goes no further than the resemblance in the clinicalsymptomsn ....::..
and without more substantial proof, one mzghta. well.say.that all -ceOR, ,
tinued fevers have the same etiology, as to assert thqt biuipe ha' he 5.-'
globinuria in animals is due to. a specific. organ"i, it:fo.llq .tta,:,;;:
similar organism produces the. disease in. man,. .: .l.
Hemoglobinuria in animals depends etintely iM i
definite organism, which is present in numbers
. . ... ... .. ...
.. .... . .' .....

.: ". ......"
": "" :" .... [ ] :n : ":
....~,.,
'' hEI ~~T EEIII
.. ." ': A .;d .." ,ii:: iiiiiiii !i ~ id

57

severity of the disease. The insect host of the parasite is well known,
and no previous illness is necessary before the disease is manifested.
Immunity against the disease is not obtained unless the animal recovers
from an attack or is artificially protected by inoculation methods,
when an immunity is established. All non-immune animals suffer in
proportion to the extent to which they are exposed to infection, and
in cattle, as far as we have been able to ascertain, there is no natural
immunity.
On the other hand hemoglobinuric fever in man exhibits entirely
different characteristics. It prevails exactly in proportion to the
extent of previous or present malarial infection, and where this is absent,
hemoglobinuric fever is absent also. No organism except the malarial
parasite is found constantly associated with the disease. A relative
immunity exists against hemoglobinuric fever only in those races that
are relatively immune to malaria. An attack of the disease does not
confer immunity, in fact, the opposite belief is held by most writers,
and in our cases we were able to find sixteen instances of recurrence
excluding those cases that relapsed in the ward. This comparison is
Sufficient to show that aside from the clinical symptoms no.further
relationship can be traced between the diseases in man and in animals.
Our patients were admitted from all parts of the Canal Zone, but to
no locality could be attributed a number of cases disproportional to
..-. that of the others. If the disease be due to a specific organism, it is
evident that this organism does not exist in any very great numbers.
,. It is true that there are diseases here that occur less frequently than
Does hemoglobinuria, which are due to infections with recognized para-
sites-for example, leprosy, quartan malaria, filarial disease, and very
rarely a skin disease, oriental sore, due to the presence of L. tropical
an organism resembling the Leishman-Donovan body, as reported by
Darling.1 But these are chronic.diseases for the most part; their
occurrence has no relation to that of any other malady, nor do they
Show a seasonal prevalence.
Hemoglobinuricfeverjpa very acutedisease, and if it dependsupon an
undiscovred parasite, this parasite must have exceedingly remarkable
powers of vitality in its extra-corporeal existence. That a malady so
acute as hemoglobinuric fever is not in the least infectious is evidence
i against editing agent being a parasite. It is not difficult to under-
stas .. d how rare disdases such as leprosy.and filariasis are continually
endPi'i;.. e lc, for such maladies are infective over a long period of time, but
iiii.l:,:, thiii::. ere are intervals when almost no'hemoglobinuria is present, and it is
Sount for: the srvival of the supp&ed parasite at ich

,i!::E :. : I. .. "..... .. .

.i,:..,,." ..": ..". .:: i'. .." .:. iiiii.. ';;itll~ii;.::- .. .. .

which hemoglobinuria follows malaria is not an argument in favor of
the latter as the cause of the former. Manson argues that because
tuberculosis frequently follows typhoid fever, it would be unreasonable
to say that the first disease is etio'ogically dependent on the second.
But this authority overlooks the fact that tuberculosis for the most
part develops without a previous typhoid infection, whereas hemoglo-
binuric fever never develops unless there has been at least one previofds
attack of malaria.
Craig states": "This fact (Stephens' observations of the number of
times the malarial parasite is found associated with hemoglobinuric
fever) has been used in the endeavor to discount the proofs of the
absence of the plasmodia in hemoglobinuric fever, but there are scores of
cases upon record in which the blood was examined both before, during,
and after the attack, and no plasmodia were ever found. If the fever
is due to the presence of plasmodia, why is it that in case after case these.
organisms are not found though repeated and careful search is made
for them, the spleen having been punctured in some cases with a
negative result?"
Stephens does not claim that hemoglobinuric fever. is due solely to
the presence of parasites at the time of the blackwater. And though
"scores of cases" are on record in which the blood was negative for
*malarial parasites, it should be remembered that such cases are not
taken from records extending over a certain length of time in a
given locality. Arguing from such premises, it would be as easy to
show 100 per cent of positive malarial infections associated with hemo-
globinuria, as to exclude the coincidence of the parasites altogether..
The almost constant presence of malarial parasites, when sought
for properly, in the disease is proof of a connection between hemo-
globinuria and malaria, but this presence is not urged as the actual
cause of the disease. The point is, that malarial infection produces.
in the body some condition that determines hemoglobinuric fever,-
and this condition, while frequently associatedgwith malarial parasites, .
may exist without them.
By some who uphold the. hypothesis that a specific organism iq
responsible for hemoglobinuric fever, it is urged that the same climb .a- .....
tological and epidemiological factors that cause the seasonal change in
the malarial rate, and that produce epidemics, may also cause simil .- ::
seasonal changes and produce similar epidemics in hemoglobinuri
In other words, since filariasis and probably dengue are disseminatezm :0i
means of the mosquito, the organism of hemoglobinmev.ermat y '||||al"i.l
be disseminated in the same manner. If so then certainlyth.
... .".. E .:: .::7" ca:taw o .::..

'. OF *-:'
.. ... ......

59

resemblance between malaria and hemoglobinuric fever would be in
great part accounted for, although the higher prevalence of the latter
in theory season would need additional explanation. But the analogy
implied in the hypothesis is not confirmed by existing facts.
Negroes expose themselves far more to mosquitoes and all other insects
that act as endo-parasitical hosts than do the Europeans. Filariasis
and quartan malaria, for instance, are conveyed by means of mosqui-
toes, and, although rarer diseases than hemoglobinuria, are found in
greater proportion among the negroes than among the Europeans and
Americans.
We do not know of any possible means of conveying any endo-
parasitical infectious disease in the Canal Zone which would not obtain
more among the negroes than among the other races, when the manner
of living of the former is considered. In order to sustain the hypothesis,
it is necessary to infer either that the agent which distributes the
.organism is more partial to Europeans than to Americans or negroes
(and we are unable to understand how this can be true to the extent
that the hypothesis would imply), or else, to presuppose that although
- the negro is more exposed to the suppositious infection, he is relatively
immune to it in the same manner that he is to malaria. And if this
last be true, the difference between the epidemiological and etiological
factors that determine the life history of the hemoglobinuric parasite,
and those that affect the life history of the malarial organism, is so
small that the former would probably exist symbiotically with the
S.... latter.
Against the hypothesis of a specific organism we wish to urge the
following facts. If hemoglobinuric fever be due to a specific organism,
then at some time this disease should complicate a malady other than
malaria, or should manifest itself during the process of some of the
I.. chronic affections so prevalent here. The records of Ancon Hospital
show instances of malaria complicating practically every other disease
That is admitted. Pneumonia is seen with and without typhoid fever;
tuberculosis and even leprosy are sometimes associated with amoebic
dysentery; all varieties of nephritis occur in acute and chronic ailments;
but neither clinically nor at autopsy has hemoglobinuric fever com-
plicated any -infectious disease other than malaria. Of the many *
thousand .patients who have been admitted to the surgical side of
this hospital only four have exhibited hemoglobinuric fever, and in
each of'these, the onset of the disease was preceded by the symptoms
of positive or clinical malaria. In not one case of hemoglobinuria
".an evidence of malaria, either remote or immediately prior, be ex-

... .... " "

until such an organism will have been found, we prefer to believe that ..S
previous malaria, as we have endeavored to show, is the predisposing
cause of hemoglobinuric fever. In this connection we wish to state
that hemoglobinuric fever is almost unknown among the adult natives
of this country, and that acute malaria is also rare.
4. That'hemoglobinuric fever is the result of a condition brought
about by previous malarial infection.
The data above submitted apparently leave no alternative to the ::..
conclusion that the chief and necessary etiological factor in the pro-
duction of hemoglobinuric fever is malaria. It would appear as a rule :*:
that not one but several attacks are necessary, either by recurrence
or re-infection, or that a state of chronic malaria is produced, -before
the toxicity accumulating in the system is sufficient under come exciting
cause to precipitate the hemolysis. 4
As above stated, though tertian and quartan organisms have been
found in patients coincident with or prior to the hemoglobinuric attack,
we are inclined to the belief that estivo-autumnal parasites are respon- .;
sible. If so, this would account for the statement so often made that
hemoglobinuric fever does not always occur where inalaria flourishes;
for tertian and quartan malaria may be endemic where no estivo-autum- ...
nal malaria exists.
That estivo-autumnal parasites are solely responsible as predispos-
ing factors for hemoglobinuric fever we are at present unable.. to.: ..':
prove. The exciting factor, however, is another question, which. per- ..
mits discussion, and probably depends on more than one agent. .
The malarial organisms in their parasitical development within the
human host generate toxins. This is evident, not only from the. on-; .,!
stitutional disturbances present and the pathological findings, but also.
because such generation is a necessary result in all endo-parasitlal
processes. The important investigations on the toxins ofU bacterial .
invasions elucidate the analogous processes in malarial infections.. .': ....
Thereappearstobe a specific toxin not only for every infective agent, :
but also for other closely related substances which play a different role~i; i .::
physiologically and chemically.. Immunity apparently depends oA "
the production of bodies which result from the reaction of the speaifik.':. .
toxin on the tissues, while the related substances, heiiolysiis, :a ..d
cytolysins, lead to blood and other cell destruction.. H im' nI pt b ;'liii
the result invariably of the action of a specific tn~x~o un ton ssues a,)1:
if it -can be shown that malarial'immunity exishtS i
that a specific malarial toxin exists. Cell.:Zt isa

.... ...... .. .. ......,

61

immunity, and also states that there are individuals immune not only
from natural but also from experimental malaria.
What is our experience here? As can be seen from the above charts;
the negro and the negroid races have undoubtedly a certain degree of
natural immunity. The amount of malaria in the newcomers is out
of all proportion to that which occurs in the native population, a fact
in itself sufficient to prove that acquired immunity exists. Whether
or not a permanent immunity can be established is a problem, but in
any case there undoubtedly is a temporary immunitas non slerilisans
in malarial patients. In these patients, though they seem apparently
well, some form of the parasites persists in a quiescent state, and lights
..up when the resistance of the body is lowered from any cause.
If, then, analogous to bacterial infections, a specific toxin exists,
what of the related substances, the hemolysins and cytolysins, with
which we arejnore directly concerned ?
.In the course of an acute malarial attack it is not an unusual clinical
Observation to see a sub-conjunctival hemorrhage, either slight or
S" involving the whole surface of the eyeball. This is particularly true
Sin the cerebral forms. These hemorrhages are due to a loss of the
capillary continuity by a cell solvent or cytolysin. They are not dpe
to an alteration in the blood or to hemophilic tendency, for the clotting
index is unchanged.
ii. Cytolysis is also responsible for some forms of paralysis, aphasias,
|;" hemiplegias, etc., which are occasionally met with in severe malarial
infections. We have observed patients in whom these forms occur
att the same time as the sub-conjunctival hemorrhages and clear
up simultaneously. In favorable cases the paralyses, due to capillary
blocking by malaria-infected blood and endothelial cells, clear up in a
few hours after the administration of quinine hypodermically. This
is not the case where blood is effused into the tissues.
Furthermore, every severe malarial attack is associated with more
ior less kidney irritation. At times this amounts to a severe general
: diffuse nephritis of: peculiar type, and may result in death, or after a
tedious convalescence, leave the kidneys permanently damaged. Un-
... doubtedly the kidney cell destruction is the result of cytolytic toxemia.
il -Post-mortem focal necroses in the parenchyma of other viscera
:;i .. ... to the same agent of cell destruction.
S .. "" rolYasisIs a phenomenon closely related to cytolysis, caused by a
*Ad:, active for the erythrocytes. It plays a role in the pathological
""u'i;:....alev...e ia- rebacterialinfections, particularly in some forms
~li bacterial infections the growth and the multipli-
mms is:not paroxyamal, as in malaria, neither is. the
.. .... ...

l.ill; i.';I.M1i i:.. ;.. :. .....
... E [ :?:ii:'l! Hi[ :;lP .:] '.'' .:" .:.L .". ."

pFUUULLIUII U ,LICII LUll aiiU LIAC IIVCI Ia 1UlC LU LdSC aiUC Ul LIIC U .
cell destruction as it occurs without the production of marked hemo-
globinemia and subsequent hemoglobinuria. If Ponfick's'3 experi--
Inents be true, then one-sixth of the red cells must be destroyed simul-
taneously before hemoglobinuria results. In some of our observations, ..
from red cell counts and hemoglobin estimations it would appear that
less than that number is necessary, though it is not uncommon for
25 per cent or more to be destroyed in a single paroxysm.
We are therefore forced to the conclusion that, as cytolysis and hemo-
lysis are regular concomitant phenomena of bacterial development in
the human host, so also are they in those cases where malarial organisms
are the parasites, the main difference being that in one type the patho-
logical changes are more or less continuous, in the other, paroxysmal,
thus corresponding to the respective life histories of the infective agents, :::-
In patients who develop hemoglobinuria there is a combination of red
cell and toxin, or in Ehrlich's terminology, of the haptophore group of
the toxin, which when sufficiently saturated becomes united with the
toxophore element, leading to the destruction of.the red blood cell.
Corresponding to the physiological and chemical nature of a 4.pxin,
an.,hemolysin has two groups, a combining group, and an injuring or
destructive group. Before a cell can be destroyed there must be a
union of the first group of the hemolysin with the cell before the other
group can act to destroy it. The natural protective agents of the body
prevent or attempt to prevent this destruction by their action on the
injuring or toxophore group of the hemolysin by converting hemolysin
into hemolysoid. Whatever, therefore, that would tend to prevent
this action would precipitate the cell destruction.
Three groups of conditions suggest themselves as exciting factors
to that end. First, renewed malarial paroxysms with the production
of sufficient accumulated toxin to overwhelm the cell. Second,, a
lowering of body resistance by any of the causes mentioned in connec-.i
tion with malarial relapses. Third, the. administration of quinine, ,,::
which may act in either of the two ways: (a) by depressing the
vital processes of the body (it is well known that in large doses "::
quinine depresses the circulatory system, interferes with blood
oxygenation, and leucocyte activity), and (b) by acting as the. toxo-
phore radical of the hemolysin. That quinine is-sometimes a factor.in
the production of hemoglobinuric fever is beyond question. ..;:!
Since Tomaselli," in 1874, first reported "that thereswere persons
who every time they took quinine, even in small doses, msanifesteda, ':.
severe fever paroxysm with hemoglobinuria," there has been a coni...... i .
of authority as to the etiological importance of this A it :he b.

.... ...
.. .. . ..

-H

ti.

63

duction of hemgolobinuric fever. It was observed that in some persons
hemoglobinuria regularly followed the administration of quinine, and
on the other hand that hemoglobinuric fever developed at times when
the prior administration of quinine could be excluded. Between these
two extremes every possible variation has been observed. Hemoglo-
binuria that followed one dose of quinine did not occur when the second
dose was administered; in some instances paroxysms followed after
successive administrations of the drug, and did not recur when it was
given later; quinine was sometimes given throughout the attack and
subsequently, with no further hemoglobinuria, and at other times the
hemoglobinuria persisted; and finally, death followed in some instances
whether or not quinine was administered.
In our cases all of the foregoing incidents were observed in such
variety that we were unable to classify the results which followed the
administration of quinine. We present in detail at the end of this
paper the treatment of each case of hemoglobinuric fever that we have
admitted to this series, and a careful study of all the cases so reported
will convince the reader that no regularity of results following the
administration of quinine can be predicated.* We do not mean to
infer that quinine does not play an important part in the etiology of
the disease, but simply to state that the part so played is very
complex.
That there are persons in whom hemoglobinuria follows the admin-
istration of quinine we are able to affirm. Case No. 42 was that of a
young Frenchman who had been on the Isthmus for six years. He had
suffered from several attacks of malaria, and during each attack had
taken quinine, with the result that he invariably manifested a paroxysm
Sof hemoglobinuria. He was admitted to the service of Dr. A. B. Her-
i:. rick, Chief of the Surgical Clinic in Ancon Hospital, on February 14,
1907, with a fracture of the external condyle of the right humerus.
Histemperature was irregular after his admission (see report, Case 42),
S and although no parasites were found in his blood on admission or
immediatley prior to the onset of hemoglobinuria, Dr. Herrick felt
that quinine should be exhibited. The patient told Dr. Herrick that
blackwater always followed when he took quinine, and for that reason
he, the patient, had suffered much from malaria, as he was afraid of
the result of taking quinine. Dr. Herrick obtained his consent to
administer a very small dose, and on February 21, at 11 a. m., one
grain of quinine was exhibited. Prior to this the urine was examined
S and fond to contain no albumin. At 1 p. m. the patient voided

....... .....u t.. .....p................. ..

r

ALL. I fJi Lii.' CL. .Z11 VU llt.Of A*fLLJ L I L..A a CUL.L.LJj U J & fLi U.Jl LLJli ". :';:
At 8.40 p. m., twelve ounces, light red.
At 4 a. m., sixteen ounces of urine, clear in color were passed. No
albumin was found.
We are indebted to Dr. Herrick for permission to report this case. .
The prompt occurrence of hemoglobinuria after the administration
of quipine in several of the patients who were admitted to the hospital
with positive or clinical malaria has led us to believe that such cases as
the one just recorded are not uncommon. In some of the patients in
whom hemoglobinuria was manifested until death, and to whom ..?
quinine was administered throughout their illness, perhaps such an *" :r
idiosyncrasy obtained. Other cases, however, in which, under similar .
treatment the urine cleared before death, demonstrate that the result
of the administration of the drug cannot be foretold with any certaifity. .
It can be affirmed that hemoglobinuria following the administration
of quinine does not occur except in those who have had a previous
attack of malaria. In the large number of patients admitted to this. '
hospital, to whom quinine was giveri, and whose illnesses at the time
that they were in the hospital were not malaria, no hemoglobinuria
followed the administration of the drug. And in many cases of malaria,'
in which the exhibition of quinine.was followed by hemoglobinuria,
the length of the time that elapsed, and the varying amounts of the
drug that were taken, before the hemoglobinuria developed, make it
impossible to state how much the administration of the drug had to.do
with the eventuation of the disease. We shall give below the details.
of a few such cases.
Case No 205.-The patient was an Italian, who had been thirty- :: .
seven months on the Isthmus. He was admitted to Paraiso Hospital.
on April 5, 1910, with symptoms of malaria. On that day three tea- ..iiI
grain doses of quinine were given. On April 6, about 4 p. mr., after his'.."."
fifth dose of quinine, he had a severe chill, and fifteen minutes later ":
hemoglobinuria developed. The next morning the patient waitran-; .......::"..i
ferred to Ancon Hospital. His blood was examined on admission ati.' ".
was negative for malarial parasites. The urine was loaded with 4aI h:10.-i
* min, iwas dark red in color, and hemin crystals: wee IOt nl ii ..
quinine was administered and on April 10 th"e i....ui w l
April 20 the afternoon temperature was 101; on tf

'.* .. .. .. ..
....

... ... .. ... ..

fever; on the 22d there was a febrile paroxysm (see report, Case 205)
and a double infection with tertian parasites was found in the blood.
Twenty grains of quinine were given at once and doses of ten grains
three times a day were ordered. On the morning of the 23d hemoglo-
binuria was present. The quinine was continued, and on the morning
of the 25th, the urine was clear. On April 28 the drug was discon-
tinued and renewed on May 2, without further hemoglobinuria.
SCases similar to this and others, that varied somewhat in the results
following the administration of quinine, are Nos. 4, 12, 33, 67, 128,
S 142, 164, 172, 174, 186, 187, 189, 190, and 221. For details of these
cases see their reports in Appendix A.
That hemoglobinuria will develop when no quinine has been admin-
istered immediately prior to the onset of the attack we can affirm also.
*Case No. 185 was admitted on November 21, with a history of
hemoglobinuria for two days past. On admission the urine was dark
I: red in color, and hemin crystals were demonstrated in it. Twenty
grains of quinine were given on admission, and ten grains the following
morning, when the drug was discontinued,after which the urine cleared.
On the 30th, at 4 p. m., hemoglobinuria began, which cleared on
Sthe next day. On December 10, and again on the 12th, there were
febrile paroxysms, these times without hemoglobinuria, and on the"
latter date the blood was found to contain estivo-autumnal parasites.
Quinine was given in full doses, thirty grains per day, and no hemoglo-
binuria followed. This case is most interesting in that it exhibits a
hemoglobinuria not due to quinine, that of November 20, followed by
malarial paroxysms and the administration of quinine without further
hemoglobinuria.
Case No. 200.-This patient manifested true paroxysmal hemoglo-
:binuria that did not follow the use of quinine. He was admitted on
February 11, with hemoglobinuria. Prior to admission he had taken
some quinine, and he claimed that the hemoglobinuria had preceded
the taking of the drug. No quinine was given on admission, and the
urine cleared on the 14th. On the 17th the urine was clear and did
n.ot contain albumin.. On the 18th there was a febrile attack, accom-
*.:.. panied by hemoglobinuria, and hemin crystals and albumin were found.
i'.:';" On t.he. 19th the. urine was clear. On the 20th there was another
... febrile attack, with hemoglobinuria. On the 21st the urine cleared

istred hypodermic, as the patient was unable to take anything

Sce 'bee rported' prWiously by Dr. R. C. Connor, Proc. Canal Zone

.. . '. : .. ... .... I T .
t. ... .. .

i ..;:liii' li~i~ !!! 'ii !; @ ;, ,i !,;,,! % .,".; ..:' . :. .

the amount of hemoglobinuria. A careful search for parasites was
made every day for ten days after admission, but none were found.
The patient was critically ill for several days after the last appearance ..
of the hemoglobinuria, and his symptoms resembled those of a severe :
malaria. Ultimately he made a good recovery and has remained well.
He has taken quinine several times since without untoward results.
Case No 226.-The patient was admitted with hemoglobinuria on
July 26, 1910. On the 28th and 29th quinine was administered in :
moderate doses. The urine cleared on the 29th. On August 9 thymol ."
treatment for uncinariasis was administered. On the Ilth there was a
febrile paroxysm, with hemoglobinuria. As this occurred forty-eight
hours after the last dose of thymol had been administered, in the
meantime the patient had remained without any untoward symptoms, ,
and the thymol had been cleared from his intestinal tract by the purges
that we give after such treatment, it is improbable that the hemoglo- .
binuria developed as a result of poison by the drug. On the 17th
quinine was given in doses of ten grains three times a day and continued
with no further hemoglobinuria. His attack may have been caused
by lowered resistance due'to thymol treatment. "
A consideration of these cases, and the case reports at the end of this
paper, will make it very clear that, as we have stated, the part played
by quinine in the eventuation of hemoglobinuria is very complex.
Hemoglobinuria has developed from within an hour or two after the
administration of the drug to as late as twenty-two days after the first .
dose, the quinine being given in doses of ten grains three times a day
in the meanwhile. From this it is very plain that some factor other .
than the action of quinine must be present in order to produce the
hemoglobinuria, and such an hypothesis would explain the variety of
conditions under which hemoglobinuria appears and disappears fo- ..
lowing the administration of the drug. :.
In considering the production of hemoglobinuria, the question arises,
if certain red cells are destroyed, why not all? ::
According to physiologists, the life history of a red blood cell is ...l
probably not more than four weeks, and naturally this means the corn-
plete regeneration of the erythrocytes every twenty-eight days.
Having red cells, then, of different ages, exposed to a toxin with which
they enter into chemical combination, it means that different degrees *i;i'
of toxicity are present, and the older cells, having absorbed. m te.;:.
toxin, are more prone to destruction. So that in cases in which quia
has been given, we do not believe that quinine alone,-but q:iii i:

..
. .. ......
".. . . . .. ..... ..: :. .

67

malarial toxicity is necessary to produce the phenomenon. One must
exclude individual idiosyncrasy for drugs.
It is known further, that bacterial toxins, like enzymes, unite with
the tissue units they act on, and if Marchoux's's observations that
quinine elimination does not take place during the attack, but subse-
quently, be correct, we have positive proof that quinine can unite with
some constituent of the body tissues under hemoglobinuric conditions,
* which conditions prevent its immediate elimination, and we have every
reason to infer that this union is with the stroma of the erythrocytes.
It has been stated that chemically and physiologically cytolysins
and hemolysins are closely related, and that malarial toxicity plus
quinine poisoning is responsible frequently for hemoglobinuria; can
evidence be produced to show that malarial toxemia plus quinine can
produce cytolysis? Cytolitic phenomena, as previously mentioned, are
not uncommon in the course of malarial infection, but quinine as an
exciting factor was not discussed.
A case recently came under our observation which is unique, and
bears directly on this point, paralleling exactly those cases of hemoglo-
binuria in which,quinine is a factor.
A. H- negro, Barbadian, age 22, was admitted to the hospital on
,. August 15, 1910, after residence of twenty-six monthson the Isthmus.
During 1908 he was admitted to this hospital in June and again in
December with fever. Although the blood was found negative, the
temperature curve and the manner in which his fever yielded to
"' quinine on one of these admissions suggested malaria of the estivo-
autumnal type. However this may be, quinine was given in doses of
. ten grains three times a day on one occasion for seven days, and on the
other for eight days, and no note was made of any untoward effect.
In 1909 he suffered from an attack of diarrhea, but there has never been
a history of bleeding from any part of his body previous to his last
admission. There is no history or stigma of syphilis, and physically
the patient is a well-built negro. On the present admission he com-
plained of headache, fever, chills, and nausea. He had the usual signs
.of malaria, and his blood was positive for estivo-autumnal parasites.
SOn the day of his admission twenty grains of quinine, with the usual
calomel and salts, were given. On the next day he began to bleed
Ii" from the mouth. On examination there could be seen two patches
of capillary oozing, one on the cheek and one on the soft palate, each
ii'i out thelsize of a ten cent piece, and also a series of smaller spots on
the gums. All of these patches were covered by a fungating, dirty
loldtfg i:mss, which examination showed to be blood clots. These
we |ad ly removed, 'nd the bases showed no ulceration, but a torn

... .. .. .

bases of three of these fungating masses showed gram-positive diplo-
cocci, and a few gram-positive micrococci and bacilli; fto fungi were
discovered. The blood culture was negative. He received thirty .
grains of quinine on the 16th and on the 17th; thirty grains hypd-
dermically on the 18th, 19th, and 20th, when it was discontinued. On
the 17th hematuria was present, red blood cells appearing in the urine, I
This hematuria persisted until the quinine was discontinued on the
21st; his pulse rate rose from 90 on admission to 120 on that date.: ;
On the 20th petechial hemorrhages appeared all over his body.
These hemorrhages also ceased with the withdrawal of the quinine.
By the 23d, the hemorrhagic symptonis had all disappeared, and on
the 24th quinine was again administered in three ten-grain doses, with
the reappearance of all the hemorrhagic symptoms. On the 25th .
quinine was again discontinued, with the disappearance of.the hemor-
rhages. On the 29th quinine was again resumed, and on the following
day the gums began again to bleed. The quinine was continued until
September 3, with more or less constant oozing from the gums during
the whole time. Quinine was then discontinued and the patient ::i
rapidly cojialesced. On the 10th, 1lth, and 12th, the patient received
fifteen grains .of quinine daily, without recurring hemorrhagic "
symptoms, and was discharged on the 15th, having recovered entirely.*
This case demonstrates beautifully the development of a cytolysin .. 'i
affecting the capillaries, and determining hemorrhages, more or less
general, in a patient with no hemophilic tendencies, inherited or
acquired, during the past twenty months, excited by. quinine, and
apparently inactive without it. .
That the patient had no inherited idiosyncrasy is evidenced by his ,.
former hospital histories,'and we know that he had malaria on admis-
sion, and this is the probable source of his cytolysin. This case is of
great value because of the light that it throws upon thg etfioogy of
quinine hemoglobinuria, which is an analogous phenomenon.' '
It would appear, then, beyond question that malarial toxin,';or a
toxin developed in the human organism as a direct.result of. malaal.
infection, plus quinine, does produce hemoglobiaUria.. .. .
We have now to consider hemoglobinuria which develops. withpu ...'
the exhibition of quinine when no more than slight:traces hemingl ei .
can be detected in the urine. It.has been stated abovp t.tht h. t

*This patient was admitted subsequentiy with esti"vo- ittumn .,4I Qei.. 14 e
* was given in full doses without the reapif~raea of. the thu

A ; .. .. . .... :. .. ..

."'
..... + .: ... .. .. ..... ....., ...++:..,+++;+ii ;i:,:ii+ i: i"

69

autumnal parasite is probably responsible for hemoglobinuric 'fever.
* In the intra-cellular development of the tertian and quartan parasites
all of the hemoglobin of the erythrocyte is utilized as a pabulum. The
estivo-autumnal parasite, however, does not use up all of the hemo-
globin of the cell, probably not more than one-half or two-thirds of it.
At every sporulation, therefore, free hemoglobin is liberated in the
blood stream, producing thereby a certain degree of hemoglobinemia.
This accounts for the transitory trace of hemoglobinuria detected in
patients suffering from severe estivo-autumnal infections. This,
however, is not hemoglobinuric fever as we understand it.
To sum up. All bacterial infections produce at least three sub-
stances in the human organism:
1. Specific toxins, which cause tissue reactions that result in im-
munity.
2. Cytolysins, which produce cell destruction.
3. Hemolysins, which are selective for the erythrocytes.
Malarial infections produce analogous substances, and this pro-
duction is paroxysmal.
The selective force of the individual agents is expended according to
personal idiosyncrasy, natural cell resistance, occupation, habit, etc.
Although usually the accumulative toxic effects of more than one
malarial attack are necessary to produce hemoglobinuria, even the toxic
effects of one attack may be sufficient, depending upon the personal
equation.
When the natural protective agents of the body, the alexins and
opsonions, are unable to take care of the hemolytic effects of the toxins,
as in the sudden production of an overwhelming amount of these, or
through a variety of agents which lower body resistance, or through
S the administration of quinine, then hemolysis with hemoglobinemia
and hemoglobinuria results.
The coincident development of cylotic phenomena, and particularly
: their action on the kidneys, goes far in determining the prognosis.

::.

*I I..; ..
;;iiig :' ;";

Clinically, we may divide hemoglobinuric fever into three types.
1. The paroxysmal, when aftkr a severe chill with attendant fever,
there is an onset of blackwater, the duration of the whole attack being
from a few to twenty-four hours.
2. The sub-continued, when the febrile attack or the blackwater,
: r. both, persist from one to three dhys.
..:i.,S.-:,,Th.e continued, when the passage of blackwater persists for four
StiAi ea,. .i: ~yijh iogh fever; or the fever may be moderate or absent.
; :, ',:-h -i" th fee may be m

..' .... ... U . ..,
...... ..... ..

70

In all types at the onset of the attack there is some suppression of
urine, followed as a rule by a hypersecretion. The degree of suppres-
sion determines frequently the gravity of the case. We have seen a
comparatively mild paroxysmal attack, associated after the passage
of the first urine with complete suppression and apparently but little "
blood destruction, go on to a fatal issue in from one to two weeks.
Suppression occurs in all types and is a symptom of the greatest gravity.
In our cases we have had but one recovery when suppression was *
complete.
Apparently the suppression is associated with more or less complete
destruction of the epithelium of the straight and convoluted tubules.
Hypersecretion is always a favorable sign in prognosis if the pissirig
of blackwater does not persist too long, or until the degree of anemia
is so great as to bring about death from it. We have seen a red blood
count of 800,000 with subsequent recovery, when the hemoglobin .
estimate was as low as 10 per cent, too low in any case to be read-by
a Dare's or a Sahli's hemoglobinometer. When recovery does take
place in these cases convalescence is very tedious, and more or less
permanent damage to the kidneys is frequent. ':ii
The condition of the blood is fairly characteristic of the disease.
During the first few hours after the onset of the attack the appearance
of the corpuscles, fresh or stained,-is practically normal. Later, there
is great difficulty in making good smears, owing to the apparently in- |
jured condition of many of the cells: A tendency to all forms of bizarre
shapes and poikilicytosis is seen, but an examination of the fresh sped-
men will show that these appearances are due to accidentsin the spread-
ing of the smears, for in the fresh specimen the erythrocytes are normal
in shape and size. In a day or two more, however, the blood takes on
the appearance of an anemia more or less profound, and macrocytes, :.
microcytes, and nucleited red blood cells are fouid.. ,"
There is no fixed characteristic febrile curve in hemoglobinuric
fever. With the onset there may be only ah acute febrile paroxysmrf
and a subsequent normal temperature, or the fever may persist as lotnig i
as the patient is passing blackwater. It is not uncommon to observe
a post-hemoglobinuric fever that persists from several days :"t twd or
three weeks, very irregular, and often as high as 101 or 102. Odea' .
sionally this fever appears to have been favorably affected by qqiii,' I:: i
and at other times it has persisted notwithstanding the very .laIg,. :::
amounts of the drug that often were given by mouth and 'hy
dermically. ;
The jaundice in this disease is a very striking ch*li.l. .hi .t
varies from a pale, lemon-yellow t the depth of oi

i. ."l.lHg.:,'.' ll '[ il
.. ... ; i: ;,: :;:: ;: ~,H:! H~ :;i; :i
: :, :% .i :
" " ::E~ tf l:ll.F..
. .: .. .. .......a.d .

71

complete biliary obstruction. This symptom, of course, depends not
only on the amount of blood destruction, but also on the ability of
the liver to handle the destroyed cells. The jaundice and the anemia
together make a very characteristic clinical appearance.
We have very little to add to the symptomatology of hemoglo-
binuric feverin general. Manyauthors have done justice to this subject,
but there are a few points whose importance has not been dwelt on
sufficiently, from the diagnostic as well as the therapeutic standpoint.
Frequently these cases of hemoglobinuric fever develop prior to the
admission of the patient to the hospital, and an unreliable history leaves
the clinician in doubt as to the diagnosis. The blackwater may have
disappeared and no urinary findings sufficiently characteristic are
present. In such instances evidence of a confirmatory character can
*, be obtained by a careful examination of the liver, spleen, and eye.
The liver of a patient suffering from malaria of any variety is enlarged
unless either cirrhosis or atrophy is present. In hemoglobinuria
this enlargement is more pronounced and the liver is distressingly
tender on palpation during the acute attack. If the fever persists, as
frequently it does after the blackwater has ceased, the liver symptoms
are usually more marked than in malaria, and this will help to deter-
mine the diagnosis. In tertian and quartan infections the parasites
will always be found if there is any degree of fever whether or not
quinine has been administered, but in estivo-autumnal infections there
is often fever when the parasites are absent from the peripheral blood.
In post-hemoglobinuric fever, however, the liver is more swollen and
tender than in the estivo-autumnal malaria.
In. tertian or quartan infections the spleen is considerably enlarged
and most always palpable. As a result of repeated infections with
estivo-autumnal malaria, the spleen may attain a size sufficient to
render ft palpable, but a primary infection very seldom produces a
4* palpable spleen. From a great many examinations we believe this
statement to be clinically correct. In hemoglobinuric fever, however.
the spleen is always enlarged and tender as long as the fever persists,
and certainly this suggests accumulated toxicity.
These symptoms, manifested in the liver and spleen, are not in
S .themselves sufficient to determine a diagnosis after the blackwater has
"disappeared, although they are of considerable collateral importance.
But the clinical picture presented by the appearance of the eye, which
S feature has not been dwelt upon in the literature, as far as we have been
: able to learn, is very characteristic, and persists for a considerable
Si.;iii period after the blackwater has ceased. The conjunctiva is of a uni-
,l .iii mon,., yellow tint, varying in depth of fhade, but always lighter

., .
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="ii~ ""=u;i;] ii=i ii!u =i=: = =]:;.u .. .".. .'u

stormed ot granular detrtus, consisting ot minute hemoglobin bars,
apparently secreted by the kidney epithelium independent ofay ny
kidney lesions. This detritus appears frequently in the form of kidney
tubule casts more or less closely cemented together by some hyaline
substance. They disintegrate readily, forming the granules of the
detritus. Frequently granular, epithelial and hylaine casts are found, '
indicating an old or a fresh nephritis. With proper tests, nucleo-
albumin, serum-albumin, and serum-globulin can be demonstrated in
the urine, and with a spectroscope the bands characteristic of oxyhemo-
globin or of reduced hemoglobin are visible, depending on the length
of time that has elapsed since the specimen was passed.
In the severe forms of nephritis going on to suppression, the lethal
outcome takes place within three weeks. We have not witnessed .;
any cases that outlasted that period. In such cases the .rinaii y
findings are those of a severe acute nephritis. .:,
The treatment of hemoglobinuria is of great importance, and the
relatively low death rate (15.5 per cent) that we are able to sho
speaks eloquently for the method followed here. ." i
If malaria, recurring or due to re-infections, is the necessary;. tie.-
logical factor in the production of hemoglobinuria, with;,os e super-
added factor, such as an acute exacerbation'of. ,alaria quinine :..:
administration, or lowering of the natural resistance by some depressing .
agent, then the treatment must be conducted along certain lines which :
vary with the existing conditions. Often we a .in the predicament '
of treating a patient suffering.from malaria for which. we have but: .ne. .,,
known remedy, and that remedy likely to provoke a hemoglobinua ..:. '::::.i
which may result fatally. ; ., ..
In August, 1908, one of us (W. E. D.).instituted .in ti.s ho itai "
a more or less, systematic treatment of hemoglobinuric feve wlh .:i :.
has given favorable results. This may described, (a) aps.e a
adopted during the acute attack. and (6) thosa~.adpted.afe t s.0 :,
sidence of the acute symptoms. :, ., N:
During the acute attack, vomiting, *pigastridis-.tai Et h
thirst, and hiccough-are the prdonaitig ig *
calls for water, which, 'laen tat is m jeq
.. .. .. ..... .

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73

distressing symptoms are very often immediately relieved by the
administration of normal saline solution per rectum or by hypoder-
moclysis. As a rule, the former is sufficient, eight to sixteen ounces
every two or three hours are readily absorbed, and it is astonishing and
gratifying to note how quickly this simple measure relieves the patient.
Hot moist applications over the stomach and loins are also grateful.
The only medication given in the early stages is calomel, followed in
a few hours by magnesium sulphate.
If parasites are present, then quinine is indicated, and its effects are
carefully watched. If the stomach is sensitive, then the drug must be
given by the rectum, or hypodermically, the latter is better, in doses
of ten to fifteen grains every four to six hours. It must be borne in
mind that hypodermic injections of quinine are very prone in these
patients to provoke tissue necrosis, as in every other condition of
lowered tissue resistance. Massage must be used over the deep-
seated intra-muscular injection, and subsequent hot applications
made. If, however, quinine aggravates the hemoglobinuria it should
be withdrawn temporarily and the expectant treatment be used for a
few days. Even when the parasites are not present, and the fever and
the hemoglobinuria persist, it is often wise to try the hypodermic
administration of quinine, as the absence of parasites is no proof that
the organisms are not active in the deep seated tissues.
When no impending danger to the patient's life exists, generally
it is best to use the expectant treatment, giving a milk diet for a few
days. We favor the use of-some mild ferruginous preparation, such as
Basham's Mixture, to help supply the necessary elements for red cell
Reproduction; later we give Fowler's Solution.
The greatinajority of our patients get no quinine until such time
Sin the course of the disease as convalescence is established. Occa-
sionally at this time a paroxysm of fever occurs and parasites are found.
Quinine is 'then indicated and may or may not produce hemoglo-
binuria. If it does, the further administration of the drug is postponed
.; for a few days; for, as has been pointed out, quinine may produce
.hemoglobinuria at one time and have no such effect subsequently.
Just.as in the case of cytolysis above reported, in malaria, patients
come several times to the hospital, take quinine without untoward
results, and are discharged, only to return later with an attack of
ihemooglobinuria apparently the result of.quinine administration; and
then return later with malaria, when quinine is safely administered
li..n.....thilt the development of hemoglobinuria.
.I;,,::.. .. y... o iay plays a .very 'fportant part in the etiology of chronic. and
"TZ.ing sn r~ and for ts reason its presence-should be looked for

.. ....'... . ............ . .

in cases oi nemogioDinuria ana proper treatment msntutea, it t is
present. This disease may play some part in the direct etiology of
hemoglobinuric fever, as'evidenced by the great preponderance of
both diseases among the European laborers. This class is heavily
infected with hereditary and acquired lues.
We believe, however, that the chief influence of syphilis is exerted in
the production of recurrences and cachexia in malaria, and in this way
predisposes to hemoglobinuria. It is a frequent observation here that ..
malaria and syphilis flourish together, both exerting a debilitating
effect on the host, and both have to be treated simultaneously if the
patient is to be relieved. In this combination of malaria and syphilis,
the physical and blood findings sometimes resemble so closely those of
liver abscess that a diagnosis is particularly difficult, and the former
condition has led here occasionally to an exploration for the latter. ":
We have dwelt upon this concurrence of syphilis and malaria, for in
hemoglobinuric fever this conditions is sometimes present, and if
one would prevent a recurrence of hemoglobinuria, under such circum-
stances, it is necessary to treat the patient for malaria and any other
condition which militates against a normal resistance. Therefore,
the treatment of hemoglobinuric fever often resolves itself into the
treatment of malaria and the complications of the latter. It is well
known that many cases of malaria improve on rest and good food with-
out medication, when the natural resistance is sufficient. In .those
fortunately rare cases in which quinine cannot be administered on
account of the amblyopia and optic atrophy that sometimes follow
the exhibition of this drug, such means as absolute rest and nutritious ..
food are our only resources. In such cases the temperature alone
should not be the guiding factor in this treatment, but careful exam-
inations of the blood, liver, and spleen are also necessary.
Similarly, a number of patients who have hemoglobinuric fever also *
recover without the use of quinine, but in such cases, as in similar one
in malaria, the danger of a relapse, with fatal consequences, must be
always kept in mind. The reader will remember the case of the young
Frenchman which we described, in whom the administration of quinine
always was followed by hemoglobinuria. This man died subsequently
of the disease.
Sometimes thirty grains of quinine a day is insufficient to bring
about convalescence in hemoglobinuria complicated with malaria, nd
forty-five grains daily, or even more, is necessary before the tempera ....:i.
ture will yield.
Again, some cases necessitate -the use of ~qiniane hypodermica l
The reason for this appears to depend upon loealizataion of the patrbgaf
...... ..... .
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........ .r ..:;. /..' ..:,d ? i: ; '.'. :;d~ ii !! ii|

7:,

75

a condition so frequently seen in this country. Parasites may localize
in any part of the body, and interfere with tissue function; and in the
brain such localization may produce cerebral symptoms of every
known kind; aphasia, hemiplegia, local paralyses, tics, neuralgias,
mania, delirium, stupor, coma, convulsions, hyperesthesia, and other
." affections are all simulated. Such symptoms, due to localization in the
systemic circulation, necessitate the administration of quinine hypo-
dermically.
When quinine is given by the mouth, or rectum, before it reaches
the systemic circulation apparently the metabolic action of the liver
modifies the effect of the drug, as happens with several well known
alkaloids. Such a process may account for those cases in which hemo-
globinuria ensues after the drug has been administered by the mouth
for several days. The hypodermic use of quinine would therefore be
indicated if the patient were not making satisfactory progress toward
Recovery, and no other constitutional cause were present to prevent
convalescence.
The nephritic complications must be cared for as in any other severe
nephritis, acute or chronic.
The practical importance of determining the relationship of prior
malarial infection to hemoglobinuric fever is obvious. In those cases
Sof malaria, particularly among women, in which quinine.cannot be
Administered, such knowledge is indispensable if proper prophylaxis
'against blackwater is to be instituted. In our series, four cases,
three of which were fatal, occurred as the result of a neglected
Malaria in women.
IE: Ina malarial country, the physician who has in his care patients who
cannot or will not take quinine should not fail to acquaint them with
I; the grave danger'of a subsequent pernicious malarial attack, or with
I the ever present possibility of the eventuation of hemoglobinuric fever,
or both,. and he should use every persuasion to induce such patients
Sto leave, the country. Anyone who has witnessed the distressing com-
bination of optic atrophy and amblyopia following the necessary
administration of quinine in a pernicious malaria, or who has seen a
fatal hemoglobinuric fever supervene during the treatment of a neg-
leeted malaria, cannot fail to be impressed by a result which the
ie cise of common semse on the part of his patient would have
prevented.
We" are indebted to Drs. A. B. Herrick, Wm. Shaw, and R. C.
Idiott, of Acon Hospital, for" case reports and to Col. W. C. Gorgas,
Ml: .,kA, for permission to publish this paper,

.. 7
. .... .. ...
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ii .i::;:. : .;::E, .:: !i ::" ." H -..

for the most part brought about by repeated attacks of malaria.
2. It may appear coincidently with an acute malarial paroxysm.
3. It may be determined by any depressing influence.
4. It may be induced by the administration of quinine. iNi
5. Quinine alone, nor malarial infection alone, do*not cause hemo-
globinuria, but one or both of these conditions, plus the toxin eventu-
ated during the course of one or more malarial attacks.
6. Syphilis is a predisposing factor, because of its influence in the
production of malarial recrudesences.
7. The treatment varies with the condition present. :
8. To insure against recurrent attacks of malaria, with the subse- :;::
quent production of hemoglobinuric fever, it is necessary to raise the.
patient's resistance to a maximum, and to eradicate the malaria, by
a thorough course of treatment with quinine.

BIBLIOGRAPHY.

1. Gorgas. W.C.: Malaria in the Tropics, Jour. Am. Med.Assn., 1906,xlvi,1906,1417.
2. Brem, V.: Malarial Hemoglobinuria, Jour. Am. Med. Assn., 1906, xlvii, Nos.
23 and 24.
Brem, W.: Studies of Malaria in Panama. II. Treatment o .Blackwater
Fever: Pernicious Malaria with Hemoglobinuria and Erythrolytic Hemoglobinuria, .
Arch. of Int.'Med., 1911, vii, 2, 153..
In this paper Brem reports 162 cases of blackwater fever that occurred in Ancon
Hospital from 1904 to April, 1910. These cases include those reported by Connor h ::
and Gorgas, and are included also in our case reports in Appendix A. At the end
of Brem's paper are given the admission numbers of the 162 cases reported by him. :. i
3. Connor, R. C.: Hemoglobinuric Fever, Proc. Canal Zone Med. Soc., 1909, 83. **
4. Marchiafasa, E. and Bignami, A.: Malaria, Twentieth Century Practice of
Medicine. New York, 1901, xix, 483.
5. Christophers, S. R., and Bensey, C. A.: Blackwater Fever, Scient. Mem., Med.
and San. Depts. Govt. India, Simla, 1908, N. S., No. 35. W*.
6. Darling, S. T.:'Factors in the Tranimission and Prevention of Malaria in the ...
Panama Canal Zone, Reprinted from the Annals ofTrop. Med. and Parasit., Liver-
pool, 1910, iv, No. 2.
7. Stephens, J. W. W.: Blackwater Fever, in Osler's Modern Medicine, Phila-
delphia, 1907, i, 449.. . . : il
8. Manson, Sir Patrick: Tropical Diseases, New York, 1909. "
8a. Deaderick, W. Hf.: A Practical Study of Malaria, Philadelphia, 1900.
9. Craig, C. F.: The Malarial Fevers, New York, 1909. '
10.'Daniels, C. W. and Wilkinson, E.: Tropical Medicine and Hygiea New ::::::i::ii
York, 1909, Part 1. " .
11. Darling, S. T.: Autochthonous Oriental S6re 1h Panaina, iv printe1sd fro
Trans. Soc. Trop. Med. and Hyg., 1910, iv., No. 2, Pages .-63.
12. Celli A.: Malaria, New York, 1900. .
13. Ponfick: Cited by Chrisiophers and Bentley, Blacl i1aer V5w ,. .
14. Tomasell: Ibid. : :: :ia
15. Murchoux: Ibid.

'K
... .. N. ..:....::.... 4::
....tF ....

77

APPENDIX A.

CASE REPORTS.
These case reports include all cases of hemoglobinuric fever upon
which our statistics are based.
Under the head of "History" the temperature records are shown.
The temperature was taken twice a day when two records are shown;
at 8 a. m., 12 noon, 4, and 8 p.m., when four records are shown; and
every four hours otherwise.
All dates are inclusive when shown as follows: 24-28th.
Under the head of treatment we have shown only whether or not
quinine was given, and in what doses. I. and Q. Tonic is a preparation
of iron and quinine in which there are ten grains of quinine to the
dose. It was given three times a day. All quinine was given by the
mouth, and mostly in liquid form, unless otherwise indicated. Quinine,
grs. X, hypo, four doses, means that on the date or dates included
quinine was given every four hours, hypodermically, for four doses, etc.
Most of the hemoglobin estimates were taken % ith Dare's instrument.
When the amount of albumin is shown in percentage, the heat and acetic
acid test was used, and the albumin estimated in the proportion that
it occupied of the total amount of urine in the tube. In other cases
the cold nitric acid test was used, and the amount estimated as plus,
and in various degrees of traces.
The following abbreviations are used:
Ad.--...-.... .Date of admission.
Alb.................Albumin in the urine.
Disc ............ Date of discharge.
E. A ........Estivo-autumnal.
Ft....... ........... aint.
Grs.. _... ........Grains.
Hb.............Hemoglobin estimation.
Hbg ..-....-. ..... Hemoglobinuria.
Ma-.... ....-Malaria.
Mal. Clin....Malaria, clinical.
Pra................Previous admissions.
Prf......................Previous attacks of fever.
Rbc.. ....:....Number of erythrocytes per cubic millimeter.
Res............. Length of residence in the Canal Zone.
T ....... ........ Tertian.
Tr......................Trace.
Wbc.. .............Number of leucocytes per cubic millimeter.
Z -,.... ...... OuncesA
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	Front Cover
	Title Page
	Letter of transmittal
	Introduction
	Main
	Appendices
	Back Cover

MILLISECOND	CLASS.METHOD	MESSAGE
0	sobekcm_page_globals.constructor
0	sobekcm_page_globals.constructor	Application State validated or built
0	sobekcm_database.verify_item_lookup_object
0	sobekcm_page_globals.constructor	Navigation Object created from URI query string
0	sobekcm_database.verify_item_lookup_object
0	sobekcm_page_globals.display_item	Retrieving item or group information
0	sobekcm_page_globals.get_entire_collection_hierarchy	Retrieving hierarchy information
0	sobekcm_assistant.get_entire_collection_hierarchy
0	cached_data_manager.retrieve_item_aggregation
0	cached_data_manager.retrieve_item_aggregation	Found item aggregation on local cache
0	item_aggregation_builder.get_item_aggregation	Found 'all' item aggregation in cache
0	system.web.ui.page.page_load (ufdc.page_load)
0	sobekcm_page_globals.constructor.on_page_load
0	html_echo_mainwriter.add_style_references	Adding style references to HTML
0	html_echo_mainwriter.add_text_to_page	Reading the text from the file and echoing back to the output stream
54	html_echo_mainwriter.add_text_to_page	Finished reading and writing the file