Malaria
Life cycle of Malaria. Source: CDC.
Mature Plasmodium vivax schizont containing 18 merozoites. The malaria parasite life cycle involves two hosts; during a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host, which infect the liver, mature into tissue schizonts, and rupture releasing merozoites which in turn infect red blood cells. Those red blood parasites mature into blood schizonts (shown here). (Source: CDC; Credit Dr. Mae Melvin) Malaria is a mosquito-borne disease caused by a parasite. Each year 350-500 million cases of malaria occur worldwide, and over one million people die, most of them young children in sub-Saharan Africa. Malaria is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and sub-Saharan Africa. Malaria is caused by a protozoan parasite of the genus Plasmodium and is transmitted to animals by the bite of a female mosquito of the genus Anopheles. Malaria can cause many symptoms, the most common of which include fever, fatigue, chills, and many other flu-like symptoms. Although there is no vaccine to protect against this disease, many preventative and treatment methods are available.
Contents
History
Malaria, or a disease resembling malaria, has been noted for more than 4000 years. From the Italian for "bad air," malaria has probably had a huge influence on human populations throughout human history. The symptoms of malaria were first described in ancient Chinese medical writings. In 2700 BC, several characteristic symptoms of what would later be named malaria were described in China within the Nei Ching, the Canon of Medicine. Malaria became widely recognized in Greece by the 4th century BC, and it was responsible for the decline of many of the city-state populations. By the age of Pericles, there were extensive references to malaria in the literature and depopulation of rural areas was recorded. In a Sanskrit medical treatise, the symptoms of malarial fever were described and attributed to the bites of certain insects. A number of Roman writers attributed malarial diseases to the swamps.
In 1880, Charles Louis Alphonse Laveran, a French army surgeon stationed in Constantine, Algeria, was the first to notice parasites in the blood of a patient suffering from malaria. This occurred on November 6, 1880. For his discovery, Laveran was awarded the Nobel Prize in 1907. On August 20, 1897, Ronald Ross, a British officer in the Indian Medical Service, was the first to demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes. In further work with bird malaria, Ross showed that mosquitoes could transmit malaria parasites from bird to bird. This necessitated a sporogonic cycle, which is the time interval during which the parasite developed in the mosquito. Thus, the problem of malaria transmission was solved. For his discovery, Ross was awarded the Nobel Prize in 1902. In 1899, led by Giovanni Batista Grassi, a team of Italian investigators collected Anopheles claviger mosquitoes and fed them on malarial patients. The complete sporogonic cycle of Plasmodium was demonstrated. That year, mosquitoes infected by feeding on a patient in Rome were sent to London where they fed on two volunteers, both of whom developed benign tertian malaria.
The CDC's mission to combat malaria began at its inception on July 1, 1946. The Communicable Disease Center, as CDC was first known, stemmed from a United States organization called Malaria Control in War Areas. Thus, much of the early work done by CDC was concentrated on the control and eradication of malaria in the United States. With the successful reduction of malaria in the United States, the CDC switched its malaria focus from eradication efforts to prevention, surveillance, and technical support both domestically and internationally. This is still the focus of CDC's Malaria Branch today. The National Malaria Eradication Program, a cooperative undertaking by state and local health agencies of thirteen southeastern states and the CDC, originally proposed by Louis Laval Williams, commenced operations on July 1, 1947. By the end of 1949, over 4,650,000 house spray applications had been made. In 1947, 15,000 malaria cases were reported. By 1950, only 2000 cases were reported. By 1951, malaria was considered eradicated from the United States.
With the success of DDT (Public Health Statement for DDT, DDE, and DDD), the advent of less toxic, more effective synthetic anti-malarial drugs, and the enthusiastic and urgent belief that time and money were of the essence, the World Health Organization (WHO) submitted at the World Health Assembly in 1955 an ambitious proposal for the eradication of malaria worldwide. Successes included eradication in nations with temperate climates and seasonal malaria transmission. Some countries such as India and Sri Lanka had sharp reductions in the number of cases, followed by increases to substantial levels after efforts ceased. Other nations had negligible progress, such as Indonesia, Afghanistan, Haiti, and Nicaragua. Some nations were excluded completely from the eradication campaign, including most of sub-Saharan Africa. The emergence of drug resistance, widespread resistance to available insecticides, wars and massive population movements, difficulties in obtaining sustained funding from donor countries, and lack of community participation made the long-term maintenance of the effort untenable. Completion of the eradication campaign was eventually abandoned and replaced by a campaign centered on control.
Transmission and Infection
In humans, malaria is caused by one of four species of the protozoan parasite genus called Plasmodium. These species are P. falciparum, P. vivax, P. ovale, and P. malariae. The first two species cause the most infections worldwide. P. vivax and P. ovale have dormant liver stage parasites, called "hypnozoites", which can reactivate, or relapse, and cause malaria several months or years after the infecting mosquito bite. P. malariae can produce long-lasting infections and, if left untreated, can persist asymptomatically in the human host for years, even a lifetime. P. falciparum is the most common cause of severe, potentially fatal malaria, causing an estimated 700,000 to 2.7 million deaths annually, most of them in young children in Africa.
Female Anopheles mosquito. (Source: CDC) In nature, malaria parasites spread by infecting, successively, two types of hosts: humans and female Anopheles mosquitoes. In humans, the parasites grow and multiply first in the liver cells and then in the red blood cells. In the blood, successive broods of parasites grow inside the red blood cells and destroy them, releasing daughter parasites, called "merozoites" that continue the cycle by invading other red blood cells. The blood stage parasites are those that cause the symptoms of malaria. When certain forms of blood stage parasites, called "gametocytes" are picked up by a female Anopheles mosquito during a blood meal, they start another, different cycle of growth and multiplication in the mosquito.
After 10-18 days, the parasites are found, as "sporozoites", in the mosquito's salivary glands. When the Anopheles mosquito takes a blood meal on another human, the sporozoites are injected with the mosquito's saliva and start another human infection when they parasitize the liver cells. Thus the mosquito carries the disease from one human to another, acting as a vector. Unlike the human host, the mosquito vector does not suffer from the presence of the parasites.
Following the infective bite by the Anopheles mosquito, a period of time, the incubation period, goes by before the first symptoms appear. The incubation period in most cases varies from 7 to 30 days. The shorter periods are observed most frequently with P. falciparum and the longer ones with P. malariae. Such long delays between exposure and development of symptoms can result in misdiagnosis or delayed diagnosis because of reduced clinical suspicion by the health-care provider.
Malaria in humans develops via two phases: an exoerythrocytic (hepatic) and an erythrocytic phase. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the human host, they infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days. In the liver they differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of its life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell. Within the red blood cells, the parasites multiply further, asexually, periodically breaking out of their hosts to invade fresh red blood cells. Several amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.
Symptoms
Uncomplicated malaria is the classical case of malaria, but is rarely observed, and lasts for six to ten hours. It is characterized by a cold stage, consisting of cold sensations and shivering followed by a hot stage, consisting of fevers, headaches, vomiting, and seizures. Theses seizures are only seen in young children. The final stage is a sweating stage, consisting of sweats followed by a return to normal temperature accompanied by tiredness. Classically, but infrequently observed, the attacks occur every second day with the "tertian" parasites (P. falciparum, P. vivax, and P. ovale) and every third day with the "quartan" parasite (P. malariae). More commonly, the patient will display any combinations of the following symptoms: fever, chills, sweats, headaches, nausea, vomiting, body aches, and general malaise. In countries where malaria cases are not frequent, the symptoms may be attributed to influenza or the common cold. Physical findings for malaria may include elevated temperature, perspiration, weakness, or an enlarged spleen. In P. falciparum malaria cases, additional findings may include mild jaundice, enlargement of the liver, and increased respiratory rate.
Severe malaria occurs when P. falciparum infections are complicated by serious organ failures or abnormalities in the patient's blood or metabolism. The manifestations of severe malaria are numerous. Cerebral malaria can cause abnormal behavior, impairment of consciousness, seizures, coma, or other neurological abnormalities. Other symptoms are severe anemia due to hemolysis, which is destruction of the red blood cells, hemoglobinuria, which is hemoglobin in the urine, due to hemolysis, and pulmonary edema, or fluid buildup in the lungs. Severe malaria can cause acute respiratory distress syndrome (ARDS), which may occur even after the parasite counts have decreased in response to treatment. Also, abnormalities in blood coagulation and thrombocytopenia, which is a decrease in blood platelets, have been observed. Cardiovascular collapse and shock can occur as well. Other manifestations that should raise concern are acute kidney failure, hyperparasitemia, where more than 5% of the red blood cells are infected by malaria parasites, and metabolic acidosis, or excessive acidity in the blood and tissue fluids, often in association with hypoglycemia. Hypoglycemia, or low blood glucose, may also occur in pregnant women with uncomplicated malaria.
Severe malaria occurs most often in persons who have no immunity to malaria or whose immunity has decreased. This includes all residents of areas with low or no malaria transmission, young children, and pregnant women in areas with high transmission. In all areas, severe malaria is a medical emergency and should be treated urgently and aggressively.
Diagnosis
Malaria must be recognized promptly in order to treat the patient in time and to prevent further spread of infection in the community. Malaria can be suspected based on the patient's symptoms and the physical findings at examination. However, for a definitive diagnosis to be made, laboratory tests must demonstrate the malaria parasites or their components.
Diagnosis of malaria can be difficult where malaria is no longer endemic, such as in the United States. Because health care providers may not be familiar with the disease, clinicians seeing a malaria patient may forget to consider malaria among the potential diagnoses and not order the needed diagnostic tests. Laboratory technicians may lack experience with malaria and fail to detect parasites when examining blood smears under the microscope. In some areas, malaria transmission is so intense that a large proportion of the population is infected, but not made ill, by the parasites. Such carriers have developed just enough immunity to protect them from malarial illness but not from malarial infection. In that situation, finding malaria parasites in an ill person does not necessarily mean that the illness is caused by the parasites. In many malaria-endemic countries, lack of resources is a major barrier to reliable and timely diagnosis. Health personnel are under-trained, under-equipped, and underpaid. They often face excessive patient loads, and must divide their attention between malaria and other equally severe infectious diseases such as pneumonia, diarrhea, tuberculosis, and HIV/AIDS.
Clinical diagnosis is based on the patient's symptoms and on physical findings at examination. The first symptoms of malaria, most often fever, chills, sweats, headaches, muscle pains, nausea, and vomiting, are often not specific and are also found in other diseases, such as influenza and common viral infections. Likewise, the physical findings, elevated temperature, perspiration, and tiredness, are often not specific. In severe malaria, caused by P. falciparum, clinical findings such as confusion, coma, neurological focal signs, severe anemia, and respiratory difficulties are more striking and may increase the suspicion index for malaria. Thus, in most cases, the early clinical findings in malaria are not typical and need to be confirmed by a laboratory test.
Laboratory diagnosis of malaria depends on the demonstration of parasites on a blood smear examined under a microscope. Malaria parasites can be identified by examining a drop of the patient’s blood under a microscope, spread out as a "blood smear" on a slide. Prior to examination, the specimen is stained with the Giemsa stain to give to the parasites a distinctive appearance. This technique remains the gold standard for laboratory confirmation of malaria. However, this method depends on the quality of the reagents, of the microscope, and on the experience of the laboratory technician. In P. falciparum malaria, additional laboratory findings may include mild anemia, mild decrease in blood platelets (thrombocytopenia), elevation of bilirubin, elevation of aminotransferases, albuminuria, and the presence of abnormal bodies in the urine, called urinary casts.
Alternative methods for laboratory diagnosis include antigen detection, which involves test kits to detect antigens derived from malaria [[parasite]s]. Such immunological tests most often use a dipstick or cassette format, and provide results in 2-10 minutes. These "Rapid Diagnostic Tests", or RDTs, offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not available. Another alternative is molecular diagnosis in which parasite nucleic acids are detected using polymerase chain reaction (PCR). This technique is more accurate than microscopy. However, it is expensive and requires a specialized laboratory. Finally, malaria can be diagnosed by serology. Serology detects antibodies against malaria parasites, using either an indirect immunofluorescence assay (IFA) or an enzyme-linked immunosorbent assay (ELISA). Serology does not detect current infection but rather measures past experience.
Treatment
Malaria can be potentially fatal disease, especially when caused by P. falciparum and treatment should be initiated as soon as possible.
In endemic areas, the World Health Organization recommends that treatment be started within 24 hours after the first symptoms appear. Treatment of patients with uncomplicated malaria can be conducted without hospitalization, but patients with severe malaria should be hospitalized if possible. In areas where malaria is not endemic, all patients with malaria, uncomplicated or severe, should be kept under clinical observation if possible. Patients who have severe P. falciparum malaria or who can not take oral medications should be given treatment by continuous intravenous infusion. In some countries, some anti-malarial drugs are found in suppository form. Globally, several anti-malarial drugs are available for treatment by continuous intravenous infusion; Quinidine is the only intravenous medicine available in the United States, Quinine is the only one in Canada, and Artesunate is available in some countries.
Most drugs used in treatment are active against the parasite forms in the blood that actually cause the disease. These include chloroquine, mefloquine (Lariam), atovaquone-proguanil (Malarone), quinine, and doxycycline artemisin derivatives, which are not licensed for use in the United States but are often found overseas. In addition, primaquine is active against the dormant parasite liver forms (hypnozoites) and prevents relapses. The atremisinin based combination therapy is now the first line treatment for malaria worldwide. Primaquine should not be taken by pregnant women or by people who are deficient in glucose-6-phosphate dehydrogenase. Patients should not take primaquine until a screening test has excluded glucose-6-phosphate dehydrogenase deficiency. The methods for malaria treatment depend on multiple factors. These include the species of the infecting parasite, the area where the infection was acquired, and its drug-resistance status. Other factors considered are the clinical status of the patient, any accompanying illness or conditions, pregnancy, drug allergies, or other medications taken by the patient.
Control and Prevention
The goal of malaria control in malaria-endemic countries is to reduce as much as possible the health impact of malaria on a population, using the resources available, and taking into account other health priorities. Malaria control does not aim to eliminate malaria totally. Complete elimination of the malaria parasite, and thus the disease, would constitute eradication. While eradication is more desirable, it is not currently a realistic goal for many of the countries where malaria is endemic. However, there is a renewed interest in malaria eradication by many folks in the malaria control field. Malaria control is carried out through many types of interventions, including case management, which involves diagnosis and treatment of patients suffering from malaria, prevention of infection through vector control, and prevention of disease by administration of anti-malarial drugs to particularly vulnerable population groups such as pregnant women and infants.
Persons who are sick with malaria should be treated promptly and correctly. In addition, treatment eliminates an essential component of the cycle, the parasite, and thus interrupts the transmission cycle. The World Health Organization recommends that anyone suspected of having malaria should receive diagnosis and treatment with an effective drug within 24 hours of the onset of symptoms. When the patient can not have access to a health care provider within that time period, as is the case for most patients in malaria-endemic areas, home treatment is acceptable.
Infection is prevented when malaria-carrying Anopheles mosquitoes are prevented from biting humans. Vector control aims to reduce contacts between mosquitoes and humans. Some vector control measures, such as destruction of larval breeding sites and insecticide spraying inside houses, require organized teams and resources that are not always available. An alternate approach, insecticide-treated bed nets, combines vector control and personal protection. This intervention can often be conducted by the communities themselves and has become a major intervention in malaria control.
Administration of anti-malarial drugs to vulnerable population groups does not prevent infection, which happens through mosquito bites. But drugs can prevent disease by eliminating the parasites that are in the blood, which are the forms that cause disease. Pregnant women are the vulnerable group most frequently targeted. They may receive, for example, "intermittent preventive treatment" with anti-malarial drugs given most often at antenatal consultations during the second and third trimesters of pregnancy.
The main activities necessary for carrying out malaria control interventions include health education, where the communities are informed of what they can do to prevent and treat malaria. Other interventions include training and supervision of health workers to ensure that they carry out their tasks correctly and provision of equipment and supplies, such as microscopes, drugs, and bed nets, to allow the health workers and the communities to carry out the interventions.
Malaria control is made difficult by several technical and administrative problems. Drug-resistant malaria parasites hinder case management by decreasing the efficacy of anti-malarial drugs and by requiring the use of alternate drugs that are often more costly, less safe, and less easy to administer. Insecticide resistance decreases the efficacy of interventions that rely on insecticides such as insecticide-treated bed nets and insecticide spraying. Also, inadequate health infrastructures in poor countries are unable to conduct the recommended interventions. The people most exposed to malaria are often poor and lack education. They often do not know how to prevent or treat malaria. Even when they do know, they often do not have the financial means to purchase the necessary products, such as drugs or bed nets.
Geographic Distribution
The distribution of malaria across the globe depends mainly on climatic factors such as temperature, humidity, and rainfalls. Malaria is transmitted in tropical and subtropical areas, where Anopheles mosquitoes can survive and multiply. Malaria parasites can complete their growth cycle in the mosquitoes. Temperature is particularly critical. For example, at temperatures below 20°C (68°F), P. falciparum, which causes severe malaria, can not complete its growth cycle in the Anopheles mosquito, and, thus, can not be transmitted.
Distribution of Malaria. (Source: CDC) Even within tropical and subtropical areas, transmission will not occur at high altitudes, during cooler seasons in some areas, in deserts, and in some islands in the Pacific Ocean, which have no local Anopheles species capable of transmitting malaria. Also, malaria does not occur in some countries where transmission has been interrupted due to successful eradication. Generally, in warmer regions closer to the equator, transmission will be more intense, malaria is transmitted year-round, and P. falciparum predominates. The highest transmission rates are found in sub-Saharan Africa. In cooler regions, transmission will be less intense and more seasonal. There, P. vivax might be more prevalent because it is more tolerant of lower ambient temperatures. In many temperate areas, such as Western Europe and the United States, economic development and public health measures have succeeded in eliminating malaria. However, most of these areas do have Anopheles mosquitoes that can transmit malaria, and reintroduction of the disease is a constant risk.
Impacts of Malaria
Malaria is one of the most severe public health problems worldwide. It is a leading cause of death and disease in many developing countries, where young children and pregnant women are the groups most affected.
Malaria imposes substantial costs to both individuals and governments. Costs to individuals and their families include purchase of drugs for treating malaria at home, expenses for travel to, and treatment at, dispensaries and clinics, lost days of work, absence from school, expenses for preventive measures, and expenses for burial in case of deaths. Costs to governments include maintenance of health facilities, purchase of drugs and supplies, and public health interventions against malaria, such as insecticide spraying or distribution of insecticide-treated bed nets. Such costs can add substantially to the economic burden of malaria on endemic countries and impede their economic growth. It has been estimated in a retrospective analysis that economic growth per year of countries with intensive malaria was 1.3% lower than that of countries without malaria.
Further Reading
- Centers for Disease Control and Prevention—Malaria Homepage
- Schematic, Malaria Lifecycle
- World Malaria Day
