Original Editors - Aaron Hume from Bellarmine University's Pathophysiology of Complex Patient Problems project.
- 1 Definition/Description
- 2 Prevalence
- 3 Characteristics/Clinical Presentation
- 4 Associated Co-morbidities
- 5 Medications
- 6 Diagnostic Tests/Lab Tests/Lab Values
- 7 Systemic Involvement
- 8 Causes
- 9 Medical Management (current best evidence)
- 10 Physical Therapy Management (current best evidence)
- 11 Prevention Advice (current best evidence)
- 12 Differential Diagnosis
- 13 Case Reports
- 14 Resources
- 15 References
Malaria is a parasitic infection caused by the bite of a female Anopheles mosquito. The infection can result from any one of five parasites from the Plasmodium group including Plasmodium flaciparum (P. flaciparum), Plasmodium vivax (P. vivax), Plasmodium ovale (P. ovale), Plasmodium malariae (P. malariae), and Plasmodium knowlesi (P. knowlesi). Malaria causes fever, chills, malaise, headaches, and myalgia and can result in death if not treated appropriately. The disease is most prevalent in Sub Suharan Africa and Southeast Asia. It has been eliminated from the United States, but is still one of the most common causes of fever in travelers that have returned from the aforementioned areas. 
Picture courtesy of the Center for Disease Control: http://www.cdc.gov/malaria/about/biology/mosquitoes/
An estimated 500 million cases of Malaria occur each year, with 1-2 million deaths and about 90 % of these deaths occuring in Sub-Saharan Africa. Severe Malaria (caused by P. falciparum) has a mortality rate of about 15-20%. An estimated 50% of the world’s population, about 3.3 billion people, are at risk for Malaria. The following areas are most commonly affected by malaria : Africa, India, Pakistan, Southeast Asia, Paupa New Guinea, Haiti, and parts of South America. 109 countries and territories are affected worldwide and the disease is most prevelant in area of tropical climate, as the Anopheles mosquito is able to live in areas with warm temperatures. Transmission of Malaria has been eliminated from the U.S., Puerto Rico, Jamaica, Chile, Israel, Lebanon, North Korea, and Europe. However, Anopheles mosquitos are found throughout the world, except for Antarctica. The below picture shows the distribution of Malaria transmission throughout the world (Picture courtesy of the Center for Disease Control Prevention: http://www.cdc.gov/malaria/about/distribution.html
The person infected with Malaria will not present with symptoms until about 7 days to 4 weeks after he or she has been bitten by the mosquito. However, symptoms may not occur until up to 6 months to 1 year after the bite. The bite of a female Anopheles mosquito produces infection and consequent death to erythrocytes, or red blood cells, (see the Plasmodium life cycle in “causes” for more information) which causes hemolysis, anemia, and tissue hypoxia. Symptoms could include fever, chills, malaise, headaches, and myalgia. Cough, abdominal pain, and diarrhea may also occur, but are less likely.
Infection by the P. Falciparum parasite produces the most severe form of Malaria and is the most life-threatening. When diagnosed with Malaria, the patient is classified as either severe (complicated) or uncomplicated. The criteria for diagnosis of severe Malaria is listed in the “diagnosis” section. If infected by P. vivax or P. ovale, the patient may experience relapsing Malaria in which the infection can lie dormant in the body for up to 4 years.
Co-morbidities caused by severe Malaria (P. flaciparum) could include cerebral malaria, hypoglycemia, severe anemia, pulmonary edema, respiratory failure, renal failure, and metabolic acidosis. Below is a description of each, and an explanation of the pathophysiology as it relates to Malaria.
Cerebral Malaria: This form of Malaria can only be caused by P. Flaciparum. It is characterized by “the intense sequestration of parasites in the cerebral microvasculature.” In other words, the parasite invades the blood vessels of the brain and disallows blood to circulate as it normally would. Furthermore, oxygen and glucose supply to the brain is compromised because of improper amounts of blood flow. Cerebral Malaria causes over 80% of the casualties caused by Malaria. Symptoms of cerebral Malaria include seizures, stupor and focal neurological symptoms.
Hypoglycemia: In children, hypoglycemia is caused by the inability of the liver to make new forms of glucose (hepatic gluconeogenesis) because the hepatocytes (liver cells) have been infected. In adults, hypoglycemia is caused by increased amounts of insulin in cells which is a result of stimulation of the islet cells in the pancreas, which are responsible for some insulin production.
Anemia: Loss of red blood cells results not only from phagocytic removal of infected erythrocytes, but also removal of uninfected erythrocytes. The bone marrow, which is responsible for blood cell production,is defective in the Malaria infected individual and the result is a decreased level of erythroprotein production and an increased level of phagocytic activity within red blood cells. 
Pulmonary Edema and Respiratory Failure: Inflammatory cytokines (substances that carry signals between cells) are produced in the lungs in response to erythrocyte sequestration (microvascular obstruction). As a result, capillary permeability is increased which can produce pulmonary edema, dyspnea, hypoxia, or acute respiratory distress syndrome. 
Metabolic Acidosis: Lack of oxygen to the tissues produces acidosis (High H+ concentration and low pH). The effects of anemia, microvascular obstruction, and hypovolemia (reduced perfusion of the tissues) can cause this lack of oxygen.
Malaria is treated with various drugs based upon three characteristics about the nature of the infection that affect the selection of the drug including the species of Plasmodium, whether the case is complicated or uncomplicated (see explanation in the “characteristics” section), and the resistance of a certain species of Plasmodium to the drug. The infection has developed resistance to certain drugs in various regions of the world. Therefore, some drugs have been rendered ineffective in the treatment of certain species of the Plasmodium parasite which has been contracted from certain areas of the world . Furthermore, if a woman who has been infected with Malaria is pregnant, many of the below drugs are contraindicated. The main medications used include the following:
1.) Cholorquine Phosphate
a.) species of plasmodium: used for P. vivax, P. malariae, P. ovale, and sensitive strains of P. Flaciparum
b.) type of medication: oral or parenteral
c.) side effects: parenteral dose can be associated with hypotension, cardiac arrest, and seizures
If it is used for acute malarial attacks it can produce gastrointestinal upset, pruritis, headache, and visual disturbance.
a.) species of plasmodium: used for Chloroquine resistant P. flaciparum
b.) type of medication: oral
c.) side effects: nausea, vomiting, abdominal pain, and dizziness
a.) species of plasmodium: all forms of Plasmodium but more commonly used for Chloroquine resistant P. flaciparum
b.) type of medication: oral, intravenous, rectal, or intramuscular
c.) side effects: The intravenous dose can cause cardiac arrhythmias and hypotension. The oral dose can cause nausea, vomiting, diarrhea, and hypoglycemia.
a.) species of plasmodium: all forms of Plasmodium but more commonly used for Chloroquine resistant P. flaciparum
b.) type of medication: oral
c.) side effects: abdominal pain, nausea, vomiting, diarrhea, headache, rash
a.) species of plasmodium: most commonly used for the liver phase of P. vivax and P. ovale
b.) type of medication: oral
c.) side effects: gastrointestinal distress, should not be used during pregnancy
6.) Doxcycline, Tetracycline, Clindamycin
a.) species of plasmodium: should be used in coordination with Quinine and is most commonly used for chloroquine resistant flaciparum and P. vivax from chloroquine resistant areas.
b.) type of medication: oral
c.) side effects: can be associated with sun sensitization, diarrhea, nausea, rash, vomiting, dizziness, and should not be used during pregnancy
Species and Drug of Choice
1.) Uncomplicated Malaria P. Falciparum with Chloroquine Resistance (Countries with resistance include all those that are classified as malarious regions except Central America west of the Panama Canal, Haiti, Dominican Republic and most of the Middle East.
c.) Quinine Sulphate plus one of the following: Doxcycline, Tetracycline, Clindamycin
2.) Uncomplicated Malaria P. Falciparum Cholorquine Sensitive (Countries that are Cholorquine sensitive include all those that are classified as malarious regions except Central America west of the Panama Canal, Haiti, Dominican Republic and most of the Middle East.
a.) Cholorquine Phosphate
3.) Uncomplicated Malaria P. Malariae or P Knowlesi 
a.) Cholorquine Phosphate
4.) Uncomplicated Malaria P. Vivax or P. Ovale Cholorquine Sensitive 
a.) Quinine Sulphate plus either Doxycycline or Tetracycline plus Primaquine Phosphate
b.) Atovaquone-proguanil plus Primaquine Phosphate
c.) Mefloquine plus Primaquine Phosphate
5.) Uncomplicated Malaria P. Vivax with Cholorquine Resistance 
a.) Quinine Sulphate plus one of the following: Doxcycline, Tetracycline, Clindamycin
b.) Atovaquone-proguanil plus Primaquine Phosphate
c.) Mefloquine plus Primaquine Phosphate
6.) Uncomplicated Malaria, Treatment for women who are pregnant 
a.) Chloroquine-Sensitive (any species): Cholorquine Phosphate or Hydrooxychloroquine
b.) P. Falciparum with Chloroquine Resistance: Quinine Sulphate plus Clindamycin
c.) Vivax with Cholorquine Resistance: Quinine Sulphate
7.) Complicated (Severe) Malaria Treatment:
a.) Quinidine gluconate plus one of the following: Doxcycline, Tetracycline, Clindamycin
For a complete list of dosages for each drug please visit the Center for Disease Control Website at www.cdc.gov/malaria/pdf/treatmenttable.pdf
The primary mode of prophylaxis (prevention) for years has been the use of Chloroquine. However, with chloroquine resistance present in most malarious countries, the choice of drug is now based upon whether or not the country is chloroquine resistant. The choice of drug may also rely upon the patient. As mentioned before, some drugs are contraindicated for pregnancy as well as small children.
1.) Country with Chlorquine Resistance Treatment Options:
a.) Doxycycline Prophylaxis
2.) Country without Chloroquine Resistance 
a.) Chloroquine Prophylaxis
3.) Country with Chlorquine Resistance Treatment Options for Child < 5 kg or 1st Trimester of pregnancy
a.) Mefloquine Prophylaxis
Diagnostic Tests/Lab Tests/Lab Values
Malaria should be expected in any traveler who presents with a fever who has returned from a Malarious region within the past year. The standard for diagnoses of malaria is through microscopic analysis of thick and thin blood smear tests. Of the two, a thick blood smear test is more sensitive than a thin blood smear test because a greater volume of blood can be analyzed. However, the thin blood smear can more accurately detect the correct species of malaria that is involved. The test should be repeated 2-3 times if the smear shows a negative result for Malaria because a low parasitic level may not be detected by blood smear in the first test. Diagnosis is determined by examining the parasite density. Parasite density is determined by the percent of infected red blood cells that are found in the blood smear.  The below picture shows malarial parasites within the red bed blood cell on a microscopic blood smear.Picture courtesy of the Center for Disease Control: http://www.cdc.gov/malaria/about/biology/parasites.html
Rapid Diagnostic Tests (RPTs) are used when blood smears are unavailable or examination is delayed. They are based upon recognition of the antigens Histadine Rich Protein 2 (HRP2) and Parasyte Lactate Dehyrdrogenase (pLDH) by dipstick analysis. The HRP2 antigen detects P. falciparum and pLDH can detect any form of Plasmodium.
There is no proven or accepted gold standard for the diagnosis of Malaria. However, evidence shows that microscopy is the most reliable test for non-falciparum infections. However, HRP2 showed a high sensitivity (92.7 %) and high specificity (99.2 %) for detecting P. falciparum in Malaria endemic areas. The use of flurescent microscopy with an acidine orange stain has also been proven to be highly sensitive (97.9%) for determining P. falciparum.
Lab Values 
Lab values can also be a good indication of malarial infection. The following is a table with values that can be expected:
Diagnosing Severe Malaria 
Diagnosis of severe Malaria can be aided by recognition of specific criteria designated by the World Health Organization. Any one of the following criteria along with a positive blood smear for the parasite P. falciparum establishes the diagnoses of severe or complicated Malaria:
Cerebral Malaria- symptoms include decreased consciousness and seizures
Respiratory distress- symptoms include dyspnea and nasal flaring
Prostation-lying in the prone position due to a decline in fluid and electrolytes
Hyperparasitemia- parasite density greater than or equal to 500,000/mm3
Severe anemia- hemoglobin less than or equal to 5 g/dL
Hypoglycemia- blood glucose less than or equal to 5 g/dL
Jaundice/icterus- characterized by yellowing of the skin as a result of loss of red blood cells
Renal Insufficiency- classified as anuria for at least 24 hours
Hemoglobinuria- dark colored urine
Shock- decreased perfusion of tissues due to infection of erythrocytes
Cessation of eating and drinking
Hyperpyrexia- axillary temperature greater than or equal to 40 degrees celsius
Because of the drastic effect that the parasitic infection associated with Malaria has on the red blood cells, the infection can easily spread to various parts of the body and can potentially have sever systemic effects. The following is a description of the systems that may be invloved in the symptoms of Malaria:
Vascular: loss of erythrocytes causes hemolysis, anemia, and tissue hypoxia. Sequestration (microvascular obstruction) of infected erythrocytes can cause cerebral malaria (see “co-morbidities” section).
Pulmonary: infected erythrocytes can sequester throughout the lungs which could cause respiratory failure because of lack of blood flow and lack of oxygen.
Gastrointestinal: Initially, the Malarial infection spreads in the liver killing hepatocytes (see sequence of infection in the "causes" section) which could cause liver dysfunction and possible failure. Hemoglobinuria is caused by the excess hemoglobin left over from destroyed red blood cells. The remnants of the red blood cells are cleaned up by the kidney and released in the urine, producing a dark red color. Repetitive vomitting can also occur in severe anemia.
Genitourinary: Renal failure can occur as a result of blood flow obstruction and destruction of red blood cells.
Gynecologic: Infected erythrocytes can sequester in the female placenta compromising the blood flow and oxygen supply. 
Integumentary: Jaundice, yellowing of the skin, is caused by decreased amount of red blood cells and also an increase in bilirubin, which is a product of hemoglobin breakdown.
Malaria is most commonly caused by the bite of the female Anopheles mosquito. Transmission occurs because of the bite of two mosquitos. The following steps occur in the sequence of infection:
Mosquito # 1
1.) mosquito bites the host and releases sporozoites (parasite)
2.) sporozoites invade the hepatocytes in the liver and turn into schizonts
3.) schizonts rupture forming merozoites (10,000-30,000) which invade erythrocytes
4.) asexual reproduction occurs within the erythrocyte (immature trophozoite grows into a mature trophozoites) forming more schizonts which again rupture producing more merozoites. The merozoites then invade more erythrocytes.
5.) death of erythrocytes causes the symptoms of malaria
6.) some trophozoites form gametocytes
Mosquito # 2
1.) mosquito bites the host infected by Malaria and male and female gametocytes enter the mosquito’s stomach
2.) male and female gametocytes sexually reproduce within the mosquito’s abdomen forming zygotes
3.) zygotes develop into Ookinetes
4.) Ookinetes develop into Oocysts
5.) Oocyst ruptures forming sporozoites
6.) sporozoites travel to the mosquito’s saliva and can initiate infection in the next host
Picture curteousy of http://qspace.library.queensu.ca/dspace/html/1974/421/pfalcip01.htm
Transmission can also occur by way of blood transfusion, organ transplant, the sharing of needles with contaminated blood, or by congenital means when a mother passes the infection to her unborn baby. Furthermore, “Airport” Malaria can occur when infected mosquitos are transported from a Malarious region to an area not affected by Malaria. Subsequently, civilians of the non-endemic region can be infected by Malaria without having traveled to a foreign country.
The below video describes the the sequence of events causing an infection by a Malarial parasite and also descibes how the infection can spread throughout the body
Medical Management (current best evidence)
History of Treatment:
In 1955 the World Health Organization created a program with the use of Chloroquine and Dichlorodiphenyl (DDT) spraying in an effort to eradicate the disease. However, the disease spread so rapidly that the program was terminated in 1967. Although the disease was not eradicated, death rates declined in the 1970’s because of the effectiveness of Chloroquine, especially in the treatment of the P. flaciparum species. With such a large use of Chloroquine, many regions have became resistant to the drug, causing death rates to soar in the 80’s and 90’s, especially in Africa. Recently, drugs have been developed to be used in chloroquine resistant areas.
Treatment in the U.S. vs Malarious Regions
A detailed description of all drugs and treatment options can be found in the medications section. There is currently no vaccine for the prevention of Malaria. Therefore, treatment is based upon prevention by way of prophylaxis and drug therapy if the infection is diagnosed. If the illness if treated with appropriate medications, all the parasites can be eliminated and the disease can be totally cleared from the body. The treatments in the medications section are those used to treat Malaria within the United States. Artemisinin, a investigational category of drug in the U.S., is now being used regularly for the treatment of uncomplicated and severe Malaria in countries that are endemic with Malaria. For more information on detailed treatment plans with the use of Artemisinin please visit the World Helath Organization Website: http://www.who.int/malaria/diagnosis_treatment/treatment/en/index.html 
In clincial trials, Artemisinins have been proven to be effective in combination with other drugs including artesunate-mefloquine, artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine. Artemether, a type of Artemisinin been shown to more effective than Quinine (the drug currently used in the US) in the treatment of severe Malaria. Because there has been a great deal of strong evidence to support the use of Artemisinin, it is available for treatment of severe Malaria under the IND (investigational new-drug) application by way of the CDC in the U.S. The FDA has not yet approved the drug and Quinidine is therefore the only readily available treatment for severe Malaria in the US. However, there is strong clinical evidence for the use of the medications listed for treatment of various types of Malaria in the United States.
Artemisinin is derived from the sweet wormwood plant called "quinghaosu" or, "Artemisia Annua", found in China. Picture courtesy of http://www.rollbackmalaria.org/psm/artemisia.html
A detailed description of the preventative medications for Malaria can be found in the medications section. The treatments that are listed are those used in the United States. A systematic review proved Atovaquone-Progunil to have a 95.8 % efficacy rate and was proven to be better tolerated and have less adverse side effects when compared to other chemoprophylactic agents. When compared to other chemoprophylactic agents in efficacy, Atovaquone-Progunil was proven to be more effective than chloroquine and mefloquine individually. However, there is insufufficient evidence of Atovaquone-Progunil compared to combination therapies of sulfadoxine-pyrimethamine, halofantrine, artesunate plus mefloquine, quinine plus tetracycline, and dihydroartemisinin-piperaquine-trimethoprim-primaquine in treating malaria.
Physical Therapy Management (current best evidence)
The most important part of physical therapy management of Malaria is the ability to recognize the signs and symptoms of Malaria and quickly refer to a physician for treatment. An efficient diagnosis and treatment can help reduce morbidity and mortality associated with Malaria. Therefore, a physical therapist should always be aware of a patient who has traveled to a Malarious region and Malaria should be considered in any traveler who experiences symptoms of fever within the first year of returning from a Malarious region. However, fever does not have to present to diagnose Malaria. Therapsists should be cognizant of other symptoms of Malaria including chills, headache, malaise, nausea, vomitting, diarrhea, abdominal pain, myalgias, back pain, weakness, dizziness, confusion, cough, and/or coma. A thorough history can help prevent spread of infection and even death.
Furthermore, it may be necessary for a therapist to educate a patient who is palnning on traveling to a Malarious region on the options for prevention. The best resource for explainating options would be the Center for Disease Control website:
Prevention Advice (current best evidence)
Alternative treatment for Malaria is based upon prevention of infection. Prophylaxis (explained further in “prevention” section of medications) is not 100 % effective. Therefore, to prevent the bite of a female Anopheles mosquito one should always wear long sleeves and pants during dusk in Malarious regions and should also sleep under impregnated bed nets.
Bed nets not only prevent mosquitos from biting while an idividual is sleeping, but they also kill the mosquitos, helping reduce the risk of infection to everyone in the surrounding community. The nets are made out of either cotton, polyethylene, or polypropylene and are impregnated with the insecticide, pyrethroid. These nets usually retain the insectiside for about 6-12 months, but a new line of bed nets called long-lasting insecticide treated nets (LLIS) can last for up to 3 years. The World Health Organization has organized a list seven LLIS that are recommended in all Malarious regions, which can be found at http://www.who.int/whopes/en/
According to the CDC, The use of insecticide treated bed nets has been proven to be effective in preventing deaths of children under the age of 5. Other clinical trials have proven that the nets are effective at reducing the rate morbidity and mortality among people living in Malarious regions.  They are also effective for the prevention of Malaria in pregnant women, although coverage of bed nets is lacking in Malarial areas such as Kenya. Therefore, programs have been established to help raise money for the funding of nets. Information about these programs can be found at the following websites:
Picture courtesy of the President's Malarial Initiative http://www.pmi.gov/technical/itn/index.html
IRS, or Indoor Residual Spraying, involved spraying insectiside inside houses in Malarious regions. N,N-diethyl-3-methylbenzamide (DEET), an insect repellant, has been shown to be effective in killing mosquitos, thereby preventing the infectious bite.
Malaria can be similar to multiple other illnesses because of its common symptoms of fever, chills, headache, and malaise. However, Malaria is considered the most likely cause of fever if the patient has recently returned from travel to a Malrious region. The following are other possible diagnoses.
Influenza- The flu is similar to Malaria in that they share multiple symptoms including fever, malaise, headache, and myalgia. However, upper respiratory symptoms are more likely to present in a patient who has the flu.
Typhoid Fever- Similar symptoms including fever, headache, nausea, and malaise make it difficult to distinguish Malaria from enteric fever. The diagnosis is likely to be enteric fever if the patient has a history of unsanitary food or water intake as well as gastrointestinal symptoms.
Bacteremia/Sepsis- Bacteremia can often accompany Malaria, especially in children and can present with fever, hypotension, and confusion.
Dengue Fever- Although this illness, like Malaria, is contracted from a Mosquito, symptoms arise more quickly compared to Malaria (4-7 days). The two infections have similar symptoms, but patients with Dengue fever will likely have a rash, erythema, and bradycardia to accompany fever, headache, nausea, and malaise.
Acute Schistoosomiasis (Katayama Fever)- The signs of Katayama fever present about 4-8 weeks after exposure fresh water in a tropical region. Like Malaria, the patient may have fever, headache, and malaise, but will more than likely also present with a rash, urticaria, lymphadenopathy, and blood eosinophilia.
Leptospirosis- Similarly to Malaria, symptoms of fever, headache, nausea, and malaise, arise in about 7-12 days in a patient infected with Leptospirosis. However, the illness is caused by exposure to fresh water and the patient will present with a rash. Also, extremely high bilirubin levels could be present in the patient with Leptospirosis.
African Tick Fever- Also known as Rickettsia Africae, the Tick Fever can present with fever, headache, and myalgias. Unlike Malaria, it is likely that the patient will have lymphadenitis and inoculation eschars.
East African Trypanosomiasis (Sleeping Sickness)- Symptoms of fever, malaise, headache, and myalgia, are likely but the Sleeping Sickness can also present with a red rash because of the bite of a tsetse fly. Also, posterior cervical lymphadenopathy (rash) is a common sign of Trypanomiasis.
Yellow Fever- The Yellow Fever, like Malaria, is caused by a mosquito bite in a tropical region and both illnesses have similar symptoms. However, bradycardia can present in the patient with Yellow Fever and symptoms take effect within 3-6 days, unlike Malaria.
Malaria transmission in non-endemic areas: case report, review of the literature and implications for public health management
Atypical aetiology of a conjugal fever: autochthonous airport malaria between Paris and French Riviera: a case report
Congenital malaria in neonates: two case reports and review of the literature.
There are several established programs worldwide with the goal of preventing further infection byt Malaria. Please visit the following websites for more information:
Global Malaria Action Plan to Eradicate Malaria
Malaria Eradication Research Agenda
President's Malaria Initiative
World Malaria Day Website
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