NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
177
CHAPTER IV.
THE NATURE OF THE BLACK-WATER FEVER PROCESS.
All our researches point to Black-water Fever being simply the effect of poison-
ing by a hæmolysin.
Nor does it seem to us that this hæmolysin poisoning should be conceived
of as some vague process spoken of without recognition of the method of action of
these poisons.
We have already seen that in Black-water Fever the blood destruction is
mainly of that nature to which we have given the name lysæmia.
It is not simply the action of a hæmolysin but a hæmolysin acting under special
conditions. The fact that in Black-water Fever the hæmolysin has not been
demonstrated, is for reasons we have shown not remarkable. For in the case
of dogs actually injected with hæmolytic serum it is quite impossible with the
knowledge we possess to demonstrate, apart from its effects, the presence of the
substance (hæmolysin) that we have injected ; though in vitro its presence is
easily demonstrable.
As regards the hæmoglobinuria in Black-water Fever we have seen that to
look upon the presence of hæmoglobin in the urine as an indication of the amount
of blood destruction is quite misleading ; that hæmoglobinæmia does not neces-
sarily result from even the greatest amount of blood destruction ; that in malaria
although an enormous amount of blood may be destroyed this is mainly due to
the corpuscles being retained and broken down in the organs and not to their
solution in the plasma ; and that for hæmoglobinuria to ensue only a trace of
hæmoglobinæmia is necessary. We have seen also that this hæmoglobinæmia is a
superimposed condition of blood destruction, characterised by solution of the red
cells or lysæmia ; that this is not due to osmotic variations in the plasma, to changes
in the resistance of the red cells to salt solutions or to invasion of these cells by any
parasite. Coming to broader issues we have seen that Black-water Fever results
from a condition induced by repeated attacks or infections by malaria ; that it is
precipitated by an acute attack of malaria, especially when under certain conditions
this is associated with the administration of quinine.
We have seen that quinine in itself is innocuous and cannot have such an
effect on a subject not previously prepared; that the consistent use of the remedy
by a community may even diminish the incidence of Black-water Fever by reduc-
ing the liability to malarial infection.
227 H.D.
2Y
178
The production of the hæmolysin we have seen is in some way the result of
malaria, and it is generally considered by those who take the malarial view that
it is in the form of a toxin derived from the malarial parasite.
Such a toxin has never been demonstrated and the fever and other symptoms
of malaria are explicable without assuming its presence. Also if such a toxin
were the cause we should not expect length of residence to play so important
a part in the ætiology of the disease, for there seems no reason why the action of
quinine in a severe attack of malaria, in a new-comer, should not bring about the
liberation of a hæmolysin from the malarial parasite, with resulting Black-water
Fever ; the length of residence suggests changes produced in the body itself.
It is desirable to consider what are the possible changes that long-continued
malaria might bring about. In the injection of goat's blood into goats for short
periods Ehrlich was once able to demonstrate an, autolysin.
It is by no means improbable that malaria which gives rise to periodical
destruction of red cells might have the same effect in man. No other patholo-
gical condition known to us is so likely as malaria to give rise to an autolysin.
It, more than any other disease or experimental condition, demands of the
organism the repeated destruction and the absorption of its own red cells.
We have seen that there is a close resemblance between. Black-water Fever
and paroxysmal hæmoglobinuria ; both are conditions of unstable equilibrium,
the one apparently natural to the subject the other induced; in both the exciting
causes are such as under normal conditions produce no effect.
In paroxysmal hæmoglobinuria mere local cold is sufficient to cause hæmo
- g l o b i n u r i a . T h i s i s a n i n d i r e c t a c t i o n , f o r c o l d a c t i n g u p o n b l o o d h a s n o s u c h
effect ; and the hæmolysin responsible for the blood destruction must therefore
be thrown out by the body cells in response to stimulation.
Such considerations suggest reasons why the malignant tertian parasite
should be chiefly concerned in Black-water Fever. For it is in infections by the
malignant tertian parasite that we find the organs most actively engaged in holding
up the infected red cells, the very perniciousness of infections by this parasite
being suggestively bound up with such an action.
If we conceive of the hæmolysins being derived not from the parasite but
thrown out as a result of the constant phagccytosis of red cells, we shall also
understand better why it is that the apparently robust should suffer. Able to
make good the loss of his red cells the actual infection by the parasites affects
the well-fed adult European or better class native but moderately and the very
179
power of reaction which we know to be associated with healthy rather than
diseased conditions may be his undoing.
If hæmolysins are formed against the blood there seems no agent so likely to
effect this as the endothelium which everywhere is the tissue in contact with the
blood and is largely concerned in regenerative and phagocytic functions.
This view receives support on a consideration of certain conditions associated
with paroxysmal hæmolglobinuria, Raynaud's disease in particular, where local
vascular spasm is connected with the occurrence of the disease.
In this connection malaria again comes prominently to the fore as a factor
likely to have a marked effect upon the vascular endothelium. For months and
years this tissue has to experience the constant association with altered and broken
down red cells and parasites, with consequent stimulation to active phagocytosis
of these bodies.
Our work shows, however, that whatever the origin of the hæmolysin (h
æ- molytic amboceptor) may be we have still to ascertain why the lysæmic condi-
tion results. If we consider the possibility of its being due to the sudden libera-
tion of complement in the living body many otherwise inexplicable facts become
readily understandable, but such an hypothesis at present rests upon no actual
data.
In few diseases do we know the ultimate working of the morbid process, so
that because we do not yet know the whole mechanism of Black-water Fever it
does not follow that we are totally ignorant of the nature and origin of the disease.
Our researches we think have helped to make this nature of the disease clearer
than it has hitherto been. We have as a result of our observations come to a
truer conception of the conditions under which the hæmoglobinuria of Black-
water Fever occurs, than has previously been possible and this conception of the
disease is a strong incentive to further experimental work
181
PART V.
PROPHYLAXIS AND TREATMENT OP BLACK-WATER FEVER.
We have still to discuss what steps are possible in regard to the prophylaxis
of Black-water Fever and in regard to the treatment of the condition when it has
once arisen.
Prophylaxis.
If our conclusions as to the origin of Black-water Fever be correct the
prophylaxis of the condition is simply the prevention as far as possible of malarial
infection, and the prompt and efficient treatment of this disease, with the view
to prevent the occurrence of relapses.
It would be foreign to our purpose to enter fully into the large question of
anti-malarial sanitation in this memoir, but it will not be without interest to
ascertain as far as possible whether in actual practice there are any examples
of a reduction in the incidence of Black-water Fever due to the adoption of
prophylactic measures directed against malaria, especially to the active pushing
of quinine, the very drug which is generally looked upon as largely responsible
for the occurrence of Black-water Fever.
According to Deaderick (92) such a reduction is reported by Mercier in
German East Africa, by Ziemann in the Kameroons, by A. Plehn in Togo and
by Kohlbrugger in the Malay Archipelago.
Quinine prophylaxis, it is obvious, to be of any use must be effectively pushed.
In the Duars already a large proportion of the European population has
taken to the systematic use of quinine. The result has so far been not only a
much reduced amount of malaria amongst those taking the precaution but a very
small number of cases of Black-water Fever in this community.
The only three cases which occurred among Europeans during the past twelve
months were among those who professed not to believe in quinine and only
took it when they felt unwell. Whether the explanation we have given be the
correct one will be shown in time.
Treatment.
It is not our intention to touch upon the ordinary palliative treatment of
Black-water Fever. Our object is to show that there are excellent reasons for
believing that good results may be expected from serum therapy.
We have shown that a toxin derived from the malarial parasite is an unlikely
cause of Black-water Fever and that the active agent is probably one derived
from auto-immunisation against the organism's own red cells.
227 H.D.
2z
182
The attempt to produce an anti-amboceptor against the cytophile group of a
hæmolysin which we are unable to isolate seems to us at present useless. It is
otherwise, however, as regards the production of an anti-complement or an anti-
amboceptor directed against the complementophile group. Ehrlich in his studies
upon complement has come to the conclusion that these exist in any serum in
great variety. Observations upon the absorption of complement show, however,
that in spite of this multiplicity, the whole of the complement in a serum may
be abstracted by a single type of amboceptor, provided that its cytophile group is
able to combine with a suitable receptor. The received explanation of these
apparently contradictory results has led to a further modification in the conception
of the amboceptor and complement. In a recent paper Ehrlich and Sachs (93)
conceive of the amboceptor as having a single specific cytophile group but a
large number of complementophile groups which, vary considerably in detail but
in their entirety represent a uniform complex. This complex is reproduced in all
amboceptors of the same serum.
Anti-amboceptors directed against the complementophile groups and obtain-
ed through immunisation with any particular amboceptor will act against all
amboceptors of the same animal species, no matter whether these amboceptors
are normally present in the serum or have been produced by immunisation.
Immunisation of small animals with human serum should offer no insurmount-
able difficulty, but until a considerable number of experiments have been car-
ried out it is not possible to say whether by such means we might be enabled to
produce an anti-amboceptor or anti-complement suitable for use in the treatment
of Black-water Fever.
That treatment on these lines is not chimerical is shown by the work of Widal
and Rostaine (62) on paroxysmal hæmoglobinuria, who made use of a serum
obtained by the immunisation of a rabbit against human serum. The administra-
tion of this serum to the subject of the paroxysmal hæmoglobinuria served
to counteract the effects of exposure to cold which previous to its use was invari-
ably followed by hæmoglobinuria.
In Black-water Fever we have a condition often lasting several days during
which the blood destruction steadily continues. To be able to check this
destruction early in the disease would be no small achievement and enormously
increase the chance of a favourable termination.
The feasibility of these suggestions, however, can only be shown by further
experiment.
183
PART VI.
APPENDIX.
RECORD OF CASES INVESTIGATED.
Case I.—Chengmari Garden. August 1907.
Bengali Babu.
Seen on 3rd day. Hæmoglobinuria over. No malarial parasites. Scanty pig-
mented leucocytes. Decolourised corpuscles in cells of monornuclear and macrophage
type. Leucocytes.
Polymorphonuclears
. .
..
. .
..
57%
Large mononuclears
. .
. .
..
..
24.9%
Small mononuclears
..
. .
..
..
16.6%
Eosinophile
. .
..
..
. .
1 5%
Macrophage type conspicuous.
Case II.—Chengmari Garden, August 1907.
Uriah mall. Age 35.
Native country.—Cuttack.
Length of residence in Duars. —3 years.
History.—Had suffered from fever and enlarged spleen. Was treated for about a month,
but has had no treatment for last two months.
On 28th July got high temperature with diarrhœa, bloody urine and vomiting
of green bile.
Seen by Dr. Babu on 30th July. He then had suppression of urine. Died 31st
July.
Autopsy.—Liver very congested, enlarged, granular and friable.
Spleen much enlarged, soft, tumid, and greatly congested.
Kidneys greatly enlarged and dark purple in colour.
Much malarial pigment in macrophages and mononuclear cells of liver and spleen.
Many macrophages and large mononuclear cells in the liver loaded with greenish
pigment. Liver cells themselves contain similar greenish pigment. Sections
shew many engulfed red cells lying in large macrophages.
Case III.—Meen Glas Garden. July 1907.
Babu's servant.
History.—Came on 26th July to Meen Glas looking for work. Was obviously very
ill and was sent by the manager to the Dr. Babu. Was given 10 grains of
quinine, mid-day, 27th July. When seen that night he had high fever, vomiting
and some jaundice. Urine was then seen to be black. Died 28th July.
184
Autopsy.—Made by Dr. Babu who supplied us with portions of the liver, spleen and
kidneys.
In films macrophages and mononuclear cells are seen loaded with malignant ter-
tian pigment scattered and in blocks. In sections immense numbers of
engulfed red cells are seen in the macrophages of the spleen and liver but especially
in the former, red cells are also seen in small cells lying in the venous sinuses of
the splenic pulp. Almost every macrophage in the spleen contain also one or
more nuclear masses which seem to be engulfed and altered portions of leuco-
cytes these masses stain very intensely but often shew a somewhat clear
central or eccentrally placed space. Yellow or greenish-yellow pigment is seen
especially in large macrophages in the hepatic capillaries and in the liver cells.
The hepatic veins contain much granular matter.
Case IV.—Chalouni garden. August 1907.
Dhoby. Age 21.
Native country.—Muzuffarpur.
Length of residence in Duars. —Nine months.
History. —Was noted to be suffering much from fever by Dr. Babu in April. His
spleen was found enlarged in June, but may have been so earlier.
On 11 th August 1907.—Complained of fever. Was given quinine, but it is uncertain
if he took this.
On 15th August 1907.—Again complained of an attack of fever, and is stated to have
swallowed two tabloids of 5 grains each quinine sulphate at 9-30 A.M., but to
have vomited these undissolved at 10 A.M. He was noted on this morning to be
very anæmic, reduced, and jaundiced. At 6 P.M. the urine brought to the Dr.
Babu was dark-red. He states that the first red urine was passed at 2 P.M.
7 P.M.—Temperature 104.8. Pulse 174. Respirations 44. Spleen and liver
enlarged.
12 MID-NIGHT.—Temperature 106. Pulse 182. Respirations 56. Thirst.—Vomit-
ing. Later unconscious.
5 A. M.—Temperature 100. Pulse 96. Respirations 26. Blood showed many
pigmented leucocytes. No parasites on first examination, but one small
malignant tertian accole form found subsequently.
17th August 1907.—Red cells 942,000. Hæmoglobin 15%. A few pigmented leuco-
cytes still present.
Blood —
16th August 1907.—Leucocytes counted 700.
Polymorphonuclears
. .
. .
. .
..
59%.
Large mononuclears
. .
. .
. .
. .
20.5%
Small mononuclear
Eosinophiles
..
. .
. .
..
. .
..
. .
..
20%
. 5 %
Macrophage type abundant.
185
Case V. —Meen Glas garden. August 1907.
Bengali Babu.
Length of residence in Duars.—Twenty years.
History.—Has been 7 years at Meen Glas. Had lately been having fever and was getting
10 grains quinine a week for this. Ten days prior to attack had fever.
19th August 1907.—Was given 10 grains quinine ; the same day he had a slight
rigor, vomiting, and passed dark urine which contained hæmoglobin. He
refused to believe he was suffering from Black-water Fever because his urine was
not exactly " the colour of ink."
Seen by us within a few hours of the onset of the attack. Examination of his
blood showed a few malignant tertian rings and many leucocytes showing includ-
ed red cell shadows. Twelve hours later the number of parasites was much
reduced.
On the day following the attack no parasites were found. Hæmoglobin was 44%.
Red cells 2,460,000.
Ten days later he had a malarial attack with malignant tertian parasites which was
successfully treated with quinine.
Conditions under which the case occurred. The patients house was close to ex-
tensive coolie lines. For some months his children had been living with him.
Both were infected, one with maligant tertian and one with simple tertian para-
sites.
Blood
—
19 th August 1907.—Leucocytes counted 500.
Polymorphonuclears ..
. .
..
..
..
49.7%
Large mononuclears
.. .. .. .. ..
26.3%
Small mononuclears ..
.. .. .. ..
23.8%
Eosinophiles
.. .. ..
..
..
.2%
4 cells containing shadow corpuscles. 48 pigmented cells of which about
one-third are small cells resembling small mononuclear leucocytes.
One small malignant ring parasite.
17th August 1907.—Leucocytes counted 550.
Polymorphonuclears ..
.. .. .. ..
54.3%
Large mononuclears
.. .. .. ..
..
27.4%
Small mononuclears
.. .. .. .. ..
18.3%
Eosinophiles
.. .. .. .. ..
0
4 cells containing shadow corpuscles.
87 pigmented cells.
No parasites.
227 H. D.
3A
186
18th August 1907.—Leucocytes counted 600.
Polymorphonuclears ..
. .
. .
. .
.. 55.6%
Large mononuclears ..
. .
. .
..
. . 21.6%
Small mononuclears ..
. .
. .
..
. . 22.8%
Eosinophiles.
..
. .
. .
..
. .
0
A few cells with included shadow corpuscles and a few pigmented leucocytes
only.
19 th August 1907.—Leucocytes counted 600.
Polymorphonuclears ..
. .
. .
. .
. .
53.6%
Large mononuclears ..
..
..
. .
. .
16.6%
Small mononuclears ..
. .
. .
..
. .
2 4%
Eosinophiles
..
. .
. .
. .
. .
5.6%
A few pigmented cells. Many small mononuclears show an accessory nuclear
(?) mass.
Case VI.—Meen Glas garden. August 1907.
Mohamedan bearer.
Native country. —North-West Provinces.
Length of residence in Duars. —Two years.
History. —States that he has had no fever this year though he previously had a good
deal. The manager states that he has had fever. Was taking 10 grains of quinine
a week.
Friday night had a little fever.
Saturday took his weekly dose of quinine. In the evening had a slight attack of fever
but did his work.
Sunday morning the Dr. Babu gave him 10 grains quinine. His master seeing
that he had fever gave him another 10 grains quinine. About mid-day he had a
slight chill and passed dark brown urine. containing hæmoglobin. Hæmoglobinuria
was over in less than twenty-four hours. Temperature never rose above 100.
Seen by us on the following day. Spleen enlarged. No malarial parasites. Four
pigmented leucocytes found in a count of 500 cells.
Was given quinine subsequently without return of condition.
Case VII.—Nagasuri bazaar. September 1907.
Bengali shopkeeper.
Length of residence in Duars.—Five years.
History.—Had been getting much fever and went to Calcutta for a change. On return-
ing was taken with fever in the train, and took 10 grains of quinine. A few hours
after passed dark urine.
187
Seen by us on the third day when hæmoglobinuria had ceased. Blood showed
pigmented leucocytes. A few red corpuscle shadows in leucocytes. A count of
500 leucocytes gave as follows :—
Polymorphonuclears .. ..
..
..
..
53.8%
Large mononuclears ..
..
..
..
..
28.5%
Small mononuclears ..
..
..
..
..
17.2%
Eosinophiles
.. .. .. .. .. ..
.2%
Case VII. —Bagracote garden. September 1907.
Bengali Babu.
History.—Was at . Chalouni for five years. Went to his country for several months,
and on returning to the Duars went to Bagracote, where he had been living for
three months before his attack. Whilst at Bagracote had a good deal of fever.
Had an attack of fever a fortnight before the Black-water Fever for which he had
taken quinine after the fever was over.
Since Friday had had fever. On Sunday for the first time took 15 grains quinine.
Quinine was taken 7 A.M. At 11 A.M. had a severe rigor, vomiting, and passed
very black urine.
Seen by us on first day. His blood taken within four hours of the onset showed
malignant tertian rings. Later on on the same day no parasites could be found.
During the attack the spleen underwent considerable enlargement and was very
painful. Epigastric pain very marked and vomiting very severe.
Hæmoglobin when first seen 70%. Following day it was 30% and subsequently at
the cessation of the Black-water Fever it was still lower.
Hæmoglobinuria ceased on the third day and the urine became clear. Suppression
of urine then supervened. Death followed. No autopsy.
Blood—
Malignant tertian parasites and a few pigmented leucocytes. A few red cell shadows
in mononuclear cells.
2nd day Leucocytes counted 500.
Polymorphonuclears ..
..
..
..
..
60.9%
Large mononuclears ..
.. .. .. ..
18.1%
Small mononuclears ..
..
..
.. ..
21.9%
Eosinophiles ..
..
..
.. .. ..
.1%
No parasites. Pigmented leucocytes and cells containing red blood corpuscles more
numerous than on first day.
1st day Leucocytes counted 500.
Polymorphonuclears ..
..
.. .. ..
45.7%
Large mononuclears ..
..
.. .. ..
23.1%
Small mononuclears ..
..
..
..
..
32.2%
Eosinophiles ..
..
..
..
.. ..
0
188
Condition under which attack occurred.—His wife and three children had been with him
for a fortnight. Two of the children were infected. The house abutted on coolie
lines. Twenty-five children whose bloods were examined were all infected, eleven
showing simple tertian, thirteen quartan, two malignant infections. Fifty yards
away a Paharia child was found whose blood was swarming with crescents.
Case VIII.—(a)
Dhoby.—Living within one hundred yards of where the last case occurred was noticed
to be suffering from anæmia with a temperature of a 100º F. Examination of
the blood showed nucleated red cells. No parasites were present in spite of
the fact that he had not been getting quinine. His urine contained albumen.
History.—He had come to the garden somewhat over a year ago. Up to ten days ago
he had been doing his work though on enquiry it was found that he had suffered
from frequent attacks of fever. A few days before he was seen by us he was
seized with shivering bilious vomiting and passed dark urine. He died two days
later.
Case VIII.—(b)
On the railway line in the garden a Paharia boy intensely anæmic and jaundiced was
found dead by the police.
Case IX.—Ranachera garden. September 1907.
China-man.
History.—Has had two previous attacks of Black-water Fever. Had fever for three days.
On the second day took quinine. The next day no quinine. The day following
at 10 A.M. took 10 grains quinine. At twelve noon had a slight rigor and
at 2 P.M. passed black urine.
Seen by us at 4 P.M. Spleen not palpable at this time. Five hours later the spleen was
two finger breadths below the costal margin. The next morning it was a hands-breadth
below. There was marked præcordial pain and breathlessness.
A single small malignant ring found after a long search and few pigmented parasites.
A count of 500 showed :—
Polymorphonuclears
. .
. .
. .
. .
. .
66.3%
Large mononuclears
. .
. .
. .
. .
. .
27.8%
Small mononuclears
. .
Eosinophiles
. .
. .
. .
..
. .
..
. .
. .
. .
4.7%
1.2%
Second day.—Hgbn. 55 per cent. Red cells 2,560,000. White cells 8,690.
Hæmoglobinuria continued for three days followed by fever for about a week. After
an apyretic period more fever occurred, but no parasites could be found at this time. Quinine
also had no effect on this fever. After eight or nine days during which he was still getting
f ever he went to Calcutta.