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Blackwater Fever

Black Water Fever

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.


Presentation

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.

Fever
  • Rates of blackwater fever per 1,000 malaria cases varied over two orders of magnitude. Islands, such as the Andaman Islands and New Guinea, had lower blackwater fever rates than continental areas.[ncbi.nlm.nih.gov]
  • There has been a marked reduction in the incidence of blackwater fever since 1950 and only sporadic cases occur nowadays.[ncbi.nlm.nih.gov]
  • Blackwater fever is a rare manifestation of falciparum malaria characterized by sudden intravascular hemolysis followed by fever and hemoglobinuria.[ncbi.nlm.nih.gov]
  • Easmon coined the name "blackwater fever" and was the first to successfully treat such cases following the publication of his pamphlet. Signs and symptoms[en.wikipedia.org]
  • This complication of malaria is termed Blackwater fever (BWF).[symptoma.com]
Chills
  • Sudden onset stunning chills, alternating with the temperature increase up to 39-40º, vomiting, General razbitosti. Already in the first hours of the disease noted the appearance of bloody urine is dark beer. Sometimes there is complete anuria.[lecheniebolezni.com]
  • Its symptoms include a rapid pulse, high fever and chills, extreme prostration, a rapidly developing anemia, and the passage of urine that is black or dark red in colour (hence the disease’s name).[britannica.com]
  • Clinical presentation: Within a few days of onset there are chills, with rigor, high fever, jaundice, vomiting, rapidly progressive anemia and the passage of dark red or black urine. The cause of hemolytic crises in this disease is unknown.[histopathology-india.net]
  • Other symptoms include chills and convulsions, headache, passage of bloody stools, coma, nausea and vomiting , sweating and abdominal pain.[wisegeek.com]
  • Indian J Med Microbiol 2016;34:393-4 Dear Editor, A 32-year-old gentleman admitted with high-grade intermittent fever associated with chills, headache and fatigue for 2 days and passage of dark urine for last 6 hours.[ijmm.org]
Rigor
  • Clinical presentation: Within a few days of onset there are chills, with rigor, high fever, jaundice, vomiting, rapidly progressive anemia and the passage of dark red or black urine. The cause of hemolytic crises in this disease is unknown.[histopathology-india.net]
  • ) R50.9 ICD-10-CM Diagnosis Code R50.9 Fever, unspecified 2016 2017 2018 2019 Billable/Specific Code Applicable To Fever NOS Fever of unknown origin [FUO] Fever with chills Fever with rigors Hyperpyrexia NOS Persistent fever Pyrexia NOS West African B50.8[icd10data.com]
Vietnamese
  • We prospectively studied 50 Vietnamese patients with blackwater fever (BWF). All patients had fever and hemoglobinuria, 40 (80%) were jaundiced, 25 (50%) had hepatomegaly, 15 (34%) had splenomegaly, and 9 (18%) had hepatosplenomegaly.[ncbi.nlm.nih.gov]
Tachycardia
  • 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.[symptoma.com]
  • Clinical and laboratory signs of systemic inflammation, including changes in body temperature, tachycardia, respiratory rate and leucocytosis, are sensitive.[ccforum.biomedcentral.com]
Jaundice
  • Related to your query: Jaundice: Causes, Symptoms, Prognosis 22 Best Home Remedy for Treatment of Jaundice Ayurvedic Cure for Jaundice[home-cure.net]
  • All patients had macroscopic hemoglobinuria, jaundice, and anemia. Acute renal failure occurred in 15 patients (71%), 7 of whom required dialysis.[ncbi.nlm.nih.gov]
  • All patients had fever and hemoglobinuria, 40 (80%) were jaundiced, 25 (50%) had hepatomegaly, 15 (34%) had splenomegaly, and 9 (18%) had hepatosplenomegaly.[ncbi.nlm.nih.gov]
  • There is rapid and massive destruction of red blood cells with the production of hemoglobinemia, hemoglobunuria, intense jaundice, anuria, and finally death in the majority of cases.[histopathology-india.net]
  • BWF cases typically presented with both clinical jaundice (254/318 [80%]) and severe anemia (hemoglobin level 5 g/dL) (238/310 [77%]).[ncbi.nlm.nih.gov]
Hepatosplenomegaly
  • All patients had fever and hemoglobinuria, 40 (80%) were jaundiced, 25 (50%) had hepatomegaly, 15 (34%) had splenomegaly, and 9 (18%) had hepatosplenomegaly.[ncbi.nlm.nih.gov]
  • He had an axillary temperature of 103.6 F, severe pallor, mild icterus, hepatosplenomegaly and coca-cola coloured urine [Figure 1] . Peripheral capillary-blood smear (PBS) showed ring forms of Plasmodium falciparum (28,312 parasites/μl).[ijmm.org]
  • These symptoms are generally accompanied by jaundice, hepatosplenomegaly, abdominal pain, vomitus and fever. Due to anemia, tachycardia, dyspnea and dizziness may also be observed.[symptoma.com]
  • The remainder of the physical examination was unremarkable, including a normal neurologic examination and no hepatosplenomegaly. Urine was light tea coloured.[malariajournal.biomedcentral.com]
  • Splenomegaly was present in 14 patients (67%), hepatomegaly in 11 (52%), and hepatosplenomegaly in 9 (43%). Ten patients (48%) had evidence of minor neurological dysfunction. Laboratory features .[academic.oup.com]
Agalactia
  • Streptococcus agalactiae Nos. Streptococcus haemolyticus Nos. Streptococcus pyogenes necrosing fascitis Streptococcus uberis Streptococcus viridans Nos. Sycotic compound (Paterson) Taenia saginata Nos. Taenia solium Nos. Tetanus Nos.[remedia.at]
Suggestibility
  • The syndrome observed in the remaining 28 cases was strongly suggestive of blackwater fever (BWF) as described in malaria patients by several authors under the french name "fièvre bilieuse hémoglobinurique".[ncbi.nlm.nih.gov]
  • Our data and 13 cases reported in the literature suggest a resurgence of classic BWF among Europeans living in Africa and a need to discuss attendant therapeutic implications.[ncbi.nlm.nih.gov]
  • Taken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion.[ncbi.nlm.nih.gov]
  • There was considerable overlap in the occurrence of G6PD deficiency, quinine ingestion, and malaria, suggesting that these factors may interact and that it may not be justifiable to regard hemoglobinuria caused by G6PD deficiency as a separate syndrome[ncbi.nlm.nih.gov]
  • Plasmodium falciparum parasitemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum histidine rich protein 2 (192/246 [78.0%]) vs 811/1154 [70.3%]; P .014), suggesting recent antimalarial treatment.[ncbi.nlm.nih.gov]
Withdrawn
  • Usually, amino-alcohol drugs were rapidly withdrawn when it was suspected that they had triggered the BWF. Background epidemiological data .[academic.oup.com]
Dark Urine
  • […] noun mass noun A severe form of malaria in which blood cells are rapidly destroyed, resulting in dark urine.[en.oxforddictionaries.com]
  • […] noun A severe form of malaria in which blood cells are rapidly destroyed, resulting in dark urine. ‘Diseases such as malaria were endemic, while blackwater fever, dengue fever, dysentery, yaws, and hookworms were a constant scourge.’[en.oxforddictionaries.com]
  • Indian J Med Microbiol 2016;34:393-4 Dear Editor, A 32-year-old gentleman admitted with high-grade intermittent fever associated with chills, headache and fatigue for 2 days and passage of dark urine for last 6 hours.[ijmm.org]
  • urine burst upon the medical scene in West Africa in 1819, described by an English surgeon named Tidlie.[ncbi.nlm.nih.gov]
  • "After several descriptions by Hippocrates and a single possible medieval description by Gilles de Corbeil, a severe febrile illness accompanied by the passage of dark urine burst upon the medical scene in West Africa in 1819, described by an English[histopathology-india.net]
Uremia
  • Sometimes death occurs in the first days of the disease, in other cases, patients die in the phenomenon of uremia. Anemia in such cases does not have time to develop. In rare cases there is a recovery.[lecheniebolezni.com]

Workup

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.

Base Deficit
  • A strong association was found between ARF and impaired consciousness. [4] , [14] , [15] , [19] , [29] In the present study, only the standard base deficit was statistically different between survivors and non-survivors.[sjkdt.org]

Treatment

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 [4] [10].

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.

Symptomatic treatment may be provided in order to alleviate other symptoms such as abdominal pain, vomitus and fever.

Prognosis

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.

Etiology

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 [2] [5] [6] [7] [8]. 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 [2] [7] [9].

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 [2] [3]. However, cases of BWF have also been registered in people not suffering from G6PD deficiency [10].

Epidemiology

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 [11].

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 [12]. 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 [4].

Sex distribution
Age distribution

Pathophysiology

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 [2] [6] [13]. 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.

Prevention

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.

Summary

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) [1].

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 [2] [3]. 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% [4]. Risks are particularly high in children developing BWF.

Patient Information

Blackwater fever (BWF) is a complication of malaria, a tropical disease whose causative agent is a parasite called Plasmodium. This parasite is transmitted by mosquitoes.

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.

References

Article

  1. World Health Organization, Division of Control of Tropical Diseases. Severe and complicated malaria. . Trans R Soc Trop Med Hyg. 1990; 84 Suppl 2:1-65.
  2. Van den Ende J, Coppens G, Verstraeten T, et al. Recurrence of blackwater fever: triggering of relapses by different antimalarials. Trop Med Int Health. 1998; 3(8):632-639.
  3. Pasvol G. The treatment of complicated and severe malaria. Br Med Bull. 2005; 75-76:29-47.
  4. Bodi JM, Nsibu CN, Longenge RL, et al. Blackwater fever in Congolese children: a report of clinical, laboratory features and risk factors. Malar J. 2013; 12:205.
  5. Tran TH, Day NP, Ly VC, et al. Blackwater fever in southern Vietnam: a prospective descriptive study of 50 cases. Clin Infect Dis. 1996; 23(6):1274-1281.
  6. Rogier C, Imbert P, Tall A, Sokhna C, Spiegel A, Trape JF. Epidemiological and clinical aspects of blackwater fever among African children suffering frequent malaria attacks. Trans R Soc Trop Med Hyg. 2003; 97(2):193-197.
  7. Bruneel F, Gachot B, Wolff M, Regnier B, Danis M, Vachon F. Resurgence of blackwater fever in long-term European expatriates in Africa: report of 21 cases and review. Clin Infect Dis. 2001; 32(8):1133-1140.
  8. Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010; 376(9753):1647-1657.
  9. Bisoffi Z, Marocco S, Monteiro G, Marsiaj M. Acute intravascular haemolysis (blackwater fever) after antimalarial treatment. Trop Med Int Health. 1999; 4(1):72-73.
  10. White NJ Malaria. In: Cook GC, Zumla AI, editors. Manson's tropical diseases. XXI ed. Philadelphia: W.B. Saunders; 2003; p. 1205–95.
  11. Price R, van Vugt M, Phaipun L, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg. 1999; 60(4):547-555.
  12. Bruce-Chwatt LJ. Quinine and the mystery of blackwater fever. Acta Leiden. 1987; 55:181-196.
  13. Bruneel F, Gachot B, Wolff M, et al. Blackwater fever. Presse Med. 2002; 31(28):1329-1334.

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Last updated: 2018-06-22 07:40