Malaria

• Reporting criteria

• The disease and its epidemiology

• Case definition

• Laboratory testing

• Case investigation

• Disease control measures

• References

What and how to report to the Colorado Department of Public Health and Environment (CDPHE) or local public health agency 

• Malaria cases should be reported within four days of diagnosis or positive laboratory results.
• Cases can be reported in EpiTrax or by faxing or phoning CDPHE or the local public health agency.

Purpose of surveillance and reporting

• To monitor for disease clusters indicating local transmission, as potential Anopheles mosquito vectors are present in Colorado.

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Etiologic agent 

Malaria is a disease caused by infection with a protozoal parasite in the genus Plasmodium. 

The Plasmodium species infecting humans are:

• P. falciparum, which is found worldwide in tropical and subtropical areas, causes the most common form of malaria. Symptoms of P. falciparum malaria can become severe in as little as 24 hours without appropriate treatment. It is estimated that every year approximately 1 million people are killed by P. falciparum, especially in African countries where this species predominates. P. falciparum can cause severe malaria when it multiplies rapidly in the blood, causing anemia and clotting. Cerebral malaria, which can be fatal, results when these clots form in the brain and can cause severe blood loss (anemia). 
• P. vivax is found mostly in Asia, Latin America, and in some parts of Africa. Because of the population densities in these countries it is probably the most prevalent human malaria parasite. 
• P. ovale is found primarily in West Africa and the islands of the western Pacific. It is biologically and morphologically very similar to P. vivax. Plasmodium vivax and P. ovale can lie dormant in an infected person’s liver, causing relapses months to years after the initial infection.
• P. malariae, found worldwide, is the only human malaria parasite species that has a three-day fever cycle. P. malariae can cause serious complications such as nephrotic syndrome.
• P. knowlesi is found throughout Southeast Asia as a natural pathogen of long-tailed and pig-tailed macaques. It has a 24-hour replication cycle and can rapidly progress from an uncomplicated to a severe infection; fatal cases have been reported. Plasmodium knowlesi is considered a more direct zoonotic infection, as vector mosquitoes of this form of malaria obtain their infective blood meals from non-human primate reservoirs in forests in southeast Asia. These mosquitoes then bite humans that enter areas where P. knowlesi malaria is circulating in the course of their work or for recreation.

Clinical description 

Malaria symptoms usually begin 10-15 days after the bite of an infected mosquito, but can start as early as 7 days after the bite. Malaria often begins with mild fever, headache, chills, and vomiting. Abdominal pain is commonly reported and fevers can increase over time. Clinical signs can include anemia, respiratory distress, renal failure, and cerebral involvement (cerebral malaria). 

Reservoirs 

Humans are the reservoir for Plasmodium species that cause human malaria, except for Plasmodium knowlesi for which the reservoir is non-human primates. 

Modes of transmission 

Malaria is transmitted by the bites of infected female Anopheles mosquitoes, which are present in many parts of the world. Malaria is not transmitted person-to-person, except in rare cases via blood and tissue donations from infected people to susceptible recipients. Rarely, malaria can also be transmitted vertically to a baby during pregnancy or birth. 

Incubation period 

Malaria symptoms usually begin 10-15 days after the bite of an infected mosquito, but can start as early as 7 days after the bite. Shorter incubation periods are observed most frequently with Plasmodium falciparum. Plasmodium vivax and P. ovale have a dormant liver stage of their life cycle that can reactivate after symptomless intervals of up to 2 (P. vivax) to 4 years (P. ovale). P. malariae can persist asymptomatically in an untreated human host for years, even a lifetime. 

Use of antimalarial drugs (chemoprophylaxis) by travelers can delay symptom onset by weeks or months. In these cases, travelers can fall ill with malaria long after they have left an endemic area. 

Infectious period 

Blood-stage parasites cause the symptomatic disease of malaria, and it is during that time that Anopheles mosquitoes are able to pick up the parasite during a blood meal and become infected. After a week or more the newly infected mosquito can transmit the parasite to new hosts by biting them. 

Epidemiology 

Malaria originated in Africa and the parasites subsequently evolved over millions of years into the currently recognized species infecting human populations. The disease was introduced into the Americas in the 1400s, and eventually became widespread throughout North and South America. Malaria persisted in North America into the 1950s when the use of insecticides and environmental modifications of mosquito habitats eradicated it from the U.S. Malaria has also been introduced into Asia and is endemic there, as well. 

The lifecycle of the malaria parasite begins in humans when a vector mosquito injects the parasite into a person during feeding. The malaria sporozoites travel to the liver and replicate there as merozoites. The merozoites then leave the liver and enter the bloodstream where they parasitize red blood cells (RBCs). Inside the RBCs the parasite develops and differentiates into several different forms including the sexual forms, i.e., the gametocytes. Each cycle of parasite reproduction in the RBCs is marked by a fever when new merozoites burst from the cells to infect more RBCs. The duration of the fever cycle in an infected person differs depending on the infecting Plasmodium species. When a mosquito bites the infected person and ingests the gametocytes in its blood meal, it becomes infected with the parasite and the cycle starts over. 

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Clinical description

The first symptoms of malaria (most often fever, chills, sweats, headaches, muscle pains, nausea, and vomiting) are often non-specific. Common physical findings are elevated temperature, perspiration, and/or tiredness. In severe malaria, clinical findings (confusion, coma, neurological focal signs, severe anemia, respiratory difficulties) are more striking and may increase the suspicion for malaria. 

Laboratory criteria for diagnosis

• Detection of circulating malaria-specific antigens using rapid diagnostic test (RDT); OR
• Detection of species specific parasite DNA in a sample of peripheral blood using a polymerase chain reaction (PCR) test. (Note: Laboratory-developed malaria PCR tests must fulfill Clinical Laboratory Improvement Amendments requirements, including validation studies); OR
• Detection of malaria parasites in thick or thin peripheral blood films, determination of species by morphologic criteria, and calculation of the percentage of infected red blood cells (parasitemia). 

Criteria to distinguish a new case from an existing case

• A subsequent attack experienced by the same person but caused by a different Plasmodium species is counted as a new case. A new CMR will be made in EpiTrax, and another public health investigation needs to be completed.
• A subsequent attack experienced in the past 12 months by the same person and caused by the same species in the United States may indicate a relapsing infection or treatment failure caused by drug resistance of a separate attack. 

Case classification 

Confirmed

• Detection and specific identification of malaria parasite species by microscopy on blood films in a laboratory with appropriate expertise, in any person (symptomatic or asymptomatic) diagnosed in the United States, regardless of whether the person experienced previous episodes of malaria while outside the country; OR
• Detection of Plasmodium species by nucleic acid test (e.g., PCR) in any person (symptomatic or asymptomatic) diagnosed in the United States, regardless of whether the person experienced previous episodes of malaria while outside the country; OR
• Detection of unspeciated malaria parasites by microscopy on blood films in a laboratory with appropriate expertise, in any person (symptomatic or asymptomatic) diagnosed in the United States, regardless of whether the person experienced previous episodes of malaria while outside the country. 

Suspect

• Detection of Plasmodium species by RDT (BinaxNOW malaria rapid diagnostic test) without confirmation by microscopy or nucleic acid testing, in any person (symptomatic or asymptomatic) diagnosed in the United States, regardless of whether the person experienced previous episodes of malaria while outside the country.

CDC Disease Acquisition Classification

• Locally acquired: In the U.S., a non-endemic setting without indigenous malaria transmission, locally acquired cases are typically classified into two categories:
  • Induced: transmission through a blood transfusion, tissue, or organ transplantation, or another parenteral route, not mosquito-borne or congenital transmission.
  • Introduced: malaria acquired by mosquito transmission from an imported case in an area where malaria is not a regular occurrence.
• Imported: malaria acquired outside the U.S. The case must have a recent (within 2 years) travel history to a country or territory with ongoing malaria transmission.
• Relapsing: recurrence of disease after it has been apparently cured. In malaria, true relapses are caused by reactivation of dormant liver-stage parasites (hypnozoites) of P. vivax and P. ovale. Typically a relapse occurs three months to three years after the initial infection. P. falciparum and P. malariae species do not have liver hypnozoites that can be reactivated. 
• Cryptic: an isolated case of malaria that cannot be epidemiologically linked to additional cases, and for which epidemiologic investigation does not identify the mode of acquisition.
• Congenital: malaria infection transmitted directly from mother to child during pregnancy or childbirth. 
• Recrudescent: a repeated attack of malaria due to the survival of malaria parasites in red blood cells can occur for any Plasmodium species and typically occurs in the first four weeks after initial illness due to failure of treatment to clear all parasites. Some explanations for recrudescence include: 
  • Incomplete adherence to an appropriate antimalarial regimen.
  • Inappropriate use of oral antimalarial for severe illness, especially if there is hyperparasitemia (at least 5% of red blood cells are infected).
  • Antimalarial drug resistance.

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The State Public Health Laboratory does not offer malaria testing. 

Blood smears from suspect cases can be referred to the CDC Division of Parasitic Diseases Diagnostic Laboratory for diagnosis confirmation by a pathologist. Consult with CDPHE’s malaria epidemiologist for further information.

Babesiosis is another intraerythrocytic parasite infection that can have similar signs and symptoms as malaria. Babesia microti (and other Babesia species) are transmitted in some parts of the U.S. by ticks and can be difficult to differentiate from P. falciparum by blood smear. PCR testing for both Babesia and Plasmodium to distinguish between these illnesses if there is any question, especially for individuals who have not traveled recently in a place where ongoing malaria transmission occurs. 

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Investigate all cases of malaria to determine:

• Symptoms and symptom onset date
• Laboratory testing results
• Infecting Plasmodium species
• Parasitemia
• Treatment details
• Travel history, including dates

Under the Investigation tab in EpiTrax, “Was malaria chemoprophylaxis used?” refers to medication taken before, during, and after travel to prevent malaria infection. Treatments given to cure the acute illness should be documented in the "Treatments" section under the “Clinical” tab.

Antimalarial treatments may not be immediately initiated, so the information available at diagnosis may not be complete. Additional follow up may be needed to collect all treatment data.

If the case is not able to be interviewed, investigators should rely on medical records or healthcare provider information. The most important task is to determine how and where malaria was acquired.

If the initial investigation does not yield a recent travel history (in the past 2 years) or prior malaria illness (within 2-3 years), then an enhanced investigation is warranted. Contact the malaria epidemiologist at CDPHE immediately for assistance. 

Forms 

Complete investigation data fields in EpiTrax, including travel history, and summarize any other pertinent case information in the Notes section. Change investigation status to “Approved by LPHA” once you have finished investigating. CDPHE will review the EpiTrax data, assign state case status, and close the case. 

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Treatment

Chloroquine was previously the most commonly used drug for treating malaria. However, P. falciparum and P. vivax have developed resistance to the drug in some areas. Chloroquine or hydroxychloroquine can still be used for treatment in areas with chloroquine-sensitive malaria. This includes parts of Central America, parts of the Caribbean, and the Middle East.

Healthcare providers should ascertain the species of malaria and the region where it was acquired before starting treatment. For uncomplicated malaria, suggested treatments are atovaquone-proguanil (brand name Malarone), artemether/lumefantrine (brand name Coartem), or quinine with doxycycline, tetracycline, clindamycin or mefloquine (brand name Lariam). For severe malaria, intravenous artesunate is recommended.  Treatment regimens for P. vivax and P. ovale should include primaquine to prevent relapse, except for patients with a glucose-6-phosphate dehydrogenase (G6PD) deficiency. A G6PD deficiency causes the body to break down red blood cells prematurely. People who have a G6PD deficiency that use primaquine run the risk of potentially life-threatening hemolysis and resulting anemia. The degree of severity of the hemolytic episode is unpredictable which is why it is recommended that people with a G6PD deficiency of any kind not use primaquine as a treatment for malaria. Glucose-6-phosphate dehydrogenase enzyme testing should be performed to identify if a patient has a deficiency before primaquine treatment is started.

Prophylaxis

There is currently no vaccine to prevent malaria licensed in the United States. Antimalarial drugs (chemoprophylaxis) are available. They do not give complete protection, but adherence to the recommended drug regimen significantly reduces the risk of infection and fatal disease. Details on recommended chemoprophylaxis regimens can be found at CDC's "Choosing a drug to prevent malaria" webpage. 

Education

Travelers to countries where malaria is present should be educated on mosquito bite prevention methods as well as options for appropriate medications to prevent malaria while traveling. CDC’s Travelers' Health webpage on malaria gives detailed information by country for travelers.

Travelers should be educated on the ABCDs of malaria protection:

1. Be Aware of the risk, the incubation period, the possibility of delayed onset, and the main symptoms.
2. Avoid being Bitten by mosquitoes, especially between dusk and dawn. Protection from biting mosquitoes is of paramount importance.
3. Take antimalarial drugs (Chemoprophylaxis) when appropriate to prevent infection developing into clinical disease. 
4. Immediately seek Diagnosis and treatment if a fever develops 1 week or more after entering an area where there is a malaria risk and up to 3 months (or, rarely, later) after departure from a risk area. Travelers to remote locations where medical care is not readily available may be counseled to carry standby emergency treatment.

Environmental measures

Methods for preventing mosquito bites when traveling to malaria endemic countries include bed nets, long sleeved clothing, insect repellent, flying insect spray, and staying in air-conditioned or well-screened quarters.

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• CDC's malaria webpage
• CDC's Traveler's Health malaria page (CDC Yellow Book)
• National Notifiable Diseases Surveillance System (NNDSS)
• CDC malaria surveillance & case investigation best practices

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Important telephone and fax numbers

• CDPHE Communicable Disease Branch
• Phone: 303-692-2700 or 800-866-2759
• Fax: 303-782-0338
• After hours: 303-370-9395

CDPHE Microbiology Laboratory: 303-692-3480

CDC malaria clinical consult line (for health care providers):

• Weekdays, 9am-5pm ET: (770) 488-7788 or (855) 856-4713.
• Afterhours: (770) 488-7100.

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