The term Blackwater Fever describes a hemolytic crisis that may occur as a complication of malaria. Severe hemolysis not only leads to anemia, hemoglobinemia and hemoglobinuria, but often provokes kidney failure.
BWF may be diagnosed in patients suffering from severe malaria. The latter may manifest in form of bouts of fever, that not necessarily occur regularly. Indeed, severe forms of malaria are characterized by irregular bouts of fever. Patients frequently claim limb and back pain as well as headaches. Diarrhea may also be observed.
If malaria had been diagnosed before, the anamnesis frequently reveals that the patient is taking antimalarial treatment, and if such treatment consists in amino alcohols like quinine, halofantrine, mefloquine or lumefantrine, the possibility that they are suffering from BWF should seriously be considered.
The main symptom of BWF is the patients' dark urine that results from severe hemolysis, hemoglobinemia and subsequent hemoglobinuria. These symptoms are generally accompanied by jaundice, hepatosplenomegaly, abdominal pain, vomitus and fever. Due to anemia, tachycardia, dyspnea and dizziness may also be observed. As renal function is being more and more affected, urine production decreases significantly. Anuria precedes renal failure.
Malaria may affect people living in or traveling to endemic regions. In industrialized countries, patients returning from such journeys that present with bouts of fever should be thoroughly examined in order to confirm or rule out malaria. Blood count and blood chemistry reveal thrombocytopenia, lymphopenia and elevated lactate dehydrogenase levels. Blood smears may confirm the tentative diagnosis of malaria, since they not only show atypical lymphocytes but also cells infected with intracellular parasites. In order to identify these parasites and verify the presence of Plasmodium, specific fluorescent days may be utilized. However, this examination requires a fluorescence microscope. Species determination may also be realized via molecular biological methods such as polymerase chain reaction assays.
In patients with BWF, additional symptoms of hemolysis may be detected by laboratory tests. Reticulocyte counts are elevated while haptoglobin levels decrease, hepatic and renal parameters as well as electrolytes are frequently altered.
Leukocytosis is neither typical for malaria nor for BWF. Thus, if leukocytosis is detected, other pathological conditions may be its trigger. Patients that have been to malaria-endemic countries may also have been exposed to other infectious diseases, so a variety of tropical diseases should be considered.
When BWF is suspected, a urine examination should also be performed. Dark coloration and hemoglobinuria are characteristic for BWF.
BWF may not be treated as an isolated disease. The aim of any BWF treatment should rather be to stabilize the patient through this severe complication of malaria and to eliminate the blood parasites by applying anti-malarial drugs. There is no consensus regarding changes in anti-malarial therapy. It has been stated that quinine treatment should be stopped as soon as other therapy options such as artemisinin become available  .
The latter has been reported to be well-tolerated and effective.
Even in mild cases of BWF, fluid therapy is indicated. If possible, active fluid intake should be encouraged to counteract loss of water, electrolytes and protein. Severe anemia and impairment of renal function may require intensive care and dialysis.
Due to the severity, medical attention should be provided in an intensive care unit. If infrastructure and hygiene conditions allow an adequate treatment of the disease, the prognosis is good. In these cases, there are usually no permanent consequences.
It is not yet known why malaria is accompanied by severe hemolysis in some patients. It has been reported that BWF is more frequently associated with Plasmodium falciparum infections, but it has also been observed in patients infected with Plasmodium vivax and Plasmodium malariae     . Heavy parasite loads presumably predispose erythrocytes for hemolysis.
To date, the hypothesis that is most widely supported is that BWF is provoked by an autoimmune reaction triggered by specific drugs administered to treat malaria. This parasitic disease has been frequently treated with amino alcohols such as quinine, halofantrine, mefloquine and lumefantrine. Quinine is particularly suspected to trigger BWF and is indeed no longer recommended by the World Health Organization (WHO) to treat malaria. Isolated cases of BWF have also been ascribed to treatment with halofantrine and mefloquine   .
Other conditions that have been suggested to increase the risk for BWF are glucose-6-phosphate dehydrogenase (G6PD) deficiency and other bacterial or viral infections  . However, cases of BWF have also been registered in people not suffering from G6PD deficiency .
Malaria continues to be a major health problem, particularly in sub-Saharan Africa. More than 200 million cases of malaria are reported annually, and more than 80% of these cases are registered in the above mentioned region. It has been estimated that more than half a million people die from malaria every year, the vast majority of deaths occurring in children aged five years or less. Infections with Plasmodium falciparum cause particularly severe cases of malaria and BWF is frequently associated with the presence of this pathogen.
While BWF has first been described in non-immune patients who moved to endemic regions and lived among the immune indigenous population, this limitation does no longer hold true and BWF has also been observed in patients belonging to the indigenous population .
However, overall case numbers of BWF have decreased considerably during the last decades. This phenomenon has been attributed to changes in malaria treatment and less use of quinine . As has been mentioned above, quinine is no longer recommended by the WHO for malaria treatment. It continues to be of certain importance though, particularly if the causative agent proves to be resistant to other compounds and resistance of Plasmodium strains against available antimalarial drugs has recently been increasing.
In a study realized with children in Central Africa, no gender preference could be detected regarding BWF. There was a significant correlation between treatment with quinine and development of hemolytic complications. About 20% of all children suffering from BWF eventually died from kidney failure .
Neither the etiology nor the pathogenesis of BWF are well understood. Immune status, quinine treatment or administration of other antimalarial drugs has been related to BWF as well as G6PD deficiency and comorbidities. How and even if these factors trigger an autoimmune response leading to severe intravascular hemolysis, anemia, hemoglobinemia and icterus, is not yet confirmed   . While the aforementioned events initially cause hemoglobinuria, anuria is characteristic for later stages of the disease. Kidney damage may result in kidney failure and death.
Because the pathogenesis of BWF is only poorly understood, no preventive measures against BWF can be recommended. But due to the fact that BWF only occurs in patients suffering from severe cases of malaria, malaria prophylaxis does also prevent BWF.
While people indigenous to malaria-endemic areas generally dispose of a certain degree of immunity against the disease, this is not the case for travelers visiting these endemic regions. Any person preparing such a journey should take preventive drugs. Indeed, the effectiveness of preventive medication has repeatedly been confirmed and the majority of travelers contracting malaria are traveling without preventive drugs. Even pregnant women are recommended to take anti-malarial drugs because their benefits outweigh possible side effects. Since malaria may be caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae as well as Plasmodium ovale and because these distinct species have developed resistances to certain anti-malarial drugs, the current resistance of these pathogens should be taken into account when prescribing preventive medication. The World Health Organization as well as the US-American Centers for Disease Control and Prevention are regularly updating their recommendations according to new findings and observed changes in resistance distribution.
It is currently recommended to take preventive drugs when visiting certain countries in Africa, the Arabian and Indian subcontinents, South East Asia, the South Pacific and South America. Several compounds are available, e.g. atovaquone-proguanil, mefloquine, primaquine, chloroquine, hydroxychloroquine and doxycycline. For some drugs, medication should start several weeks before starting a journey to a malaria-endemic country.
There is a residual risk of contracting malaria even though preventive medication is taken. Therefore, mosquito protection is required. It is generally recommended to wear protective clothing that covers arms and legs and to use effective repellents. Windows should be protected with screens and travelers should sleep under mosquito nets.
Some malaria patients suffer from severe hemolytic crisis that involves a rapid and massive destruction of erythrocytes, hemoglobinemia, icterus and subsequent hemoglobinuria, anuria and kidney failure that causes death. This complication of malaria is termed Blackwater fever (BWF) .
It has been speculated about possible triggers of BWF and while heavy parasitic loads, genetic predisposition for hemolysis and co-infection with other bacterial or viral pathogens may contribute to an increased risk for BWF, the most widely accepted hypothesis to date is that certain antimalarial drugs are responsible for BWF  . Quinine has most frequently been related to BWF, but cases triggered by application of other drugs have also been reported.
Treatment for BWF is symptomatic and consists in fluid therapy and kidney protection or even dialysis, if required. The aim of the therapy should be to control the infection with Plasmodium, since BWF only occurs in malaria patients. The overall prognosis is good if adequate treatment can be provided. In developing countries, however, the mortality associated with BWF is about 20% . Risks are particularly high in children developing BWF.
Plasmodium species infect red blood cells of the patient that contracted malaria. Under certain conditions, the human body attacks and destroys these infected red blood cells and this process is termed hemolysis. It is not yet clear which conditions trigger hemolysis in malaria patients, but there are theories about anti-malarial drugs, genetic disorders and other infectious diseases as possible causes of hemolysis.
AS a consequence of the severe hemolysis that occurs with BWF, jaundice, abdominal pain and kidney dysfunctions may be experienced. Because the destruction of the red blood cells results in anemia, an increased heart rate, breathing problems and dizziness may also be observed. Other symptoms include headaches and vomitus. Fever is usually observed but rather ascribed to underlying malaria.
During initial phases of the disease, the urine of the patient is of a very dark color. This phenomenon results from the amount of blood pigments that are excreted by the kidneys and explains why the disease is called BWF. BWF is associated with severe kidney damage and in later phases of the disease, urine production may be limited to less than 50 ml per day. If not treated adequately and early on, the disease may be lethal.
There are currently no preventive measures known against BWF, but malaria prophylaxis is readily available. While people indigenous to malaria-endemic regions generally dispose of a certain immunity against the disease, this is not the case for travelers going on a trip to these countries. Anyone planning such a journey should consult with a specialist for tropical diseases to clarify which preventive measures should be taken. It is recommended to take preventive drugs when traveling to certain countries in Africa, the Arabian and Indian subcontinents, South East Asia, the South Pacific and South America. There may be differences regarding the specific drugs that should be taken during trips because there are several species of Plasmodium and in some regions they did develop resistances to anti-malarial agents. It is necessary to consult with the respective physician early because with some drugs, anti-malarial treatment needs to be started weeks before departure.
As has been mentioned above, malaria is transmitted by mosquitoes. Thus, mosquito protection is essential while staying in endemic regions. Mosquito protection includes wearing clothes that cover arms and legs, using repellents, window screens and mosquito nets at night.