Malaria

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Definition/Description

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.

Prevalence

An estimated 500 million cases of Malaria occur each year, with 1-2 million deaths.  About 90 % of these deaths occur in Sub-Saharan Africa.⁶ Severe Malaria (caused by P. falciparum) has a mortality rate of about 15-20%.  About 1,500 cases are diagnosed within United States every year.⁴ An estimated 50% of the world’s population, about 3.3 billion people, are at risk for Malaria.⁶ 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.⁶ 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.  As a result, the disease can be re-introduced into any country.

Characteristics/Clinical Presentation

The person infected with Malaria will not present with symptoms until about 7 days to 4 weeks after he or she has been bitten.⁶ 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.⁴ 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.⁴

Associated Co-morbidities

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 pathophisiology 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 disallow 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 erythtrocytes. The bone marrow, which is responsible for blood cell production,is defected 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.

Medications 

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 in complicated or uncomplicated (see explanation in the “characteristics” section), and the resistance of a certain species of Plasmodium to the drug.⁴ The infection has developed resisitane 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 .⁴ 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: 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 used for acute malarial attacks it can produce gastrointestinal upset, pruritis, headache, and visual disturbance.

2.) Mefloquine
a.) species of plasmodium: used for Chloroquine resistant P. flaciparum
b.) type of medication: oral
c.) side effects: nausea, vomiting, abdominal pain, and dizziness

3.) Quinine
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.

4.) Proguanil/Atovaquone
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:  

5.) Primaquine
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
b.) type of medication: oral
c.) side effects: can be associated with sun sensitization 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.⁵
Treatment Options:
a.) Atovaquone-proguanil
b.) Artemether-lumefantrine
c.) Quinine Sulphate plus one of the following: Doxcycline, Tetracycline, Clindamycin
d.) Mefloquine

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.⁵
Treatment Options:
a.) Cholorquine Phosphate
b.) Hydrooxychloroquine

3.) Uncomplicated Malaria P. Malariae or P Knowlesi ⁵
Treatment Options:
a.) Cholorquine Phosphate
b.) Hydrooxychloroquine

4.) Uncomplicated Malaria P. Vivax or P. Ovale Cholorquine Sensitive ⁵
Treatment Options:
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 ⁵
Treatment Options:
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 ⁵
Chloroquine-Sensitive (any species):
a.) Cholorquine Phosphate
b.) Hydrooxychloroquine

P. Falciparum with Chloroquine Resistance:
a.) Quinine Sulphate plus Clindamycin


P. Vivax with Cholorquine Resistance
a.) Quinine Sulphate

7.) Complicated (Severe) Malaria ⁵
Treatment Options:
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

Prevention:

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
b.) Atovaquone-proguanil

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

For more information regarding the best choice of prophylactic drug, visit the center for disease control website at: www.cdc.gov/malaria/traverler/drugs.html

Diagnostic Tests/Lab Tests/Lab Values

Lab Tests

Malaria should be expected in any traveler who presents with a fever who has returned from a Malarious region within the past year.⁶  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.⁶  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.⁶

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 and form of Plasmodium.

Lab Values

Lab values can also be a good indication of malarial infection. The following is a list values that can be expected:
Hemoglobin- decreased
Hematocrit- decreased
Leukocytes- high, normal, or low
Sodium- slightly low
Platelets- normal or slightly low

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
Repetitive vomiting
Hyperpyrexia- axillary temperature greater than or equal to 40 degrees celsius

Systemic Involvement

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, which is cleaned up by the kidney, and released in the urine which produces 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 decresed amount of red blood cells and also an increase in bilirubin, which is a product of hemoglobin breakdown.

Causes

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
2.) sporozoites invade the hepatocytes in the liver and turn into schiznots
3.) schizots 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 schiznots 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

Transmission can also occur by way of blood transfusion, organ transplant, the sharing of needles with contaminated blood, by congenital means when a mother passes the infection to her unborn baby. 4 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.7 

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 1967.³ 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.³ With such a large use of Chloroquine, many regions became resistant to the drug, causing death rates to soar in the 80’s and 90’s, especially in Africa.³ Recently, drugs have been developed to be used in chloroquine resistant areas.³

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.⁶ Therefore, treatment is based upon prevention by way of prophylaxis, drug therapy if the infection is diagnosed, and relative rest. If the illness if treated with appropriate medications, all the parasites can be eliminated and the disease can be totally cleared from the body.⁶

More info to come on current evidence...

Physical Therapy Management (current best evidence)

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Alternative/Holistic Management (current best evidence)

Alternative treatment for Malaria is based upon prevention of infection. If the disease is contracted, drug treatment is the only option. 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.³ N,N-diethyl-3-methylbenzamide (DEET), an insect repellant, has been shown to be effective in preventing an infectious bite.³

More info to come on evidence...

Differential Diagnosis

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.³ However, upper respiratory symptoms are more likely to present in a patient who has the flu.³

Enteric Fever- Similar symptoms including fever, headache, nausea, and malaise make it difficult to distinguish Malaria from enteric fever.³ 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.³

Bacteremia/Sepsis- Bacteremia can often accompany Malaria, especially in children and can present with fever, hypotension, and confusion.³

Dengue Fever- Although this illness, like Malaria, is contracted from a Mosquito, symptoms arise more quickly compared to Malaria (4-7 days).³ 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.³

Acute Schistoosomiasis (Katayama Fever)- The signs of Katayama fever present about 4-8 weeks after exposure fresh water in a tropical region.³ 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.³

Leptospirosis- Similarly to Malaria, symptoms of fever, headache, nausea, and malaise, arise in about 7-12 days in a patient infected with Leptospirosis.³ 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.³

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.³

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.³ Also, posterior cervical lymphadenopathy (rash) is a common sign of Trypanomiasis.³

Yellow Fever- The Yellow Fever, like Malaria, is caused by a mosquito bite in a tropical region and both illnesses have similar symptoms.³ However, bradycardia can present in the patient with Yellow Fever and symptoms take effect within 3-6 days, unlike Malaria.³

Case Reports

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Resources

Global Malaria Action Plan to Eradicate Malaria

http://rbm.who.int/gmap/index.html

Malaria Eradication Research Agenda

http://malera.tropika.net/

President's Malaria Initiative

http://www.pmi.gov/

Center for Disease Control Malaria Information

http://www.cdc.gov/malaria/index.html

Recent Related Research (from Pubmed)

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