NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
66
organism ; but the trend of evidence is steadily in favour of a malarial, as against a
specific, origin, so that it seems to us reasonable to recognise the probability of its
being after all malarial.
Before reaching our final conclusions regarding the remoter causes which bring
about Black-water Fever, it is necessary to refer once more to the theory which
maintains this disease to be of a specific nature.
We have seen that no piroplasma-like organism can be found, either in the peri-
pheral, or visceral blood ; though in the parasitic hæmoglobinurias of animals large
numbers of these organisms are to be found in these situations : that nothing in the
peripheral or splenic blood suggests that a minute form of piroplasma is concerned :
that the examination of many hundreds of blood films from children and others
within the endemic area, and more careful search in the case of numbers of people
of the susceptible class, together with children and others living in direct association
with Black-water Fever cases or immediately around their neighbourhood, has like-
wise failed to disclose the existence of new parasitic forms.
In the face of these facts those who still maintain the specific nature of Black-
water Fever must do so apart from the analogy of piroplasmoses in animals, an
analogy which fails at the critical point. It appears to us idle to discuss in detail
the arguments for and against this contention. Those who assert Black-
water Fever to be specific must be prepared to assume the existence of an
organism distinct from the piroplasmata and a disease endemic like malaria but
not directly infectious nor epidemic like Yellow Fever. It must require even under
the most favourable conditions many months or several years' exposure to infection
for its inception, and possess the seasonal and local incidence of malaria and a
geographical distribution confined to countries and areas where intense malaria
occurs ; its manifestations must be invariably associated with coincident malarial
infection, and it must possess the power like malaria of lying dormant in the system
and of asserting its presence in subjects who have left the endemic area ; its attacks
must in the majority of cases bear a specific relation to quinine administration, and
their prevention by the systematic use of quinine must be explained (vide pro-
phylaxis, Part V) ; immunity to its action must be acquired not by recovery from
attacks, which instead seem to render the subject more susceptible, but be
associated with the occurrence of immunity to malaria. It must in fact always
exist side by side and be inseparable from malaria and yet be distinct.
The probabilities of such an hypothesis being the true explanation appear to us
to be extremely remote.
67
PART III.
BLACK-WATER FEVER DUE TO THE ACTION OF A SPECIAL
HÆMOLYSIN.
CHAPTER I.
CLINICAL AND PATHOLOGICAL OBSERVATIONS BEARING UPON THE NATURE OF THE
PROCESS CONCERNED IN BLACK-WATER FEVER.
The features of an attack of Black-water Fever have been broadly outlined
in the introduction ; but it is necessary to consider the disease in greater detail.
I . — S Y M P T O M A T O L O G Y .
Variations in the general character of an attack. —An attack of Black-water
Fever as a rule pursues a very definite course, the hæmoglobinuria usually lasting
two or three days. But, especially in the case of Bengali babus, the disease ex-
hibits considerable variations in the degree of intensity of the process, all grada-
tions between attacks of great severity and those of the mildest character being
s een. In a case of this latter type the temperature never rose above 100° F. and in
many cases the hæmoglobinuria has lasted only twelve hours or less.
The two cases among European children of which we have particulars were
both extremely mild (vide cases XIII and 67), the hæmoglobinuria being of the
most transient nature and accompanied by very few symptoms.
Relapses coming on within from one to ten days or more are very common.
They are often of equal duration with the first attack, but generally milder in
character. They appear to follow chiefly in the more severe cases.
Temperature.—With the onset of the rigor that ushers in the Black-water
Fever there is a rise of temperature to 105° or thereabouts. Taken as a whole
the curve for an attack usually extends over about forty-eight hours, falling more
or less gradually towards normal.
But the temperature does not necessarily cease with the hæmoglobinuria
; v e r y c o m m o n l y t h e r e i s e v e n s e v e r e a n d c o n t i n u e d f e v e r l a s t i n g m a n y d a y s a f t e r
the hæmoglobinuria is over, a condition termed by Daniels (24) " post-
hæmoglobinuric " fever. This has been noticeable in some degree in most of our
cases. It is doubtful if it is malarial in nature, as it usually does not yield to quinine
nor are parasites usually to be found. In mild cases the temperature does not rise
above 100° or 102°, as in one case recorded by us : Case VI. Afebrile temperatures
have also sometimes been recorded.
68
When a relapse occurs the temperature again rises and the history of the
first attack is repeated.
Splenic enlargement.—In all our cases there has been splenic enlargement.
In some cases there was a history of this condition being present before the attack,
and in two the spleen reached nearly to the umbilicus before the onset of the
Black-water Fever. In one case this organ was seen to enlarge very markedly
during the paroxysm ; and in several others we have seen a reduction in the size of the
spleen take place (vide cases) as convalescence set in. In none of our cases has
splenic enlargement been absent.
Epigastric pain.—This very characteristic symptom is practically always
present in greater or less degree. Pain is complained of not over the spleen and
liver, but over the pit of the stomach and behind the sternum. If there is a return
of the hæmoglobinuria, there is generally a return of the pain. The renal pain
mentioned by some authors has not been remarked by us.
Increased pulse tension.—There is, with the onset of hæmoglobinuria, an
almost invariable increase in the pulse tension, which lessens as the paroxysm
abates. With a recurrence of the hæmoglobinuria the high tension pulse
returns.
Icterus.—Icterus is rarely present until a certain time has elapsed after the
onset of the hæmoglobinuria. In some cases it may be confined to a slight yellow
tint of the conjunctivæ. It is associated with the existence of an intense
yellow colouring of the serum ; but not with the presence of bile salts in the urine.
The icterus of Black-water Fever is generally very transient, lasting only a few
days after the cessation of the blood destruction ; but sometimes a slight bronzing
of the skin may remain for a long period.
I I . — U R I N E C H A N G E S .
Hæmoglobinuria.—The first urine passed may be light red or quite dark.
In the latter case it often shows on the removal of the hæmoglobin by acidifying
and boiling a considerable amount of dark brownish pigment. The same brownish
yellow colour is sometimes seen in the urine passed at the height of the attack.
Later on, clearing by acidifying and boiling shows that this is not present, the
urine resembling ordinary high coloured febrile urine.
When fresh urine passed early in the disease is examined by the spectroscope,
the bands of oxy-hæmoglobin are well marked, and can easily be reduced and re-
instated by shaking ; but the band in the red indicative of met-hæmoglobin is
often very faint, and only becomes pronounced after the urine has remained standing
69
for some time. The condition in Black-water Fever seems therefore to be essentially
an oxy-hæmoglobinuria the formation of met-hæmoglobin being to a large degree
a secondary process.
The amount of urine passed varies greatly ; some cases exhibit polyuria, in
Others the amount of the urine is normal or diminished ; in some suppression
occurs very early in the disease. In the most typical condition dark urine is
passed at short intervals during the first twenty-four hours, the total amount
being in excess of the normal.
The amount of hæmoglobin passed, calculated in terms of blood necessary to
produce the colouring matter, is less than would at first sight be expected.
An estimation of the amount of hæmoglobin passed in two typical cases showing
as follows :—
Case XX.
Quantity.
Percentage Hæ-
moglobin in terms
of blood.
Amount of blood
represented.
c.c.
Urine passed prior to—
Per cent.
11 A.M., 16th January 1308
..
.. ..
60
10.
6 .
11 P.M.
,,
. .
..
. .
. .
..
750
6.6
5 0 .
9 A.M., 17th January 1908..
.. ..
550
6.6
37.
7 P.M.
"
..
..
..
..
550
6 6
37.
12 P.M.,
,,
..
..
..
..
350
6.6
2 3 .
12-A.M., 18th January 1908
..
..
..
450
5.
22.5
12-50 P.M.
„
..
..
..
..
300
2.5
8 .
Total quantity of blood represented ..
..
..
..
.. 1 8 3 . 5
c . c .
Case XXI.
Quantity.
Percentage Hæ-
moglobin in
terms of blood.
Amount of blood
represented.
Urine passed to—
Per cent.
4 A.m., 22-2-08
..
..
..
..
..
310
2
62.
7 A.M.-8-30 A.M. ..
.. .. .. ..
630
3
18.9
10 A.M.
..
.
.
..
.
.
..
..
280
5
14.2
1 P.M.—2 P.M.
..
.. .. .. ..
570
5
2 8 . 5
227 H. D, S
70
Case XXI.
Quantity.
Percentage Hæmoglobin in
terms
of blood.
Amount of
blood
represented.
per cent.
3 P.M.—4-30 P.M. ..
..
..
..
..
510
3
15.3
6 P.M.
..
..
..
..
..
..
280
3
8.4
7 P.M.—9-30 P.M. ..
..
..
..
..
650
3
19.5
10-30—6 A.M. 23-2-08. ..
..
..
..
510
3
15.3
7 A.M.
..
..
..
..
..
310
2
6.2
9 A.M.
..
..
..
..
..
..
300
5
1.5
Total quantity of blood represented ..
..
..
..
..
133.8 c.c.
As in an ordinary case the red cells are reduced to at least half their normal
number the amount of hæmoglobin passed in the urine can represent but a portion
of the full destruction. Yet if this amount of approximately 200 c. c. of blood
were dissolved in the total plasma it should make a solution of at least 10 per cent.
This we shall see is much greater than was the hæmoglobinæmia actually present
in any of our cases at any given time. Such a want of relation most probably
indicates that excretion is more or less keeping pace with the liberation of free
Hæmoglobin, and may explain observations wherein the hæmoglobinæmia has
not been noted.
Urobilinuria.—Throughout the attack urobilinuria is present. In estimating
approximately the amount of this substance we employed dilution of the zinc-
urobilin as produced in the qualitative test, until the bands could no longer be
determined with certainty. In cases in which the quantities were estimated after
boiling the acidulated urine to remove the hæmoglobin, the amount of urobilin
seemed as great in quantity in the first samples passed as later when hæmoglobin-
uria had ceased, the bands being easily visible on twenty-fold, but not on further
dilution.
For many days after the hæmoglobinuria has ceased, although hæmoglobin
may not be demonstrable in the serum, urobilinuria continues. It does not there-
fore seem to be dependent upon the actual presence of hæmoglobin in the plasma.
In several cases of fever (malarial) where it was doubtful whether there had
been hæmoglobinuria, we were able to detect the presence of urobilin in the urine
71
in quantity as large as that found in Black-water Fever. We do not know enough
to state what relation to the Black-water Fever process this condition may bear.
A l b u m i n u r i a . — A l b u m e n i s o f c o u r s e p r e s e n t i n l a r g e a m o u n t s w h e n t h e u r i n e
contains hæmoglobin. A considerable quantity is also present for a certain time
after the execretion of hæmoglobinuria has ceased. Some interest attaches
to the question of whether the passage of albumen is limited to that associated
with the hæmoglobin or passed as a result of kidney changes. Our observations
in this respect are limited, but the following example (case XX) shows a remark-
able proportion between the percentage of hæmoglobin and the amount of albumen
as estimated by Esbach's process :—
Case XX.
Percentage
h æ m o g l o b i n
in terms of blood
(normal).
Albumen in
grms. per litre
(Esbach).
Specific
g r a v i t y .
Per cent.
First urine passed 16th January 1908 ..
..
10.
1.05
1018
Urine up to 11 p.m. ..
. .
. .
. .
6.6
.6
1018
Urine up to 9 A.M., 17th January 1908 ..
. .
6.6
.5
1017
, ,
, , 7 P.m.
. .
. .
. .
. .
6.6
.7
1018
, ,
, , 12 P.M.
. .
. .
. .
. .
6.6
.7
1020
, ,
„ 12 A.M., 18th January 1908
. .
. .
.5
.5
1018
, , p a s s e d a t 1 2 - 5 0
. .
. .
. .
2.5
.3
1020
Sediment.—The sediment of the hæmoglobinous urine is of some significance.
There is usually a characteristic flocculent deposit becoming more abundant as
t h e h æ m o g l o b i n u r i a c o n t i n u e s a n d g i v i n g p l a c e e v e n t u a l l y e v e n b e f o r e t h i s c e a s e s
to a heavy deposit of febrile urates. Microscopical examination of the first urine
shows among amorphous debris an occasional granular cell, and these later increase
in number. Granular casts of a characteristic nature (so called hæmoglobin
casts) are present ; but in many cases at the height of the hæmoglobinuria the urine
deposit contains mainly isolated degenerated granular cells, without doubt
derived from the kidney.
Hœmosozic value of the urine.— I f t h e u r i n e w e r e h y p o t o n i c , a n y h æ m o r r h a g e
into the urinary passages would give rise to a condition resembling hæmoglobinuria;
and hæmorrhage into the kidney has been advanced as explanatory of the hæmo-
globinuria of Black-water Fever [Pellerin (49)]. We have therefore in several
72
cases estimated the hæmosozic value of the urine, the result in terms of sodium
chloride being as follows :—
Case XIX—
Per cent.
First urine passed
. .
. .
. .
. .
. .
. . 1.25
Urine toward end of of attack
. .
. .
. .
. .
. .
.83
Case XXVII
—
First urine passed
. .
. .
. .
. .
. .
. .
1.28
The hæmosozic value of the urine therefore even when hæmoglobinuria is
present, is far above that at which red blood corpuscles are hæmolysed ; and the
urine could not on account of its osmotic effect dissolve red cells.
Agglutinating and globulicidal effect of urine. — I n c a s e s X X V I a n d X X V I I
the effect of the urine upon the patient's corpuscles and upon normal corpuscles
was tried; but no agglutination or recognisable hæmolytic effect was produced.
The addition of normal serum (complement) to the mixture of urine and red
cells led to no further result.
Presence of preservative bodies in the urine.— A r e m a r k a b l e f e a t u r e o f t h e u r i n e
of Black-water Fever, is that it often shows little or no tendency to putrefaction
and can be kept with but little change for a long period.
III.—BLOOD CHANGES.
Recorded observations upon the blood changes in Black-water Fever are very
meagre and do not throw much light upon the nature of the process.
The relation that hæmoglobinæmia bears to the disease is still uncertain,
and recorded observations upon the changes in the red cells and leucocytes are
vague and couched in very general terms, most observers having confined them-
selves to noting the presence or absence of malarial parasites and pigment,
estimating the loss of hæmoglobin and red cells, and recording the numerical
changes occurring among the white blood corpuscles, both relative and absolute.
Especially are observations made at a very early stage, and those relating
to different phases of the attack needed. For it is obvious that observations upon
blood taken after the cessation of the hæmoglobinuria, although interesting as
regards the evidence of the occurrence of previous blood destruction, are unlikely
to give any indication of the process ; the same applies to cases seen so late that
one cannot be certain that the elimination of hæmoglobin by the kidneys may
not be the only active process.
73
Paying special attention to these points we have been able in several of our
cases to obtain blood, both peripheral and splenic, within a few hours of the onset,
and to follow out the changes from day to day.
Reduction in the number of red blood corpuscles.— T h e r e a r e o n l y t w o p o s s i b l e
sources of hæmoglobin in the body, namely, the red cells of the blood and the
muscles. The very obvious reduction in the number of the former in cases of
Black-water Fever enables us to say that the condition is due to the destruction of
the red blood corpuscles. This destruction is very marked and may proceed until
the number is less than 1,000,000 per c.m.
The reduction is quite obvious to the naked eye and in severe cases is suffi-
ciently well marked to introduce difficulties in the making of good blood films.
Hœmoglobinœmia.—In paroxysmal hœmoglobinuria the serum is generally
stated to be of a red colour. In Black-water Fever there is some doubt as to
whether this is necessarily the case ; and one of us with Dr. Stephens has recorded
cases where hæmoglobinæmia was not evident. The examination for hæmoglo-
b i n æ m i a i s g e n e r a l l y m a d e b y a l l o w i n g t h e b l o o d t o c l o t a n d t h e n e x a m i n i n g t h e
serum. But this method is open to grave fallacy; for we have not infrequently seen
rosy serum exuded from the clotted blood, when by placing the same blood in 5 per
cent. citrate of sodium solution and centrifuging, hæmoglobinæmia was not to be
detected. The red colour of the serum was due in these cases then not to hæmoglo-
bin present in the plasma during life but to changes which have taken place after
withdrawal from the body. ( Vide extra-vascular lysæmia, Part III, Chapter
III.) Examination of the blood in Black-water Fever has shown without excep-
tion the presence of true hæmoglobinæmia, demonstrated by the centrifuging of
blood received into hypertonic citrate solution ; the serum after clotting has also
always shown hæmoglobin provided the hæmoglobinuria was still in progress, but
in both cases the amount was usually small and more or less masked by the ex-
traordinarily intense yellow colouration of the serum. We have only once (case
XXVII) seen hæmoglobin so great in amount as to give a rosy colour to the serum
and its presence is generally only indicated by an orange tint.
Owing to this fact it is difficult to estimate with accuracy the amount of hæmo-
globin present ; but in most cases seen by us it does not seem to have been more
than the equivalent of a 1 per cent. solution of normal blood.
In the one case in which the serum was rosy red the percentage of hæmoglo-
bin was as high as a 3.75 per cent solution of blood.
The amount of hæmoglobinæmia in the serum exuded from the clot has not
in our cases exceeded the amount shown by centrifuging the citrated blood. In
227 H. D.
74
none of our cases have we seen solution of the clot as described by Hayem in a
case of Paroxysmal Hæmoglobinuria ; it was on the contrary very noticeable in
all our cases that however long the clot was left in contact with the serum short
of putrefactive changes, no solution of the red cells took place. The amount of
hæmoglobinæmia and its relation to hæmoglobinuria in our cases has been as
follows :—
Case XIX (mild attack)
(1) Ten hours after onset serum a deep yellow. A trace of hæmo-
globin shown by the spectroscope. Citrated blood centrifuged shows
a trace of hæmoglobin by spectroscope.
(2)
Next morning hæmoglobinuria has ceased. Serum lighter yellow in
colour. Presence of hæmoglobin in serum doubtful.
Case XX (severe attack)—
(1) Seven hours after first rigor serum a deep orange colour. Hæmoglobin
tint can be detected with the naked eye. Citrated blood centrifuged
shows a similar amount of hæmoglobinæmia.
(2) Next day, serum markedly yellow with orange tint, hæmoglobinæmia
present.
(3) Day of cessation of hæmoglobinuria, hæmoglobin not demonstrable
in the serum or plasma.
Case XXI (severe case)—
Six hours after onset. Serum markedly yellow with orange tint. Spec-
troscopically shows well marked bands of oxyhæmoglobin. Citrated
blood centrifuged also shows hæmoglobinæmia marked by yellow
tint.
Case XXIV (severe case)—
(1) Fourth day, hæmoglobinuria nearly over, suppression threatening.
Serum shows a characteristic orange tint and bands of oxyhæmoglobin.
(2) Fifth day, serum yellow, no hæmoglobinæmia.
Case XXVI (severe case)—
Second day. Hæmoglobinuria in progress, serum rosy red. Citrated
blood centrifuged shows same degree of hæmoglobinæmia. Cal-
culation of amount of hæmoglobinæmia by comparison of tint with
laked blood, diluted to various degrees, gave 3.75 per cent. hæmo-
globin.
75
Increased coagulability.— T h o u g h
w e h a v e m a d e n o a c c u r a t e e s t i m a t i o n o f
the coagulation rate, we have in a number of cases noted a distinct increase in
the rate of coagulation early in the disease. Later on this is less noticeable and
there may be delayed coagulation. In one case it was sufficient to cause buffy
coat clot.
IV.—CHANGES IN THE RED BLOOD CORPUSCLES.
Some of the earlier descriptions of the blood in Black-water Fever, remark upon
the profound alterations in the shape and condition of the red cells. There can be
little doubt that some of these descriptions referred to artifects ; for as has since been
frequently stated the general appearance of the blood in Black-water Fever is that
of normal blood. The very normal appearance of the blood cells in a disease so
obviously due to an acute blood destruction is one of the striking features of the pa-
thological picture.
During the early stage of the disease it is often only after prolonged scrutiny
and systematic examination of a number of microscopic fields that we can
appreciate the few changes which otherwise may easily pass unnoticed.
In films taken within two hours of the onset of a fairly severe attack we failed
to detect on the most careful search any abnormality whatever ; nor was there a
single " shadow " found in fifty microscopic fields.
Later in the attack certain changes are generally to be made out ; but they are
by no means so conspicuous as one might be led to expect. Thus in the blood taken
about four hours after the onset of a severe attack we found, among approximate-
ly 20,000 red cells, 150 large shadow corpuscles, 129 small shadows, and 16 markedly
anæmic cells. After the second or third day the blood changes are much more
obvious and they often reach a maximum when polychromasia of a marked degree
is established. It is these later changes, almost certainly regenerative in nature,
which have been emphasized by most observers.
We shall for the sake of clearness differentiate the early changes from these
later ones, which are usually even more marked in convalescene than during the
continuance of the disease.
Early changes.
Size of the red cells.—In order to ascertain whether m spite of the perfectly
normal appearance of the blood cells to ordinary microscopic examination, there
might be some changes found on actual measurement of the cells, a series of
observations were made on normal and abnormal bloods, including that of Black-
water Fever.