Malaria is a mosquito-borne infectious disease caused by the bite of female Anopheles mosquitoes, which spread infectious Plasmodium parasites into a host. Traditional malaria symptoms include fever, chills, headache, muscle aches and fatigue. Nausea, vomiting and diarrhea also are common. Untreated malaria can lead to severe disease, kidney failure and death. Neurological complications can occur in severe cases, most commonly in young children.

Most malaria cases occur during rainy periods in endemic regions. The World Health Organization estimates that in 2020, globally about 240 million people had malaria and about 627,000 of them died. A disproportionate burden of malarial disease occurs in Sub-Saharan Africa, where children under age 5 account for about 80% of all malaria deaths.

A vaccine to prevent malaria is available; however, its variable efficacy underscores the need for new interventions that offer high-level protection against disease. Malaria is a research priority at NIAID, which is the lead U.S. government agency investigating the disease. Scientists are researching improved vaccines and preventive interventions as well as mosquito control techniques, easy-to-use diagnostics, and improved therapies as parasites continue to develop resistance to currently available antimalarials.

Malaria is a serious and sometimes fatal disease caused by a parasite that commonly infects a certain type of mosquito which feeds on humans. People who get malaria are typically very sick with high fevers, shaking chills, and flu-like illness. Four kinds of malaria parasites infect humans: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. In addition, P. knowlesi, a type of malaria that naturally infects macaques in Southeast Asia, also infects humans, causing malaria that is transmitted from animal to human (“zoonotic” malaria). P. falciparum is the type of malaria that is most likely to result in severe infections and if not promptly treated, may lead to death. Although malaria can be a deadly disease, illness and death from malaria can usually be prevented.

About 2,000 cases of malaria are diagnosed in the United States each year. The vast majority of cases in the United States are in travelers and immigrants returning from parts of the world where malaria transmission occurs, including sub-Saharan Africa and South Asia.

Globally, the World Health Organization estimates that in 2020, 241 million clinical cases of malaria occurred, and 627,000 people died of malaria, most of them children in Africa. Because malaria causes so much illness and death, the disease is a great drain on many national economies. Since many countries with malaria are already among the poorer nations, the disease maintains a vicious cycle of disease and poverty.

Where malaria is found depends mainly on climatic factors such as temperature, humidity, and rainfall. Malaria is transmitted in tropical and subtropical areas, where

• Anopheles mosquitoes can survive and multiply, and
• Malaria parasites can complete their growth cycle in the mosquitoes (“extrinsic incubation period”).

Temperature is particularly critical. For example, at temperatures below 20°C (68°F), Plasmodium falciparum (which causes severe malaria) cannot complete its growth cycle in the Anopheles mosquito, and thus cannot be transmitted.

In many malaria-endemic countries, malaria transmission does not occur in all parts of the country. Even within tropical and subtropical areas, transmission will not occur

• At very high altitudes;
• During colder seasons in some areas;
• In deserts (excluding the oases); and
• In some countries where transmission has been interrupted through successful control/elimination programs.

Generally, in warmer regions closer to the equator

• Transmission will be more intense, and
• Malaria is transmitted year-round.

The highest transmission is found in Africa South of the Sahara and in parts of Oceania such as Papua New Guinea.

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 have Anopheles mosquitoes that can transmit malaria, and reintroduction of the disease is a constant risk.

No. Eradication means that no more malaria exists in the world. Malaria has been eliminated from many developed countries with temperate climates. However, the disease remains a major health problem in many developing countries, in tropical and subtropical parts of the world.

An eradication campaign was started in the 1950s, but it failed globally because of problems including the resistance of mosquitoes to insecticides used to kill them, the resistance of malaria parasites to drugs used to treat them, and administrative issues. In addition, the eradication campaign never involved most of Africa, where malaria is the most common.

Who is at risk for malaria?

Anyone can get malaria. Most cases occur in people who live in countries with malaria transmission. People from countries with no malaria can become infected when they travel to countries with malaria or through a blood transfusion (although this is very rare). Also, an infected mother can transmit malaria to her infant before or during delivery.

Who is most at risk of getting very sick and dying from malaria?

Plasmodium falciparum is the type of malaria that most often causes severe and life-threatening malaria; this parasite is very common in many countries in Africa south of the Sahara desert. People who are heavily exposed to the bites of mosquitoes infected with P. falciparum are most at risk of dying from malaria. People who have little or no immunity to malaria, such as young children and pregnant women or travelers coming from areas with no malaria, are more likely to become very sick and die. Poor people living in rural areas who lack access to health care are at greater risk for this disease. As a result of all these factors, an estimated 90% of deaths due to malaria occur in Africa south of the Sahara; most of these deaths occur in children under 5 years of age.

Genetic Factors

Biologic characteristics present from birth can protect against certain types of malaria. Two genetic factors, both associated with human red blood cells, have been shown to be epidemiologically important. Persons who have the sickle cell trait (heterozygotes for the abnormal hemoglobin gene HbS) are relatively protected against P. falciparum malaria and thus enjoy a biologic advantage. Because P. falciparum malaria has been a leading cause of death in Africa since remote times, the sickle cell trait is now more frequently found in Africa and in persons of African ancestry than in other population groups. In general, the prevalence of hemoglobin-related disorders and other blood cell dyscrasias, such as Hemoglobin C, the thalassemias and G6PD deficiency, are more prevalent in malaria endemic areas and are thought to provide protection from malarial disease.

Persons who are negative for the Duffy blood group have red blood cells that are resistant to infection by P. vivax. Since the majority of Africans are Duffy negative, P. vivax is rare in Africa south of the Sahara, especially West Africa. In that area, the niche of P. vivax has been taken over by P. ovale, a very similar parasite that does infect Duffy-negative persons.

Other genetic factors related to red blood cells also influence malaria, but to a lesser extent. Various genetic determinants (such as the “HLA complex,” which plays a role in control of immune responses) may equally influence an individual’s risk of developing severe malaria.

Acquired Immunity

Acquired immunity greatly influences how malaria affects an individual and a community. After repeated attacks of malaria a person may develop a partially protective immunity. Such “semi-immune” persons often can still be infected by malaria parasites but may not develop severe disease, and, in fact, frequently lack any typical malaria symptoms.

In areas with high P. falciparum transmission (most of Africa south of the Sahara), newborns will be protected during the first few months of life presumably by maternal antibodies transferred to them through the placenta. As these antibodies decrease with time, these young children become vulnerable to disease and death by malaria. If they survive repeated infections to an older age (2-5 years) they will have reached a protective semi-immune status. Thus in high transmission areas, young children are a major risk group and are targeted preferentially by malaria control interventions.

In areas with lower transmission (such as Asia and Latin America), infections are less frequent and a larger proportion of the older children and adults have no protective immunity. In such areas, malaria disease can be found in all age groups, and epidemics can occur.

Pregnancy and Malaria

Pregnancy decreases immunity against many infectious diseases. Women who have developed protective immunity against P.falciparum tend to lose this protection when they become pregnant (especially during the first and second pregnancies). Malaria during pregnancy is harmful not only to the mothers but also to the unborn children. The latter are at greater risk of being delivered prematurely or with low birth weight, with consequently decreased chances of survival during the early months of life. For this reason pregnant women are also targeted (in addition to young children) for protection by malaria control programs in endemic countries.

Behavioral Factors

Human behavior, often dictated by social and economic reasons, can influence the risk of malaria for individuals and communities. For example:

• Poor rural populations in malaria-endemic areas often cannot afford the housing and bed nets that would protect them from exposure to mosquitoes. These persons often lack the knowledge to recognize malaria and to treat it promptly and correctly. Often, cultural beliefs result in use of traditional, ineffective methods of treatment.
• Travelers from non-endemic areas may choose not to use insect repellent or medicines to prevent malaria. Reasons may include cost, inconvenience, or a lack of knowledge.
• Human activities can create breeding sites for larvae (standing water in irrigation ditches, burrow pits)
• Agricultural work such as harvesting (also influenced by climate) may force increased nighttime exposure to mosquito bites
• Raising domestic animals near the household may provide alternate sources of blood meals for Anopheles mosquitoes and thus decrease human exposure
• War, migrations (voluntary or forced) and tourism may expose non-immune individuals to an environment with high malaria transmission.

Human behavior in endemic countries also determines in part how successful malaria control activities will be in their efforts to decrease transmission. The governments of malaria-endemic countries often lack financial resources. As a consequence, health workers in the public sector are often underpaid and overworked. They lack equipment, drugs, training, and supervision. The local populations are aware of such situations when they occur, and cease relying on the public sector health facilities. Conversely, the private sector suffers from its own problems. Regulatory measures often do not exist or are not enforced. This encourages private consultations by unlicensed, costly health providers, and the anarchic prescription and sale of drugs (some of which are counterfeit products). Correcting this situation is a tremendous challenge that must be addressed if malaria control and ultimately elimination is to be successful.

Protective Effect of Sickle Cell Trait Against Malaria

The sickle cell gene is caused by a single amino acid mutation (valine instead of glutamate at the 6th position) in the beta chain of the hemoglobin gene. Inheritance of this mutated gene from both parents leads to sickle cell disease and people with this disease have shorter life expectancy. On the contrary, individuals who are carriers for the sickle cell disease (with one sickle gene and one normal hemoglobin gene, also known as sickle cell trait) have some protective advantage against malaria. As a result, the frequencies of sickle cell carriers are high in malaria-endemic areas.

CDC’s birth cohort studies (Asembo Bay Cohort Project in western Kenya) conducted in collaboration with the Kenya Medical Research Institute allowed an investigation into this issue. It was found that that the sickle cell trait provides 60% protection against overall mortality. Most of this protection occurs between 2-16 months of life, before the onset of clinical immunity in areas with intense transmission of malaria.

Mosquito-Borne Malaria

Outbreaks of locally transmitted cases of malaria in the United States have been small and relatively isolated, but the potential risk for the disease to re-emerge is present due to the abundance of competent vectors, especially in the southern states. At the request of the states, CDC assists in these investigations of locally transmitted mosquito-borne malaria.

“Airport” Malaria

“Airport” malaria refers to malaria caused by infected mosquitoes that are transported rapidly by aircraft from a malaria-endemic country to a non-endemic country. If the local conditions allow their survival upon arrival, they can potentially bite local residents who can thus acquire malaria without having traveled abroad. Airport transmitted malaria is challenging to confirm, but can be considered after exclusion of other likely explanations.

Congenital Malaria

In congenital malaria, infected mothers transmit parasites to their child during pregnancy before or during delivery. Therefore, though congenital transmission is rare, health-care providers should be alert to the diagnosis of malaria in ill neonates and young infants, particularly those with fever.

During evaluation, health-care providers should obtain a complete and accurate travel and residency history on the patient and close relatives. Patients should be asked about transfusion of blood products.

The absence of recent foreign travel or a long interval between immigration of the mother and the birth of the infant being examined should not discourage clinicians from obtaining blood films on the patient to rule out a potentially life-threatening but treatable infection.

Transfusion-Transmitted Malaria

Transfusion-transmitted malaria is rare in the United States, but it is a potential severe complication in blood recipients. On average, only one case of transfusion-transmitted malaria occurs in the United States every 2 years.

Because no approved tests are available in the United States to screen donated blood for malaria, prevention of transfusion-transmitted malaria requires careful questioning of prospective donors.

Summary of guidelines of the Food and Drug Administration for deferral of blood donors at increased risk for malaria

During April 2020, in light of the COVID-19 public health emergency, FDA issued updated guidance on blood donor screening to ensure a sufficient and safe blood supply. This revised guidance is intended to remain in effect for the duration of the public health emergency.

Defer blood donation for 3 months (previously 1 year)

• A traveler who is a resident of a country non-endemic for malaria who has been in a malaria-endemic area may be accepted as a donor 3 months after their return to the non-endemic country (irrespective of the use of chemoprophylaxis) if they have been free from malaria symptoms.

Defer blood donation for 3 years

• An immigrant or visitor from a malaria-endemic country may be accepted as a donor 3 years after departure from the malaria-endemic area if they have been if they have been free from malaria.

• Former residents of malaria-endemic countries who have lived in the United States for less than 3 consecutive years and who return to visit a malaria-endemic area may be accepted as donors 3 years after their most recent visit if they have been free from malaria.
• Former residents of malaria-endemic countries who have lived in the United States for 3 or more consecutive years and who return to visit a malaria-endemic area may be accepted as donors 3 months after their most recent visit if they have been free from malaria.
• Persons who have had a diagnosis of malaria should be deferred for 3 years after becoming asymptomatic.

How is malaria transmitted?

Usually, people get malaria by being bitten by an infective female Anopheles mosquito. Only Anopheles mosquitoes can transmit malaria and they must have been infected through a previous blood meal taken from an infected person. When a mosquito bites an infected person, a small amount of blood is taken in which contains microscopic malaria parasites. About 1 week later, when the mosquito takes its next blood meal, these parasites mix with the mosquito’s saliva and are injected into the person being bitten.

Because the malaria parasite is found in red blood cells of an infected person, malaria can also be transmitted through blood transfusion, organ transplant, or the shared use of needles or syringes contaminated with blood. Malaria may also be transmitted from a mother to her unborn infant before or during delivery (“congenital” malaria).

Is malaria a contagious disease?

No. Malaria is not spread from person to person like a cold or the flu, and it cannot be sexually transmitted. You cannot get malaria from casual contact with malaria-infected people, such as sitting next to someone who has malaria.

Where does malaria transmission occur?

For malaria transmission to occur, conditions must be such so that all three components of the malaria life cycle are present:

• Anopheles mosquitoes, which able to feed on humans humans, and in which the parasites can complete the “invertebrate host” half of their life cycle
• Humans. who can be bitten by Anopheles mosquitoes, and in whom the parasites can complete the “vertebrate host” half of their life cycle
• Malaria parasites.

Climate

Climate is a key determinant of both the geographic distribution and the seasonality of malaria. Without sufficient rainfall, mosquitoes cannot survive, and if not sufficiently warm, parasites cannot survive in the mosquito.

Anopheles lay their eggs in a variety of fresh or brackish bodies of water, with different species having different preferences. Eggs hatch within a few days, with resulting larvae spending 9-12 days to develop into adults in tropical areas. If larval habitats dry up before the process is completed, the larvae die; if rains are excessive, they may be flushed and destroyed. Life is precarious for mosquito larvae, with most perishing before becoming adults.

Life is usually short for adult mosquitoes as well, with temperature and humidity affecting longevity. Only older females can transmit malaria, as they must live long enough for sporozoites to develop and move to the salivary glands. This process takes a minimum of nine days when temperatures are warm (30°C or 86°F) and will take much longer at cooler temperatures. If temperatures are too cool (15°C or 59°F for Plasmodium vivax, 20°C or 68°F for P. falciparum), development cannot be completed and malaria cannot be transmitted. Thus, malaria transmission is much more intense in warm and humid areas, with transmission possible in temperate areas only during summer months.

In warm climates people are more likely to sleep unprotected outdoors, thereby increasing exposure to night-biting Anopheles mosquitoes. During harvest seasons, agricultural workers might sleep in the fields or nearby locales, without protection against mosquito bites.

Anopheles Mosquitoes

The types (species) of Anopheles present in an area at a given time will influence the intensity of malaria transmission. Not all Anopheles are equally efficient vectors for transmitting malaria from one person to another. Those species that are most prone to bite humans are the most dangerous, as bites inflicted on animals that cannot be infected with human malaria break the chain of transmission. If the mosquito regularly bites humans, the chain of transmission is unbroken and more people will become infected. Some species are biologically unable to sustain development of human malaria parasites, while others are readily infected and produce large numbers of sporozoites (the parasite stage that is infective to humans).

Many of the most dangerous species bite human indoors. For these species insecticide treated mosquito nets and indoor residual spray (whereby the inner walls of dwellings are coated with a long-lasting insecticide) are effective interventions. Both of these interventions require attention to insecticide resistance, which will evolve if the same insecticide is used continuously in the same area.

Humans

Biologic characteristics (inborn and acquired) and behavioral traits can influence an individual’s malaria risk and, on a larger scale, the overall malaria ecology.

Parasites

Characteristics of the malaria parasite can influence the occurrence of malaria and its impact on human populations, for example:

• Areas where P. falciparum predominates (such as Africa south of the Sahara) will suffer more disease and death than areas where other species, which tend to cause less severe manifestations, predominate
• P. vivax and P. ovale have stages (“hypnozoites”) that can remain dormant in the liver cells for extended periods of time (months to years) before reactivating and invading the blood. Such relapses can result in resumption of transmission after apparently successful control efforts, or can introduce malaria in an area that was malaria-free
• P. falciparum (and to a lesser extent P. vivax) have developed strains that are resistant to antimalarial drugs. Such strains are not uniformly distributed. Constant monitoring of the susceptibility of these two parasite species to drugs used locally is critical to ensure effective treatment and successful control efforts. Travelers to malaria-risk areas should use for prevention only those drugs that will be protective in the areas to be visited.

Animal Reservoirs

A certain species of malaria called P. knowlesi has recently been recognized to be a cause of significant numbers of human infections. P. knowlesi is a species that naturally infects macaques living in Southeast Asia. Humans living in close proximity to populations of these macaques may be at risk of infection with this zoonotic parasite.

Areas Where Malaria Is No Longer Endemic

Malaria transmission has been eliminated in many countries of the world, including the United States. However, in many of these countries (including the United States) Anopheles mosquitoes are still present. Also, cases of malaria still occur in non-endemic countries, mostly in returning travelers or immigrants (“imported malaria”). Thus the potential for reintroduction of active transmission of malaria exists in many non-endemic parts of the world. All patients must be diagnosed and treated promptly for their own benefit but also to prevent the reintroduction of malaria.

The natural history of malaria involves cyclical infection of humans and female Anopheles mosquitoes. In humans, the parasites grow and multiply first in the liver cells and then in the red cells of the blood. In the blood, successive broods of parasites grow inside the red cells and destroy them, releasing daughter parasites (“merozoites”) that continue the cycle by invading other red cells.

The blood stage parasites are those that cause the symptoms of malaria. When certain forms of blood stage parasites (gametocytes, which occur in male and female forms) are ingested during blood feeding by a female Anopheles mosquito, they mate in the gut of the mosquito and begin a cycle of growth and multiplication in the mosquito. After 10-18 days, a form of the parasite called a sporozoite migrates to the mosquito’s salivary glands. When the Anopheles mosquito takes a blood meal on another human, anticoagulant saliva is injected together with the sporozoites, which migrate to the liver, thereby beginning a new cycle.

Thus the infected mosquito carries the disease from one human to another (acting as a “vector”), while infected humans transmit the parasite to the mosquito, In contrast to the human host, the mosquito vector does not suffer from the presence of the parasites.

The malaria parasite life cycle involves two hosts.

During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host

Sporozoites infect liver cells

And mature into schizonts

Which rupture and release merozoites

(Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver (if untreated) and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony)

The parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony)

Merozoites infect red blood cells

The ring stage trophozoites mature into schizonts, which rupture releasing merozoites

Some parasites differentiate into sexual erythrocytic stages (gametocytes)

Blood stage parasites are responsible for the clinical manifestations of the disease. The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal

The parasites’ multiplication in the mosquito is known as the sporogonic cycle

While in the mosquito’s stomach, the microgametes penetrate the macrogametes generating zygotes

The zygotes in turn become motile and elongated (ookinetes)

Which invade the midgut wall of the mosquito where they develop into oocysts

The oocysts grow, rupture, and release sporozoites which make their way to the mosquito’s salivary glands.

Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.

Human Factors And Malaria

Biologic characteristics and behavioral traits can influence an individual’s risk of developing malaria and, on a larger scale, the intensity of transmission in a population.

Malaria is transmitted to humans by female mosquitoes of the genus Anopheles. Female mosquitoes take blood meals for egg production, and these blood meals are the link between the human and the mosquito hosts in the parasite life cycle. The successful development of the malaria parasite in the mosquito (from the “gametocyte” stage to the “sporozoite” stage) depends on several factors. The most important is ambient temperature and humidity (higher temperatures accelerate the parasite growth in the mosquito) and whether the Anopheles survives long enough to allow the parasite to complete its cycle in the mosquito host (“sporogonic” or “extrinsic” cycle, duration 9 to 18 days). In contrast to the human host, the mosquito host does not suffer noticeably from the presence of the parasites.

General Information

There are approximately 3,500 species of mosquitoes grouped into 41 genera. Human malaria is transmitted only by females of the genus Anopheles. Of the approximately 430 Anopheles species, only 30-40 transmit malaria (i.e., are “vectors”) in nature. The rest either bite humans infrequently or cannot sustain development of malaria parasites.

Geographic Distribution

Anophelines are found worldwide except Antarctica. Malaria is transmitted by different Anopheles species in different geographic regions. Within geographic regions, different environments support a different species.

Anophelines that can transmit malaria are found not only in malaria-endemic areas, but also in areas where malaria has been eliminated. These areas are thus at risk of re-introduction of the disease.

Life Stages

Like all mosquitoes, anopheles mosquitoes go through four stages in their life cycle: egg, larva, pupa, and adult. The first three stages are aquatic and last 7-14 days, depending on the species and the ambient temperature. The biting female Anopheles mosquito may carry malaria. Male mosquitoes do not bite so cannot transmit malaria or other diseases. The adult females are generally short-lived, with only a small proportion living long enough (more than 10 days in tropical regions) to transmit malaria.

Eggs

Adult females lay 50-200 eggs per oviposition. Eggs are laid singly directly on water and are unique in having floats on either side. Eggs are not resistant to drying and hatch within 2-3 days, although hatching may take up to 2-3 weeks in colder climates.

Larvae

Mosquito larvae have a well-developed head with mouth brushes used for feeding, a large thorax, and a segmented abdomen. They have no legs. In contrast to other mosquitoes, Anopheles larvae lack a respiratory siphon and for this reason position themselves so that their body is parallel to the surface of the water.

Larvae breathe through spiracles located on the 8th abdominal segment and therefore must come to the surface frequently.

The larvae spend most of their time feeding on algae, bacteria, and other microorganisms in the surface microlayer. They do so by rotating their head 180 degrees and feeding from below the microlayer. Larvae dive below the surface only when disturbed. Larvae swim either by jerky movements of the entire body or through propulsion with the mouth brushes.

Larvae develop through 4 stages, or instars, after which they metamorphose into pupae. At the end of each instar, the larvae molt, shedding their exoskeleton, or skin, to allow for further growth.

The larvae occur in a wide range of habitats but most species prefer clean, unpolluted water. Larvae of Anopheles mosquitoes have been found in fresh- or salt-water marshes, mangrove swamps, rice fields, grassy ditches, the edges of streams and rivers, and small, temporary rain pools. Many species prefer habitats with vegetation. Others prefer habitats that have none. Some breed in open, sun-lit pools while others are found only in shaded breeding sites in forests. A few species breed in tree holes or the leaf axils of some plants.

Pupae

The pupa is comma-shaped when viewed from the side. This is a transitional stage between larva and adult. The pupae does not feed, but undergoes radical metamorphosis. The head and thorax are merged into a cephalothorax with the abdomen curving around underneath. As with the larvae, pupae must come to the surface frequently to breathe, which they do through a pair of respiratory trumpets on the cephalothorax. After a few days as a pupa, the dorsal surface of the cephalothorax splits and the adult mosquito emerges onto the surface of the water.

The duration from egg to adult varies considerably among species and is strongly influenced by ambient temperature. Mosquitoes can develop from egg to adult in as little as 7 days but usually take 10-14 days in tropical conditions.

Adults

Like all mosquitoes, adult anopheles have slender bodies with 3 sections: head, thorax and abdomen.

The head is specialized for acquiring sensory information and for feeding. The head contains the eyes and a pair of long, many-segmented antennae. The antennae are important for detecting host odors as well as odors of aquatic larval habitats where females lay eggs. The head also has an elongate, forward-projecting proboscis used for feeding, and two sensory palps.

The thorax is specialized for locomotion. Three pairs of legs and a single pair of wings are attached to the thorax.

The abdomen is specialized for food digestion and egg development. This segmented body part expands considerably when a female takes a blood meal. The blood is digested over time serving as a source of protein for the production of eggs, which gradually fill the abdomen.

Anopheles mosquitoes can be distinguished from other mosquitoes by the palps, which are as long as the proboscis, and by the presence of discrete blocks of black and white scales on the wings. Adult Anopheles can also be identified by their typical resting position: males and females rest with their abdomens sticking up in the air rather than parallel to the surface on which they are resting.

Adult mosquitoes usually mate within a few days after emerging from the pupal stage. In some species, the males form large swarms, usually around dusk, and the females fly into the swarms to mate. The mating habitats of many species remain unknown.

Males live for about a week, feeding on nectar and other sources of sugar. Females will also feed on sugar sources for energy but usually require a blood meal for the development of eggs. After obtaining a full blood meal, the female will rest for a few days while the blood is digested and eggs are developed. This process depends on the temperature but usually takes 2-3 days in tropical conditions. Once the eggs are fully developed, the female lays them then seeks blood to sustain another batch of eggs.

The cycle repeats itself until the female dies. Females can survive up to a month (or longer in captivity) but most do not live longer than 1-2 weeks in nature. Their chances of survival depend on temperature and humidity, but also upon their ability to successfully obtain a blood meal while avoiding host defenses.

Factors Involved in Malaria Transmission and Malaria Control

Understanding the biology and behavior of Anopheles mosquitoes can aid in designing appropriate control strategies. Factors that affect a mosquito’s ability to transmit malaria include its innate susceptibility to Plasmodium, its host choice, and its longevity. Long-lived species that prefer human blood and support parasite development are the most dangerous. Factors that should be taken into consideration when designing a control program include the susceptibility of malaria mosquitoes to insecticides and the preferred feeding and resting location of adult mosquitoes.

Preferred Sources for Blood Meals

One important behavioral factor is the degree to which an Anopheles species prefers to feed on humans (anthropophily) or animals such as cattle (zoophily). Anthrophilic Anopheles are more likely to transmit the malaria parasites from one person to another. Most Anopheles mosquitoes are not exclusively anthropophilic or zoophilic; many are opportunistic and feed upon whatever host is available. However, the primary malaria vectors in Africa, An. gambiae and An. funestus, are strongly anthropophilic and, consequently, are two of the most efficient malaria vectors in the world.

Life Span

Once ingested by a mosquito, malaria parasites must undergo development within the mosquito before they are infectious to humans. The time required for development in the mosquito (the extrinsic incubation period) takes 9 days or longer, depending on the parasite species and the temperature. If a mosquito does not survive longer than the extrinsic incubation period, then she will not be able to transmit any malaria parasites.

It is not possible to measure directly the life span of mosquitoes in nature, but many studies have indirectly measured longevity by examination of their reproductive status or via marking, releasing, and recapturing adult mosquitoes. The majority of mosquitoes do not live long enough to transmit malaria, but some may live as long as three weeks in nature. Though evidence suggests that mortality rate increases with age, most workers estimate longevity in terms of the probability that a mosquito will live one day. Usually these estimates range from a low of 0.7 to a high of 0.9. If survivorship is 90% daily, then a substantial proportion of the population would live longer than 2 weeks and would be capable of transmitting malaria. Any control measure that reduces the average lifespan of the mosquito population will reduce transmission potential. Insecticides thus need not kill the mosquitoes outright, but may be effective by limiting their lifespan.

Patterns of Feeding and Resting

Most Anopheles mosquitoes are crepuscular (active at dusk or dawn) or nocturnal (active at night). Some Anopheles mosquitoes feed indoors (endophagic) while others feed outdoors (exophagic). After blood feeding, some Anopheles mosquitoes prefer to rest indoors (endophilic) while others prefer to rest outdoors (exophilic). Biting by nocturnal, endophagic Anopheles mosquitoes can be markedly reduced through the use of insecticide-treated bed nets (ITNs) or through improved housing construction to prevent mosquito entry (e.g., window screens). Endophilic mosquitoes are readily controlled by indoor spraying of residual insecticides. In contrast, exophagic/exophilic vectors are best controlled through source reduction (destruction of larval habitats).

Insecticide Resistance

Insecticide-based control measures (e.g., indoor spraying with insecticides, ITNs) are the principal way to kill mosquitoes that bite indoors. However, after prolonged exposure to an insecticide over several generations, mosquitoes, like other insects, may develop resistance, a capacity to survive contact with an insecticide. Since mosquitoes can have many generations per year, high levels of resistance can arise very quickly. Resistance of mosquitoes to some insecticides has been documented within a few years after the insecticides were introduced. There are over 125 mosquito species with documented resistance to one or more insecticides. The development of resistance to insecticides used for indoor residual spraying was a major impediment during the Global Malaria Eradication Campaign. Judicious use of insecticides for mosquito control can limit the development and spread of resistance, particularly via rotation of different classes of insecticides used for control. Monitoring of resistance is essential to alert control programs to switch to more effective insecticides.

Susceptibility/Refractoriness

Some Anopheles species are poor vectors of malaria, as the parasites do not develop well (or at all) within them. There is also variation within species. In the laboratory, it has been possible to select for strains of An. gambiae that are refractory to infection by malaria parasites. These refractory strains have an immune response that encapsulates and kills the parasites after they have invaded the mosquito’s stomach wall. Scientists are studying the genetic mechanism for this response. It is hoped that some day, genetically modified mosquitoes that are refractory to malaria can replace wild mosquitoes, thereby limiting or eliminating malaria transmission.

Malaria parasites are micro-organisms that belong to the genus Plasmodium. There are more than 100 species of Plasmodium, which can infect many animal species such as reptiles, birds, and various mammals. Four species of Plasmodium have long been recognized to infect humans in nature. In addition there is one species that naturally infects macaques which has recently been recognized to be a cause of zoonotic malaria in humans. (There are some additional species which can, exceptionally or under experimental conditions, infect humans.)

(All photos courtesy of DPDx)

The species infecting humans are the following:

• P. falciparum, which is found worldwide in tropical and subtropical areas, and especially in Africa where this species predominates. P. falciparum can cause severe malaria because it multiples rapidly in the blood, and can thus cause severe blood loss (anemia). In addition, the infected parasites can clog small blood vessels. When this occurs in the brain, cerebral malaria results, a complication that can be fatal.
• P. vivax, which is found mostly in Asia, Latin America, and in some parts of Africa. Because of the population densities especially in Asia it is probably the most prevalent human malaria parasite. P. vivax (as well as P. ovale) has dormant liver stages (“hypnozoites”) that can activate and invade the blood (“relapse”) several months or years after the infecting mosquito bite.
• P. ovale is found mostly in Africa (especially West Africa) and the islands of the western Pacific. It is biologically and morphologically very similar to P. vivax. However, differently from P. vivax, it can infect individuals who are negative for the Duffy blood group, which is the case for many residents of sub-Saharan Africa. This explains the greater prevalence of P. ovale (rather than P. vivax ) in most of Africa.
• P. malariae, found worldwide, is the only human malaria parasite species that has a quartan cycle (three-day cycle). (The three other species have a tertian, two-day cycle.) If untreated, P. malariae causes a long-lasting, chronic infection that in some cases can last a lifetime. In some chronically infected patients P. malariae can cause serious complications such as the nephrotic syndrome.
• P. knowlesi is found throughout Southeast Asia as a natural pathogen of long-tailed and pig-tailed macaques. It has recently been shown to be a significant cause of zoonotic malaria in that region, particularly in Malaysia. P. knowlesi has a 24-hour replication cycle and so can rapidly progress from an uncomplicated to a severe infection; fatal cases have been reported.

Infection with malaria parasites may result in a wide variety of symptoms, ranging from absent or very mild symptoms to severe disease and even death. Malaria disease can be categorized as uncomplicated or severe (complicated). In general, malaria is a curable disease if diagnosed and treated promptly and correctly.

All the clinical symptoms associated with malaria are caused by the asexual erythrocytic or blood stage parasites. When the parasite develops in the erythrocyte, numerous known and unknown waste substances such as hemozoin pigment and other toxic factors accumulate in the infected red blood cell. These are dumped into the bloodstream when the infected cells lyse and release invasive merozoites. The hemozoin and other toxic factors such as glucose phosphate isomerase (GPI) stimulate macrophages and other cells to produce cytokines and other soluble factors which act to produce fever and rigors and probably influence other severe pathophysiology associated with malaria.

Plasmodium falciparum-infected erythrocytes, particularly those with mature trophozoites, adhere to the vascular endothelium of venular blood vessel walls and do not freely circulate in the blood. When this sequestration of infected erythrocytes occurs in the vessels of the brain it is believed to be a factor in causing the severe disease syndrome known as cerebral malaria, which is associated with high mortality.

Incubation Period

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.

Antimalarial drugs taken for prophylaxis by travelers can delay the appearance of malaria symptoms by weeks or months, long after the traveler has left the malaria-endemic area. (This can happen particularly with P. vivax and P. ovale, both of which can produce dormant liver stage parasites; the liver stages may reactivate and cause disease months after the infective mosquito bite.)

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. Returned travelers should always remind their health-care providers of any travel in areas where malaria occurs during the past 12 months.

Uncomplicated Malaria

The classical (but rarely observed) malaria attack lasts 6–10 hours. It consists of

• A cold stage (sensation of cold, shivering)
• A hot stage (fever, headaches, vomiting; seizures in young children); and
• Finally a sweating stage (sweats, return to normal temperature, 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 presents with a combination of the following symptoms:

• Fever
• Chills
• Sweats
• Headaches
• Nausea and vomiting
• Body aches
• General malaise

In countries where cases of malaria are infrequent, these symptoms may be attributed to influenza, a cold, or other common infections, especially if malaria is not suspected. Conversely, in countries where malaria is frequent, residents often recognize the symptoms as malaria and treat themselves without seeking diagnostic confirmation (“presumptive treatment”).

Physical findings may include the following:

• Elevated temperatures
• Perspiration
• Weakness
• Enlarged spleen
• Mild jaundice
• Enlargement of the liver
• Increased respiratory rate

Diagnosis of malaria depends on the demonstration of parasites in the blood, usually by microscopy. Additional laboratory findings may include mild anemia, mild decrease in blood platelets (thrombocytopenia), elevation of bilirubin, and elevation of aminotransferases.

Severe Malaria

Severe malaria occurs when infections are complicated by serious organ failures or abnormalities in the patient’s blood or metabolism. The manifestations of severe malaria include the following:

• Cerebral malaria, with abnormal behavior, impairment of consciousness, seizures, coma, or other neurologic abnormalities
• Severe anemia due to hemolysis (destruction of the red blood cells)
• Hemoglobinuria (hemoglobin in the urine) due to hemolysis
• Acute respiratory distress syndrome (ARDS), an inflammatory reaction in the lungs that inhibits oxygen exchange, which may occur even after the parasite counts have decreased in response to treatment
• Abnormalities in blood coagulation
• Low blood pressure caused by cardiovascular collapse
• Acute kidney injury
• Hyperparasitemia, where more than 5% of the red blood cells are infected by malaria parasites
• Metabolic acidosis (excessive acidity in the blood and tissue fluids), often in association with hypoglycemia

Severe malaria is a medical emergency and should be treated urgently and aggressively.

Malaria Relapses

In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks (“relapses”) after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites (“hypnozoites”) that may reactivate. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack.

Other Manifestations of Malaria

• Neurologic defects may occasionally persist following cerebral malaria, especially in children. Such defects include trouble with movements (ataxia), palsies, speech difficulties, deafness, and blindness.
• Recurrent infections with P. falciparum may result in severe anemia. This occurs especially in young children in tropical Africa with frequent infections that are inadequately treated.
• Malaria during pregnancy (especially P. falciparum) may cause severe disease in the mother, and may lead to premature delivery or delivery of a low-birth-weight baby.
• On rare occasions, P. vivax malaria can cause rupture of the spleen.
• Nephrotic syndrome (a chronic, severe kidney disease) can result from chronic or repeated infections with P. malariae.
• Hyperreactive malarial splenomegaly (also called “tropical splenomegaly syndrome”) occurs infrequently and is attributed to an abnormal immune response to repeated malarial infections. The disease is marked by a very enlarged spleen and liver, abnormal immunologic findings, anemia, and a susceptibility to other infections (such as skin or respiratory infections).

What are the signs and symptoms of malaria?

Symptoms of malaria include fever and flu-like illness, including shaking chills, headache, muscle aches, and tiredness. Nausea, vomiting, and diarrhea may also occur. Malaria may cause anemia and jaundice (yellow coloring of the skin and eyes) because of the loss of red blood cells. If not promptly treated, the infection can become severe and may cause kidney failure, seizures, mental confusion, coma, and death.

How soon will a person feel sick after being bitten by an infected mosquito?

For most people, symptoms begin 10 days to 4 weeks after infection, although a person may feel ill as early as 7 days or as late as 1 year later. Two kinds of malaria, P. vivax and P. ovale, can occur again (relapsing malaria). In P. vivax and P. ovale infections, some parasites can remain dormant in the liver for several months up to about 4 years after a person is bitten by an infected mosquito. When these parasites come out of hibernation and begin invading red blood cells (“relapse”), the person will become sick.

How do I know if I have malaria for sure?

Most people, at the beginning of the disease, have fever, sweats, chills, headaches, malaise, muscles aches, nausea, and vomiting. Malaria can very rapidly become a severe and life-threatening disease. The surest way for you and your health-care provider to know whether you have malaria is to have a diagnostic test where a drop of your blood is examined under the microscope for the presence of malaria parasites. If you are sick and there is any suspicion of malaria (for example, if you have recently traveled in a country where malaria transmission occurs), the test should be performed without delay.

Malaria must be recognized promptly in order to treat the patient in time and to prevent further spread of infection in the community via local mosquitoes.

Malaria should be considered a potential medical emergency and should be treated accordingly. Delay in diagnosis and treatment is a leading cause of death in malaria patients in the United States.

Malaria can be suspected based on the patient’s travel history, 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 not endemic any more (such as in the United States), 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. Laboratorians may lack experience with malaria and fail to detect parasites when examining blood smears under the microscope.
• In some malaria-endemic 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.

Clinical Diagnosis

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 the “flu” and common viral infections). Likewise, the physical findings are often not specific (elevated temperature, perspiration, tiredness).

In severe malaria (primarily caused by Plasmodium falciparum), clinical findings (confusion, coma, neurologic focal signs, severe anemia, respiratory difficulties) are more striking and may increase the index of suspicion for malaria.

Clinical findings should always be confirmed by a laboratory test for malaria.

In addition to ordering the malaria specific diagnostic tests described below, the health-care provider should conduct an initial workup and request a complete blood count and a routine chemistry panel. In the event that the person does have a positive malaria test, these additional tests will be useful in determining whether the patient has uncomplicated or severe manifestations of the malaria infection. Specifically, these tests can detect severe anemia, hypoglycemia, renal failure, hyperbilirubinemia, and acid-base disturbances.

Microscopic Diagnosis

Malaria parasites can be identified by examining under the microscope a drop of the patient’s blood, spread out as a “blood smear” on a microscope slide. Prior to examination, the specimen is stained (most often with the Giemsa stain) to give the parasites a distinctive appearance. This technique remains the gold standard for laboratory confirmation of malaria. However, it depends on the quality of the reagents, of the microscope, and on the experience of the laboratorian.

Antigen Detection

Various test kits are available to detect antigens derived from malaria parasites. Such immunologic (“immunochromatographic”) tests most often use a dipstick or cassette format, and provide results in 2-15 minutes. These “Rapid Diagnostic Tests” (RDTs) offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not available. Malaria RDTs are currently used in some clinical settings and programs. The World Health Organization is conducting comparative performance evaluations of many of the RDTs which are commercially available worldwide based on a panel of parasites derived from a global network of collection sites.

On June 13, 2007, the U.S. Food and Drug Administration (FDA) approved the first RDT for use in the United States. This RDT is approved for use by hospital and commercial laboratories, not by individual clinicians or by patients themselves. It is recommended that all RDTs are followed-up with microscopy to confirm the results and if positive, to confirm the species and quantify the proportion of red blood cells that are infected. The use of this RDT may decrease the amount of time that it takes to determine that a patient is infected with malaria.

Molecular Diagnosis

Parasite nucleic acids are detected using polymerase chain reaction (PCR). Although this technique may be slightly more sensitive than smear microscopy, it is of limited utility for the diagnosis of acutely ill patients in the standard healthcare setting. PCR results are often not available quickly enough to be of value in establishing the diagnosis of malaria infection.

PCR is most useful for confirming the species of malarial parasite after the diagnosis has been established by either smear microscopy or RDT.

Serology

Serology detects antibodies against malaria parasites, using either indirect immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA). Serology does not detect current infection but rather measures past exposure.

Drug Resistance Tests

Drug resistance tests must be performed in specialized laboratories to assess the susceptibility to antimalarial compounds of parasites collected from a specific patient. Two main laboratory methods are available:

In vitro tests: The parasites are grown in culture in the presence of increasing concentrations of drugs; the drug concentration that inhibits parasite growth is used as endpoint.

Molecular characterization: Molecular markers assessed by PCR or gene sequencing also allow the prediction, to some degree, of resistance to some drugs. CDC recommends that all cases of malaria diagnosed in the United States should be evaluated for evidence of drug resistance.