CHAPTER II
BLACKWATER FEVER
DEFINITION AND SYNONYMS
=Definition.=—Blackwater fever is a disease of disputed etiology but recently there has seemed to be rather general agreement that it is connected with repeated attacks of malaria. It is prone to affect the old European residents of parts of the tropics where malignant tertian is rampant.
On the basis of lowered integrity of the red cells, by reason of repeated attacks of malaria, we may have extensive lysis of the red cells following the administration of a dose of quinine or as the result of refrigeration, excessive exposure to the sun or great fatigue.
Clinically we have a prostrating chill of asthenic type associated with early jaundice and the passage of porter-colored urine—haemoglobinuria.
=Synonyms.=—Haemoglobinuric Fever, Bilious Haemoglobinuric Fever, Haemorrhagic Malarial Fever.
French: Fièvre Bilieuse Hemoglobinurique. German: Schwarzwasserfieber.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—There is no reasonable doubt that the explanation of the fact that blackwater fever was first brought to the attention of the medical world, by Lebeau and other French naval surgeons, in Madagascar, in 1850-1853, was due to the confusion of this disease with the bilious remittent type of pernicious malaria as well as with yellow fever. Even after the clinical picture was well recognized, disputes as to the nature of the coloring matter of the characteristic urine were frequent, some considering that the dark color, which we now know to be due to haemoglobinuria, was due to haematuria or that the color was due to bile. Blackwater fever must have been the condition referred to in medical literature of the period, 1850 to 1870, under the names “Fièvre bilieuse haematurique,” “haemorrhagic malarial fever” and “febris remittens haemorrhagica.”
It was first described in the U. S. by Cummings of Louisiana in 1859. Other American physicians during the next ten years, described the disease from various other Southern states.
Veretas noted the presence of the disease in Greece, in 1858.
It is rather remarkable that the disease was not noted by so keen an observer as Torti, if it existed in his time, and Manson states that it is strange that it should not have been recognized in India if it had existed there prior to recent times. Some think that its introduction into Africa has been of recent occurrence. There are two explanations of the recent greater prominence of the disease in Africa and other tropical areas, where malignant malaria prevails extensively, which are (1) that there has been a great influx of susceptible Europeans into such areas during the past twenty or thirty years and (2) that the more frequent and excessive dosing of malarial patients with quinine is responsible.
[Illustration: FIG. 23.—Geographical distribution of blackwater fever.]
=Geographical Distribution.=—It is in tropical Africa that the disease is of prime importance as a cause of death and invaliding. Here it prevails chiefly in West, Central and East Africa from about 12° N. to 12° S. latitude. It is less frequent in Northern Africa although a considerable number of cases have been reported from Algeria. It is unknown in Egypt, a country where malaria is very rare in Europeans.
In India it occurs in several districts and Stephens states that in the Duars (Bengal) he saw more cases in a fortnight than he had seen in the same time in Africa. In Europe it occurs chiefly in Southern Italy, Sicily, Sardinia and Greece. Blackwater fever was frequently noted among the British forces in Macedonia and Palestine during the World War.
It is common in Central America and Northern South America, especially in the regions of the Amazon basin, in Brazil.
In the U. S. it is chiefly found in the most malarious sections of Arkansas, Mississippi, Louisiana, Texas, Alabama, Georgia, Florida and South Carolina. It would seem that it is becoming more rare in the Southern States.
As a result of malarial prophylaxis among the Americans working in the Panama Canal Zone it has almost disappeared among them although still common among the white Europeans in the same region who neglect quinine prophylaxis and mosquito protection.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—There seem to be cases where from very heavy infection with the malignant tertian parasite, as from 12 to 20% of the red cells, one can expect the appearance of a more or less dark urine, the color of which is due to haemoglobinuria. Such cases give support to the old view that haemoglobinuric fever was simply a type of pernicious malaria.
Brem has proposed for such cases the designation, pernicious malarial fever with haemoglobinuria.
The idea as to etiology which now seems most generally accepted is that blackwater fever occurs almost solely in those who have resided for considerable periods of time in districts where malignant tertian malaria is very prevalent and intense and who have repeatedly suffered from such malarial attacks. Rarely blackwater fever may be connected with benign tertian infections or exceptionally with quartan ones. As a result of the damage done the patient by the malarial attacks there is a tendency on the part of his red cells to haemolysis which may be due to the production of a hypothetical autolysin or to anaphylactic sensitizations, as has been suggested recently.
Malaria is the predisposing cause and the exciting cause may be any of a number of different factors capable of lowering body resistance such as the occurrence of another malarial attack, the administration of quinine, particularly of the acid salts of quinine in rather large doses, refrigeration, as brought about by one’s clothes becoming wet and then later subjected to the chilling influence of a sea breeze, to excessive fatigue or dietetic or alcoholic excesses.
Quinine administration, particularly if associated with refrigeration, is the most common exciting factor.
As regards the association of malaria and blackwater fever Stephens, in a study of 390 cases of blackwater, found that 73% of the cases showed malarial parasites on the day preceding the haemoglobinuria, 47.5% on the day of the attack and 23% on the day following the appearance of the dark urine. Other workers give higher figures as 95, 70 and 20%.
Where one utilizes the methods of examining for increased percentage of large mononuclears or for melaniferous leucocytes, in those cases not showing malarial parasites, the percentage of evidence of malaria is greatly increased. It is necessary to understand that a small percentage of cases diagnosed as blackwater fever do not show evidences of malaria at autopsy and cases are recorded where blackwater has attacked persons who had never had malarial fever, such instances, however being exceptional.
_The Quinine Theory._—This idea as to the causation of blackwater fever first originated with Veretas, in Greece, in 1858. Later Tomaselli supported this view in Italy and more recently it was advocated by Koch. Just as in connection with the influence of Koch’s great prestige much harm was done in prophylaxis against bovine tuberculosis so in this matter of quinine in the causing of blackwater the influence was unfortunate because many persons with severe malaria now refuse to take the specific quinine for fear of bringing on haemoglobinuria.
It may be stated that quinine alone, even in doses which are capable of producing profound toxic effects such as disturbances of sight and hearing, weak heart and collapse does not, other than exceptionally, cause haemoglobinuria. It has even been stated that quinine base and quinine tannate tend to prevent haemolysis, haemoglobinaemia and haemoglobinuria. Blackwater fever may develop without the previous administration of quinine.
_Theory as to Acidosis with a Damaged Liver Plus Malaria and Acid Salts of Quinine._
MacGilchrist has recently advanced the idea that blackwater fever is brought about by an acidosis in one with a damaged liver plus malaria and the administration of acid salts of quinine. He thinks that one can safely give the quinine when alkalis are being given and that quinine base is protective against haemolysis.
_Theory as to Its being Caused by a Piroplasm._
Sambon has thought by reason of the clinical resemblance of blackwater to certain haemoglobinuric diseases in cattle, dogs and sheep that such a cause might be operative. These parasites of the red cells are easily discernible in the animal infections but have never been seen in blackwater fever.
_The Chlamydozoal Hypothesis._
Leishman has recently noted appearances in the large mononuclear cells of the blood of blackwater patients of certain cell inclusions which he thought to be of chlamydozoal nature and that these chlamydozoa might be etiological factors. Such appearances may not only be absent in marked cases of blackwater but may be seen in conditions other than blackwater fever.
=Epidemiology.=—There seems to be a consensus of opinion that when malaria is kept in check by proper and persistent quinine prophylaxis or by other antimalarial measures blackwater fever becomes mild in character or even nonexistent. It is those who are careless about quinine prophylaxis or those who expose themselves to depressing influences as cold, wet, excessive fatigue or alcoholic debauches in whom blackwater shows itself.
Overexertion leading to fatigue and chilling seem to be the most common exciting factors. Those in bad health from disease or lack of proper diet seem more susceptible. A peculiar feature of the disease is that it may not be present in a district for a number of years and then assume almost epidemic proportions. Europeans are usually exempt from attacks during their first year in endemic tropical areas. Dudgeon obtained a malarial history in every one of a hundred cases observed by him in the Balkans.
PATHOLOGY AND MORBID ANATOMY
As a result of the excessive destruction of red cells the liver cannot convert the great amount of haemoglobin outpouring into bile pigment so that haemoglobinaemia and haemoglobinuria result. It has been estimated by Ponfick that if ⅙ of the red cells are destroyed the liver is unable to dispose of the liberated haemoglobin and haemoglobinuria results. A damaged liver would be less competent. Various discussions as to autolysins and complement content of serum have arisen.
Dudgeon has demonstrated active haemolysins in the tissues and urine of blackwater fever cases which bodies he was unable to note in other conditions including malaria. There was no evidence of increased fragility of the red cells. There was no evidence of auto-haemolysis. Bile pigment in the plasma occurred in most of the cases which ended fatally.
As a rule we have the pathological findings which go with malaria. As peculiarities of blackwater noted by Whipple and others may be mentioned congestion of the kidneys with purple-colored pyramids. In the spleen the Malpighian bodies are prominent and sharply outlined. Very striking are the necroses of the Malpighian corpuscles of the spleen and focal necroses of the liver. Whipple considers that this speaks for a powerful circulating toxin in blackwater fever which is not present in malaria.
The liver cells in the area of the central veins show the most marked destruction. The myocardium shows fatty change and the fat lipoid content of the adrenal is reduced.
The anuria is thought to be mechanical and due to the plugging up of the tubules by haemoglobin casts.
The urine shows a reddish to black color and has a sediment made up of granular débris with haematoidin crystals and only rarely a red cell. It is not a haematuria.
The absorption bands of methaemoglobin are usually noted spectroscopically.
Urobilin and albumin are present in large quantities.
SYMPTOMATOLOGY
=A Typical Case.=—In a person who has lived in an intensely malarious region for one or two years or even long after he has left such districts and who has had several malarial attacks, there comes on what is considered as another malarial chill, which may or may not definitely be connected with some resistance-lowering influence, as exposure to tropical sun or rain, or indulgence in dietary or other excesses, or following in one to six hours the accustomed dose of quinine. This chill, however, is more prostrating than those formerly experienced and upon passing his urine the patient notes its reddish to black coffee color and himself makes the diagnosis of blackwater fever. The attack comes on suddenly with a very severe chill, marked prostration and pain over the region of the kidneys. The temperature in a typical case rapidly goes up to 104° to 105°F.
Rather profuse sweating accompanies the fall of the fever and the patient is markedly debilitated after the subsidence of the fever. There may be a recurrence of the paroxysm the following day. The fever course, however, may be more or less continuous or remittent. In other words it tends to be irregular and atypical.
Nausea and bilious vomiting come on early with epigastric distress. Almost as pathognomonic as the haemoglobinuria is the early and intense jaundice. This comes on within a few hours or almost simultaneously with the haemoglobinuria and usually lasts for two or three days after the haemoglobinuria and fever have ceased. Itching of the skin of this jaundice is not noticeable.
The spleen and liver are enlarged and tender. Albuminuria comes on with the haemoglobinuria and shows from 1/10 to 4/10 of 1% of albumen by weight.
The pulse is rapid, 110 to 120, from the first but soon becomes feeble and of low tension. In severe cases the very rapid almost thready pulse, with pallor and cold extremities, may resemble a severe haemorrhage. Epistaxis is not uncommon. A very unfavorable symptom seems to be hiccough. Another frequent cause of death and the one against which we chiefly direct our therapeutic measures is anuria with subsequent uraemic symptoms, such as coma and convulsions. At times a nephritis may develop in the course of a blackwater attack and the case subsequently run as one of severe nephritis.
Very striking is the rapidly developing anaemia, some cases showing a loss of two million red cells in twenty-four hours.
The mind is usually clear throughout an attack, the patient showing restlessness and marked anxiety.
In mild cases the fever course and haemoglobinuria is over within twenty-four hours leaving the patient far more prostrated than would a malarial paroxysm. In severe cases, however, the fever runs a remittent course over several days, with more marked haemoglobinuria and jaundice.
There may be cases which only show haemoglobinuria. These apyretic cases have been considered by some as quinine haemoglobinuria.
Symptoms in Detail
_Fever Course._—This resembles that of a malarial paroxysm and may be intermittent in character or last several days as a remittent fever. The rigor which accompanies the febrile rise is intense.
_The Liver and Spleen._—As a result of the marked blood destruction the liver is unable to dispose of the haemoglobin outpouring and icterus, which usually comes on in a few hours and is intense, is almost constant together with epigastric distress, bilious vomiting and tenderness and slight enlargement of the liver. The spleen is also somewhat enlarged and quite tender.
_The Circulatory System._—At first the pulse is rapid with tension but soon it becomes weak, compressible and of low tension. In severe cases it may have a rate of 150 or more or even become thready.
_The Genito-urinary System._—The dark colored urine is pathognomonic of the disease and gives it its name. The reddish to almost black color is due to haemoglobin and not to bile. Bile pigments do not appear in the urine. There is but rarely a red cell to be found in the granular débris with occasional haematoidin crystals which forms the urinary sediment, hence it is haemoglobinuria and not haematuria.
The urine resists decomposition for a long time. Albumin is present in large amount and comes on with the onset of haemoglobinuria. Casts are abundant and urobilinuria is marked. As a result of the blocking up of the renal tubules with haemoglobin casts pain over the loins and anuria may occur. There may be vesical tenesmus.
_The Blood._—Cases have been reported where as many as 2,000,000 red cells have been destroyed within twenty-four hours, so that rapid and marked anaemia characterizes the disease. The blood is thin and the serum tinged. The degenerative changes of the red cells are not as commonly seen as one would expect but this is probably due to the fact that degenerated cells are first destroyed in the excessive haemolysis. Hb percentage reduction generally parallels the reduction in red cells. Melaniferous leucocytes may be found and during the leucopenia, which follows the paroxysm, the large mononuclears and transitionals may be increased to 20%. There is a reduction in the alkalinity and coagulability of the blood.
DIAGNOSIS
=Clinical Diagnosis.=—An unusually asthenic prostrating paroxysm, similar to that of a malarial chill, but with more intense rigor, during which haemoglobinuria, early jaundice and marked bilious vomiting are features, makes for a diagnosis of blackwater fever.
The two diseases which are most likely to be confused with blackwater fever are yellow fever and bilious remittent malarial fever.
In infectious jaundice the jaundice does not appear for 48 to 72 hours, the pulse is slow, there is no haemoglobinuria, although there may be a haematuria, and we have a polynuclear leucocytosis.
A case of paroxysmal haemoglobinuria occurring in a blackwater district would be impossible to differentiate from a very mild case of blackwater fever. Chlorate of potash or carbolic-acid poisoning, or snake bite, or severe burns, may produce haemoglobinuria.
-----------+-------------------+-------------------+-------------------- | Blackwater fever | Yellow fever | Bilious remittent -----------+-------------------+-------------------+-------------------- Onset |Sudden but asthenic|Sudden but asthenic|Comes on more | with marked | for two or | slowly. | rigor. | three days. | -----------+-------------------+-------------------+-------------------- Urine |Haemoglobinuria. |No blood in urine |Bile in urine. | Pink foam to | before 3d or 4th | Yellow froth on | urine. Albuminuria| day and then | shaking urine. | from first day. | haematuria. | Albuminuria | | Albumin from 2d | slight and | | day. | not common. -----------+-------------------+-------------------+-------------------- Icterus |Early and intense. |Does not appear |Jaundice develops | Comes on in a few | before 3d day | slowly about 2d | hours. | and gradually | day. | | intensifies. | -----------+-------------------+-------------------+-------------------- Spleen |Somewhat enlarged |No enlargement of |Splenic enlargement | and tender. | spleen. | is marked; may | | | have ague cake. -----------+-------------------+-------------------+-------------------- Pulse |Rapid from start |Stationary pulse |Pulse not so rapid | and becoming | with rising temp- | as in blackwater. | more so as disease| erature or falling| | progresses. | pulse with | | | stationary temp- | | | erature. (Faget’s | | | law.) | -----------+-------------------+-------------------+-------------------- Vomit |Early marked |Mucus-like followed| Bilious vomiting | bilious vomiting. | by black vomit | and gastric distress | | about 4th day. | less than in | | | blackwater. -----------+-------------------+-------------------+-------------------- Evidences |Usually present as |Negative unless |Some evidence at of malaria| parasites or | yellow fever | some time almost | melaniferous | occurs in a | always obtainable. | leucocytes or | malarial case. | | increased large | | | mononuclear | | | percentage. | | -----------+-------------------+-------------------+--------------------
=Laboratory Diagnosis.=—Other than the noting of evidences of malarial infection, rapid reduction in red-cell count and haemoglobin percentage there is little information to be derived from the blood which is thin and shows delayed coagulation time. It is difficult to make good blood smears. In the urine we note the granular sediment of débris of red-cell destruction with at times haematoidin crystals. Spectroscopically we get absorption bands of methaemoglobin and more rarely oxyhaemoglobin.
[Illustration: FIG. 24.—The most important clinical spectra. (_Monographic Medicine._ D. Appleton and Co., New York.)]
Albumin is present in quantity and urobilin is usually present in large amount.
One can examine the urine for blood by the haemin-crystals, guaiac or benzidin tests.
Burkitt has noted that his cases of blackwater have shown a very acid urine with large amounts of acetone bodies.
The serum shows haemoglobinaemia and may show reduced alkalinity.
PROGNOSIS
So far as statistics go the mortality rate would appear to be influenced by the delicateness of the tests used for determining the presence of haemoglobinuria. When a diagnosis is only made with the presence of marked haemoglobinuria, showing porter-colored urine, the mortality rate is, of course, higher than when slight haemoglobinuria is taken into consideration.
In cases treated with quinine, Deaderick, in statistics of various authorities, gives a death rate of 25.9%; in cases not so treated, of 11.1%.
Marked and persistent vomiting and hiccough are very unfavorable signs. In particular, however, it is anuria that gives us our greatest concern in the care of a case. A severe attack is followed by a marked anaemia and convalescence is usually protracted.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The view now generally entertained is that where malarial prophylaxis is properly carried out there will not be any blackwater fever. In persons who have had a previous attack of blackwater fever quinine prophylaxis should be with quinine tannate or quinine base, avoiding the acid salts of quinine.
In particular any exposure to chilling influences or conditions which lower resistance should be avoided. As blackwater fever is more prevalent among those who have been for 2 or 3 years in highly malarious, tropical regions than among recent arrivals, the former should exercise the greater care as to errors in diet, alcoholic excesses, exposure to wet and irregularity in quinine prophylaxis.
=Treatment.=—There is less unanimity of opinion as to the advisability of giving quinine during an attack of blackwater fever than exists as to any other therapeutic measure.
Of course if it be true that quinine base is devoid of haemolytic influence the fear of increasing haemolysis by giving quinine would not have to be considered. At any rate any red cells containing parasites will surely be destroyed in the general haemolysis and with them their contained parasites, so that it does not seem reasonable to give quinine during the first day or two of the attack. Quinine, if given, should not be by mouth for fear of increasing the nausea and vomiting. The majority of authorities hold that if parasites persist after two or three days from the onset quinine is indicated. Some give quinine during the first day if parasites are present but otherwise they withhold quinine.
Absolute rest in bed, avoidance of chilling and good nursing are the prime considerations in treatment.
The patients should be given alkaline waters freely, as Vichy or water containing 30 grains of bicarbonate of soda to the pint. Cracked ice often tends to lessen the nausea and vomiting. Albumin water or barley water may be retained better than milk or broths. As the condition is so asthenic one cannot disregard the nourishment of the patient during the first two or three days as is true of the sthenic first stage of yellow fever. Hot fomentations to the loins are indicated for relief of pain and the effect on the renal congestion.
Saline enemata are of particular value and may suffice in mild cases. In severe cases subcutaneous or intravenous saline injections are necessary. Sorel recommends the intravenous injection of lactose or glucose solutions in quantities of about 300 cc. (Crystallized glucose 47 grams, water 1000 cc. or C. P. lactose 92.5 grams, water 1000 cc.) He also uses these sugar solutions as enemata. Dry cupping or hot fomentations over the loins are the usual remedies in threatened suppression of the urine. If blackwater fever should be shown to be accompanied by diminished alkalinity of the serum then the intravenous injection of a 1 or 2% solution of bicarbonate of soda would be indicated. Some have recommended calcium lactate in doses of 20 grains every four hours. There is little evidence however to indicate that it is of value. Transfusion of blood has been practised but reports of such treatment indicate that while temporary improvement occurs yet this is followed by a return of haemoglobinuria. From Dudgeon’s work it would seem that the existing haemolysins would destroy the foreign red cells.
Burkitt claims excellent results by intravenous injections of alkaline solutions, similar to those recommended under “cholera.” He also finds neosalvarsan of the greatest value in treatment, as cases so treated convalesce most rapidly.
Hearsey advocates a mixture in which there is contained 10 grains of bicarbonate of soda and 1/30 grain of bichloride of mercury in each dose, to be given every two hours.
Cholesterin has been given in 15-grain doses in suspension in thick milk every four hours with the idea that it is anti-haemolytic. The dose is repeated 2 or 3 times.
Calomel in large doses has been recommended by some tropical practitioners but it would seem advisable only to use calomel to keep the bowels open and then in small divided doses.
Antipyretics should not be used from their depressing action on the heart.
For the urinary suppression, Wallace recommends salines as hot as can be borne, administered high in the colon by a double-flow tube. Since he found this treatment effective after intravenous and rectal injections had failed, it is to be inferred that the results obtained were due not to the further administration of fluid but to the action of heat applied directly to the splanchnic area.
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