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The definition of blackwater fever
T H E DEFINITION OF B L £ C K W A T E R F E V E R . BY J. Oo W A K E L I N BARR&TT, M.D., D.SC. (LOND.)
The primary requirement which the definition of a morbid condition should fulfil is that it should enumerate the essential features of the condition in question. The extent to which such definition is possible is determined by the progress of pathology, so that, as will be seen by passing in review old text-books, definitions are of slow growth~ becoming more circumscribed and more complete as knowledge advances. The conception of a morbid entity is moreover in part natural, in part artificial. Finally, definitions, which are the outcome of mental operations, are peculiarly liable to be affected by that merely human failing, slovenliness of thought. A study of the definitions of blackwater fever which are to be found in standard text-books on tropical medicine, is instructive in so far as, on the one hand, it exhibits the failure of such definitions to include the essential characters of this condition, as at present known, and, on t h e other hand, it emphasises the diffi° culty of fixing the connotation of a term, when the available data are imperfect. As illustrations of the definitions which are ~o be given by leading writers on tropical medicine the following may be selected. STEPHENS* defines blackwater • ALLBUTT ~; ROLLESTON'S S y s t e m of Medicine, London, 1907, Vol. II., P a r t 2, p. 289, Art. B l a c k w a t e r Fever.
392 fever kind,
TEE DEFINETIOP?OF BLACKWATER Fevers a8 “a which
fever, generally believed to be malarial in is accompanied by the presence of blood MARCHIAFAVA and BIGNAMI" pigment in the urine.” avoid the term “ blackwater fever” and replace it by 6~malarial haemoglobinuria,” which is defined as follows : “The hamoglobinuric attack is a syndrome which is encountered not rarely, especially in hot climates, in the course of a malarial infection. The chief symptom of the attack is the emission of urine containing albumin and haemoglobin in greater or lesser quantity.” ZIEMANN t defines blackwater fever as “ an acute erythrocytolysis during or after malaria,” with the proviso that an immediately. exciting cause, usually quinine intoxication, is also an essential factor in its production. Exception may be taken to the last definition on the ground that it confuses two different terms, since it may be taken to imply that fever and cytolysis are synonymous. The first-named writer, on the contrary, defines blackwater fever as a fever ; this, however, is at the present time an anachronism, fever no longer occupying so prominent a place in symptomatology as it formerly did ; and viewing the matter from a purely psychological standpoint, as a matter of fact, most of those who use the term blackwater fever disregard its literal meaning, and have in their minds generally haemoglobinuria as the characteristic feature of this condition. The further objection may be raised that none of the above definitions enumerate more than a few of the conditions which, in the present state of our knowledge, *Twentieth Century p. 483, Art. Malarial f&fENSE’S
558
and 566.
Handbuch
Practice OPMedicine, London, 1900,Vol.
XIX.,
Hamoglobinuria. der
Tropenkrankheiten,
Leipzig,
1906,
B.
3,
THE DEFINITION OF BLACKWATER FEVER.
393
may be regarded as the principal and essential features of blackwater fever,* These are : 1. The appearance of h~emoglobinuria. (Incidentally it may be 'observed that the necessary coexistence of albuminuria has not been established). 2. The coexistence of hmmoglobinsemia, which determines the appearance of hmmoglobinuria. 3. The absence of hsemolysinsemia. 4.
The previous administration of quinine.
5. The association with malaria. As subsidiary characters of the disease may be enumerated: the paroxysmal character of the attacks, which are not unfrequently repeated, relapses being common, and the rise of temperature. As a provisional definition based upon and including the above data the following may be suggested: Blackwater fever is the term applied to an attack of hsemoglobinuria, occurring in malarial subjects, dependent upon hsemoglobinsemia, unaccompanied with hsemolysin~emia, and following upon the administration of quinine. The attack is paroxysmal in character, is not uncommonly repeated more than once, and is attended with a rise of temperature. This definition is, however, merely a provisional one. As knowledge advances it will be augmented and varied. Up to the present the internal mechanism of production of blackwater fever has been only in part investigated, some of the earlier stages of the process being still unknown. Thus while it is known that the hsemoglobinuria is dependent upon hmmoglobin~emia, and that ~Cp. ,.]-. O. WAKELIN BARRATT a n d W. YORKE. A.n I n v e s t i g a t i o n i n t o t h e M e c h a n i s m of P r o d u c t i o n of B l a c k w a t e r . A n n a l s of Tropical ]~edicine a n d P a r a s i t o l o g y , 1 9 0 9 , Vol. III., p. 1.
394
~HE DEFINITION OF B:hACKWATER FEVEI~.
the latter is not due to h~emolysinsemia, yet it is merely a matter of inference that the haemoglobinaemia is due to laking of red cells, direct proof being strictly speaking wanting; so that at present it is not altogether admissible to introduce the term erythrocytolysis into the definition of blackwater fever, as is done in the third definition given above, As further illustrations of the present limitations of our knowledge of blackwater fever may be taken the relation of quinine and of malaria to blackwater fever. These will now be considered. The relation of quinine to blackwater fever is not a Simple one. It is a matter of common observation that in the majority of attacks the administration of quinine has been followed, within a few hours, by a rise of temperature, attended with more or less severe constitutional disturbance, and the next specimen of urine has been found to contain haemoglobin. So far the relation of quinine to the attack seems simple, but it at once becomes complex when it appears that quinine does not ordinarily cause h~emoglobinuria in malarial patients, not even in malarial subjects who have previously suffered from blackwater fever following the administration of quinine; the readministration of quinine is usually not attended with haemoglobinuria. Moreover other drugs, such as methylenblue, phenacetin, salipyrin, antipyrin and tuberculin may lead to haemoglobinuria in malarial subjects, so that the specificity of quinine in this respect has no real existence. The problem, becomes, however, still more complex when it is found that a relatively small number of malarial subjects-more than thirty such cases have already been recorded - - h a v e had an attack of haemoglobinuria clinically indistinguishable from blackwater fever, in the absence of
THE DEFINITION OF BLACKWAT]~I~FEVER.
395
the administration of quinine or other of the drugs mentioned above. It is true that in the latter cases the internal mechanism of production of the hsemoglobinuria does not appear to have been ascertained, so far as this is at present possible, to be identical with that of blackwater fever, but prima facie the two would appear to be identical. The relation of malaria to blackwater fever is also not easy to define. The maiority of attacks of blackwater fever occur in patients who are malarial subiects. Nevertheless there is no relationship between blackwater fever and the presence of malarial parasites in the peripheral blood. Indeed malarial parasites nbt unfrequently cannot be recognised in the blood during the period of hsemoglobinuria. It is, moreover, not possible to state whether the constitutional disturbance present in blackwater fever may be in part of malarial origin, since we have at present no means of identifying such disturbance as part of a malarial process. So long as the series of events, occurring in the body, whose ultimate result is the appearance of black water, is incompletely known, all that can be asserted is that the two are ordinarily associated, but the causal relationship of malaria to hsemoglobinuria cannot at present be either established or disproved. :Finally, reference may be made to the difficulty introduced by those cases ~ in which paroxysmal attacks of hsemoglobinuria, originally following the administration of quinine during malaria, continue to recur, long after all malarial parasites have died out and quinine has ceased to be given. Cases of this kind cannot, however, *Cp. ZIEMANN, 1OC. cir., p. 570.
396
THE DEFINITION OF BLACKWATER FEVER.
in the absence of more detailed investigation, be profitably considered further. They emphasise the necessity for further study of the internal mechanism of production of black water.
]DIscussIoN.
]Dr. HARFORD stated that he had special interest in the subject of blackwater fever, from which he had suffered three times, and which he had dealt with in his M.D. thesis on the fevers of West Africa. In his special work as Physician to the Church ~¢Iissionary Society, the question came very prominently before him, and he felt that great caution was needed in speaking of the connection of quinine with blackwater fever. It was important to remember that scientific discussions were often put into the hands of non-medical readers without proper explanation, and in this way the views which had in the past been put forward rather rashly about the relation of blackwater fever to quinine had done untold mischief. Missionaries had refused to take quinine as a prophylactic because they believed that by doing so they would get blackwater fever, when exactly the reverse was true, for he believed that if quinine was taken properly people would not get blackwater fever. H e was of opinion that a very large number of cases of this disease h~d nothing to do with quinine, though he had also noted cases which undoubtedly had some connection with quinine. H e drew attention to an important statement made by Professor K o c h to ]Dr. A. R. COOK, of Uganda, that if a person who had had blackwater fever would take quinine, at first in small doses and then in the usual prophylactic doses, they
DISCUSSION.
397
would not need to be invalided home, and would be free from blackwater fever and malaria. The true explanation of this was the very important connection between malignant m~laria and blackwater fever, so that if this could be prevented by the use of quinine, patients would not get blackwater fever. He had drawn attention to this in a letter which was published in the Lancet (on page 1498, in the issue for May 9~Sth, 1910), in which he showed, the great importance of maintaining the prophylactic use of quinine, for some months after returning to a cold climate, in the case of those who had suffered from malignant malaria. As an instance of the danger of failing to do this he referred to the case of a married couple, home from Portuguese West Africa, who landed in England in December, 1909. They had given up taking quinine, and somewhat unwisely went about the country, the wife took blackwater fever and was treated by Sir PATI~ICK 1V~ANSON, but suppression of urine occurred and she died. Examination of the husband's blood at the same time showed the presence of malignant parasites, and he had an attack of blackwater fever in a few days but recovered. I t is almost certain that if these people had not given up taking quinine they would not have had blackwater fever. :Professor Ross spoke of a patient suffering from blackwater fever in the Royal Southern Hospital. The case had just been seen by some of the Fellows. On admission, the p~tient contained considerable numbers of malignant tertian parasites and had the corresponding fever. After rest in bed, the parasites, as usual, began to diminish in number, the fever decreasing at the same time. Quinine (30 grains a day) was now commenced and was continued for four days, during which the
398
DISCUSSION.
parasites decreased so much that not a sing!e one could be found even in thick film preparations. The patient was now so much improved that he was given permission to go out of hospital. He went to a skating rink and there ate an ice cream when heated. Immediately afterwards violent fever with several rigors and typical hmmoglobinuria commenced, and the patient returned to hospital. The blackwater fever lasted for nearly a week, and ended in recovery; but the whole of this time not a single malaria parasite could be found. Yet if the parasites had caused the fever they should have numbered many thousands per cmm. Professor Ross argued, therefore, that blackwater fever, though dependent on the malaria parasites, is not directly proportioned to their number. H e endorsed Dr. HARFORD'S views.
The primary requirement which the definition of a morbid condition should fulfil is that it should enumerate the essential features of the condition in question. The extent to which such definition is possible is determined by the progress of pathology, so that, as will be seen by passing in review old text-books, definitions are of slow growth~ becoming more circumscribed and more complete as knowledge advances. The conception of a morbid entity is moreover in part natural, in part artificial. Finally, definitions, which are the outcome of mental operations, are peculiarly liable to be affected by that merely human failing, slovenliness of thought. A study of the definitions of blackwater fever which are to be found in standard text-books on tropical medicine, is instructive in so far as, on the one hand, it exhibits the failure of such definitions to include the essential characters of this condition, as at present known, and, on t h e other hand, it emphasises the diffi° culty of fixing the connotation of a term, when the available data are imperfect. As illustrations of the definitions which are ~o be given by leading writers on tropical medicine the following may be selected. STEPHENS* defines blackwater • ALLBUTT ~; ROLLESTON'S S y s t e m of Medicine, London, 1907, Vol. II., P a r t 2, p. 289, Art. B l a c k w a t e r Fever.
392 fever kind,
TEE DEFINETIOP?OF BLACKWATER Fevers a8 “a which
fever, generally believed to be malarial in is accompanied by the presence of blood MARCHIAFAVA and BIGNAMI" pigment in the urine.” avoid the term “ blackwater fever” and replace it by 6~malarial haemoglobinuria,” which is defined as follows : “The hamoglobinuric attack is a syndrome which is encountered not rarely, especially in hot climates, in the course of a malarial infection. The chief symptom of the attack is the emission of urine containing albumin and haemoglobin in greater or lesser quantity.” ZIEMANN t defines blackwater fever as “ an acute erythrocytolysis during or after malaria,” with the proviso that an immediately. exciting cause, usually quinine intoxication, is also an essential factor in its production. Exception may be taken to the last definition on the ground that it confuses two different terms, since it may be taken to imply that fever and cytolysis are synonymous. The first-named writer, on the contrary, defines blackwater fever as a fever ; this, however, is at the present time an anachronism, fever no longer occupying so prominent a place in symptomatology as it formerly did ; and viewing the matter from a purely psychological standpoint, as a matter of fact, most of those who use the term blackwater fever disregard its literal meaning, and have in their minds generally haemoglobinuria as the characteristic feature of this condition. The further objection may be raised that none of the above definitions enumerate more than a few of the conditions which, in the present state of our knowledge, *Twentieth Century p. 483, Art. Malarial f&fENSE’S
558
and 566.
Handbuch
Practice OPMedicine, London, 1900,Vol.
XIX.,
Hamoglobinuria. der
Tropenkrankheiten,
Leipzig,
1906,
B.
3,
THE DEFINITION OF BLACKWATER FEVER.
393
may be regarded as the principal and essential features of blackwater fever,* These are : 1. The appearance of h~emoglobinuria. (Incidentally it may be 'observed that the necessary coexistence of albuminuria has not been established). 2. The coexistence of hmmoglobinsemia, which determines the appearance of hmmoglobinuria. 3. The absence of hsemolysinsemia. 4.
The previous administration of quinine.
5. The association with malaria. As subsidiary characters of the disease may be enumerated: the paroxysmal character of the attacks, which are not unfrequently repeated, relapses being common, and the rise of temperature. As a provisional definition based upon and including the above data the following may be suggested: Blackwater fever is the term applied to an attack of hsemoglobinuria, occurring in malarial subjects, dependent upon hsemoglobinsemia, unaccompanied with hsemolysin~emia, and following upon the administration of quinine. The attack is paroxysmal in character, is not uncommonly repeated more than once, and is attended with a rise of temperature. This definition is, however, merely a provisional one. As knowledge advances it will be augmented and varied. Up to the present the internal mechanism of production of blackwater fever has been only in part investigated, some of the earlier stages of the process being still unknown. Thus while it is known that the hsemoglobinuria is dependent upon hmmoglobin~emia, and that ~Cp. ,.]-. O. WAKELIN BARRATT a n d W. YORKE. A.n I n v e s t i g a t i o n i n t o t h e M e c h a n i s m of P r o d u c t i o n of B l a c k w a t e r . A n n a l s of Tropical ]~edicine a n d P a r a s i t o l o g y , 1 9 0 9 , Vol. III., p. 1.
394
~HE DEFINITION OF B:hACKWATER FEVEI~.
the latter is not due to h~emolysinsemia, yet it is merely a matter of inference that the haemoglobinaemia is due to laking of red cells, direct proof being strictly speaking wanting; so that at present it is not altogether admissible to introduce the term erythrocytolysis into the definition of blackwater fever, as is done in the third definition given above, As further illustrations of the present limitations of our knowledge of blackwater fever may be taken the relation of quinine and of malaria to blackwater fever. These will now be considered. The relation of quinine to blackwater fever is not a Simple one. It is a matter of common observation that in the majority of attacks the administration of quinine has been followed, within a few hours, by a rise of temperature, attended with more or less severe constitutional disturbance, and the next specimen of urine has been found to contain haemoglobin. So far the relation of quinine to the attack seems simple, but it at once becomes complex when it appears that quinine does not ordinarily cause h~emoglobinuria in malarial patients, not even in malarial subjects who have previously suffered from blackwater fever following the administration of quinine; the readministration of quinine is usually not attended with haemoglobinuria. Moreover other drugs, such as methylenblue, phenacetin, salipyrin, antipyrin and tuberculin may lead to haemoglobinuria in malarial subjects, so that the specificity of quinine in this respect has no real existence. The problem, becomes, however, still more complex when it is found that a relatively small number of malarial subjects-more than thirty such cases have already been recorded - - h a v e had an attack of haemoglobinuria clinically indistinguishable from blackwater fever, in the absence of
THE DEFINITION OF BLACKWAT]~I~FEVER.
395
the administration of quinine or other of the drugs mentioned above. It is true that in the latter cases the internal mechanism of production of the hsemoglobinuria does not appear to have been ascertained, so far as this is at present possible, to be identical with that of blackwater fever, but prima facie the two would appear to be identical. The relation of malaria to blackwater fever is also not easy to define. The maiority of attacks of blackwater fever occur in patients who are malarial subiects. Nevertheless there is no relationship between blackwater fever and the presence of malarial parasites in the peripheral blood. Indeed malarial parasites nbt unfrequently cannot be recognised in the blood during the period of hsemoglobinuria. It is, moreover, not possible to state whether the constitutional disturbance present in blackwater fever may be in part of malarial origin, since we have at present no means of identifying such disturbance as part of a malarial process. So long as the series of events, occurring in the body, whose ultimate result is the appearance of black water, is incompletely known, all that can be asserted is that the two are ordinarily associated, but the causal relationship of malaria to hsemoglobinuria cannot at present be either established or disproved. :Finally, reference may be made to the difficulty introduced by those cases ~ in which paroxysmal attacks of hsemoglobinuria, originally following the administration of quinine during malaria, continue to recur, long after all malarial parasites have died out and quinine has ceased to be given. Cases of this kind cannot, however, *Cp. ZIEMANN, 1OC. cir., p. 570.
396
THE DEFINITION OF BLACKWATER FEVER.
in the absence of more detailed investigation, be profitably considered further. They emphasise the necessity for further study of the internal mechanism of production of black water.
]DIscussIoN.
]Dr. HARFORD stated that he had special interest in the subject of blackwater fever, from which he had suffered three times, and which he had dealt with in his M.D. thesis on the fevers of West Africa. In his special work as Physician to the Church ~¢Iissionary Society, the question came very prominently before him, and he felt that great caution was needed in speaking of the connection of quinine with blackwater fever. It was important to remember that scientific discussions were often put into the hands of non-medical readers without proper explanation, and in this way the views which had in the past been put forward rather rashly about the relation of blackwater fever to quinine had done untold mischief. Missionaries had refused to take quinine as a prophylactic because they believed that by doing so they would get blackwater fever, when exactly the reverse was true, for he believed that if quinine was taken properly people would not get blackwater fever. H e was of opinion that a very large number of cases of this disease h~d nothing to do with quinine, though he had also noted cases which undoubtedly had some connection with quinine. H e drew attention to an important statement made by Professor K o c h to ]Dr. A. R. COOK, of Uganda, that if a person who had had blackwater fever would take quinine, at first in small doses and then in the usual prophylactic doses, they
DISCUSSION.
397
would not need to be invalided home, and would be free from blackwater fever and malaria. The true explanation of this was the very important connection between malignant m~laria and blackwater fever, so that if this could be prevented by the use of quinine, patients would not get blackwater fever. He had drawn attention to this in a letter which was published in the Lancet (on page 1498, in the issue for May 9~Sth, 1910), in which he showed, the great importance of maintaining the prophylactic use of quinine, for some months after returning to a cold climate, in the case of those who had suffered from malignant malaria. As an instance of the danger of failing to do this he referred to the case of a married couple, home from Portuguese West Africa, who landed in England in December, 1909. They had given up taking quinine, and somewhat unwisely went about the country, the wife took blackwater fever and was treated by Sir PATI~ICK 1V~ANSON, but suppression of urine occurred and she died. Examination of the husband's blood at the same time showed the presence of malignant parasites, and he had an attack of blackwater fever in a few days but recovered. I t is almost certain that if these people had not given up taking quinine they would not have had blackwater fever. :Professor Ross spoke of a patient suffering from blackwater fever in the Royal Southern Hospital. The case had just been seen by some of the Fellows. On admission, the p~tient contained considerable numbers of malignant tertian parasites and had the corresponding fever. After rest in bed, the parasites, as usual, began to diminish in number, the fever decreasing at the same time. Quinine (30 grains a day) was now commenced and was continued for four days, during which the
398
DISCUSSION.
parasites decreased so much that not a sing!e one could be found even in thick film preparations. The patient was now so much improved that he was given permission to go out of hospital. He went to a skating rink and there ate an ice cream when heated. Immediately afterwards violent fever with several rigors and typical hmmoglobinuria commenced, and the patient returned to hospital. The blackwater fever lasted for nearly a week, and ended in recovery; but the whole of this time not a single malaria parasite could be found. Yet if the parasites had caused the fever they should have numbered many thousands per cmm. Professor Ross argued, therefore, that blackwater fever, though dependent on the malaria parasites, is not directly proportioned to their number. H e endorsed Dr. HARFORD'S views.