Communicable Diseases

Malaria

Identification

Malaria in humans is a parasitic disease caused by infection with one or more of four species of intracellular protozoan parasite: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum and P. vivax infections are the more common worldwide, but P. falciparum malaria represents the most serious public health problem, because of its tendency toward severe or fatal infections.

The early clinical manifestations of malaria are non-specific and similar enough among species to make differentiation impossible without laboratory studies. Moreover, the clinical syndrome in the first few days of infection resembles that in early stages of many other febrile illnesses due to bacterial, viral or parasitic causes, and requires the demonstration of parasites or their products in blood for confirmation. P. falciparum malaria (ICD-9 084.0, ICD-10 B50) typically presents a protean clinical picture, including fever, chills, myalgias and arthralgias, headache, diarrhea, vomiting and other nonspecific signs. Splenomegaly, anemia, and thrombocytopenia often develop after a few days. Later, if treatment is delayed, severe malaria may develop. Severe malaria may be characterized by acute encephalopathy (cerebral malaria), severe anemia, icterus, renal failure (black water fever), hypoglycemia, respiratory distress, lactic acidosis and, more rarely, coagulation defects and shock. Severe malaria is a possible cause of coma and other CNS symptoms in any partially immune or non-immune person recently returned from an endemic tropical area. Prompt treatment of falciparum malaria is essential, even in mild cases, since irreversible complications may rapidly appear. Case fatality rates of children and non-immunes with uncomplicated malaria are circa 0.1%. This increases to 15%–20% once complications appear. Untreated severe malaria is almost always fatal.

The other human malarias, vivax (ICD-9 084.1, ICD-10 B51), malariae (ICD-9 084.2, ICD-10 B52) and ovale (ICD-9 084.3, ICD-10 B53.0), are not usually life-threatening. Illness may begin with malaise and fever for several days, followed by shaking chills and rapidly rising temperature, accompanied by headache and nausea. Profuse sweating occurs with defervescence. After a fever-free interval, the cycle of chills, fever and sweating recurs daily, every other day or every third day. An untreated primary infection may last from a week to a month or longer and be accompanied by prostration, anemia and splenomegaly. True relapses following periods with no parasitemia can occur in vivax and ovale infections at irregular intervals for up to 5 years, due to a relapsing parasite stage sequestered in the liver (hypnozoites). Infections with P. malariae may persist for life with or without recurrent febrile episodes; however, as with P. falciparum, there is no relapsing liver stage.

Persons who have grown up in endemic areas and acquired partial immunity, or non-immune persons who have been taking prophylactic antimalarial drugs, may show an atypical clinical picture and a prolonged incubation period.

The diagnosis of malaria must be considered in all febrile patients who have traveled to or lived in malaria-endemic areas or who have received blood products, tissues or organs from persons who have been to such areas. There are several diagnostic methods, including microscopic diagnosis, antigen detection tests, PCR-based assays, and serological tests. Direct microscopic examination of intracellular parasites on stained blood films is the current standard for definitive diagnosis in nearly all settings. In non-immune persons, symptoms may develop before there are detectable levels of parasitemia. For this reason, several blood smear examinations taken at 12–24 hour intervals may be needed to rule out a diagnosis of malaria in a symptomatic patient.

Laboratory confirmation is possible through:

  • Demonstration of malaria parasites in a blood film. Repeated microscopic examinations every 12–24 hours may be necessary because the blood density of parasites varies, and parasites are often not demonstrable in films from patients recently or actively under treatment.

  • Detection of parasite antigens by means of rapid diagnostic tests. There are several tests for the routine detection of falciparum malaria as well as malaria in general (genus Plasmodium), based on the antigens HRP2, pLDH or Aldolase. Tests available for the detection of vivax malaria are fewer in number, and performance is more limited.


Diagnosis by PCR is the most sensitive method, but this is not generally available in diagnostic laboratories.
Antibodies, demonstrable by IFA or other tests, may appear after the first week of infection but may persist for years, indicating past malarial experience; thus antibody determinations are not helpful for diagnosis of current illness. Guidelines for laboratory diagnosis are summarized elsewhere and are available online at:

Infectious agents

Plasmodium falciparum, P. vivax, P. ovale and P. malariae; protozoan parasites with asexual and sexual phases that occur in humans and in the mosquito. Mixed species infections are not infrequent in endemic areas.

Occurrence

Endemic malaria no longer occurs in most temperate-zone countries and in many areas of subtropical countries; it is still, however, a major cause of ill health in many tropical and other subtropical areas. The disease is responsible for an estimated 1 million deaths per year globally, mostly in young children in Africa; high transmission areas occur throughout tropical Africa, in the southwestern Pacific, in forested areas of South America (e.g. Brazil), in southeastern Asia, and in parts of the Indian sub-continent. Ovale malaria occurs mainly in sub-Saharan Africa, where vivax malaria is much less frequent.

The development and the rapid spread of antimalarial drug resistance in Plasmodium falciparum has been one of the greatest threats to malaria control. Resistance to chloroquine, previously the most widely used antimalarial drug, is widespread, with a few exceptional areas where chloroquine remains effective (Central America west of the Panama Canal, Haiti and the Dominican Republic). Resistance in P. falciparum has also developed to sulfadoxine-pyrimethamine (Amazon Region, southeast Asia, sub-Saharan Africa) and mefloquine (parts of southeast Asia). Resistance has affected all the other antimalarial drugs to different degrees, and is aggravated by cross-resistance between medicines. Sulfadoxine-pyrimethamine, which replaced chloroquine, became almost totally ineffective in Thailand and neighboring countries at the beginning of the 1980s, and this resistance spread rapidly to South America and east Africa. Resistance to quinine and mefloquine is found mainly in Thailand and Cambodia. Sporadic cases of prophylactic failure of mefloquine in travelers and therapeutic failure with amino-alcohols have been reported in Africa, South America, and in other Asian countries. So far, no resistance to artemisinin or artemisinin derivative has been reported, although some decrease in in vitro sensitivity has been reported in China and increased parasite clearance time after treatment with artemisinin-based combination therapy or artesunate monotherapy has been reported at the Thai-Cambodian border.

Most P. vivax malaria infections remain sensitive to chloroquine. However, in recent years, chloroquine resistance of P. vivax has been reported in southeast Asia, in South America, and even in Africa. The relapsing hepatic stages of some P. vivax strains may also be relatively tolerant to primaquine, but its optimum regimen has not been fully defined.

Current information on drug-resistant malaria is published annually by CDC (Health Information for International Travel), and can be found at:

- or on the CDC Malaria website, at: - and by WHO, at: - and in International Travel and Health, at:

Reservoir

Humans are the most important reservoir of human malaria, except as regards P. malariae, which is common to man, the African apes and probably some South American monkeys. Non-human primates are naturally infected by malaria parasite species, some of which are closely related to the human malarias, and which therefore can infect humans experimentally. Natural transmission of these non-human primate malarias to humans occurs sporadically. Recently, P. knowlesi, a parasite of Old World monkeys, has been documented as a cause of hundreds of human infections and some fatalities in Malaysia. Investigations are ongoing to determine the extent of transmission to humans; it is suggested that non-human primates may be a more important source for malaria in humans in certain geographical situations than previously thought.

Mode of transmission

Most malaria is transmitted by the bite of an infective female Anopheles sp. mosquito. Most species feed at night; some important vectors also bite at dusk or in the early morning.

Malaria infection begins when an infective female mosquito injects Plasmodium sp. sporozoites into the bloodstream while feeding. The sporozoites pass almost immediately into the cells of the liver parenchyma, where they undergo asexual reproduction (exo-erythrocytic schizogony) and mature into schizonts. In 6 to 14 days, these schizonts mature and rupture, releasing merozoites into the bloodstream. Merozoites subsequently invade red blood cells and then undergo a second phase of asexual reproduction (erythrocytic schizogony). Once the erythrocytic schizonts mature, the infected red blood cells rupture, releasing more merozoites into the bloodstream, and beginning another cycle of asexual development and multiplication. Clinical symptoms occur with the rupture of erythrocytic schizonts, usually after several cycles of erythrocytic schizogony. The classical clinical presentation of periodic fever and shaking chills occurs when the cycles of erythrocytic schizogony are synchronized.

Some merozoites develop into sexual forms called gametocytes. Male and female gametocytes circulate in the blood without causing symptoms, and can then be ingested by a mosquito during a subsequent blood meal. Sexual reproduction occurs within the mosquito midgut, where male and female gametes unite to form an ookinete; the ookinete then penetrates the midgut wall and forms an oocyst. After maturation for days to weeks, the oocyst ruptures, releasing sporozoites, which migrate through the coelomic cavity to the salivary glands. The life cycle starts again when the infective mosquito bites another human.

The period between an infective bite and detection of the parasite in a thick blood smear is the “prepatent period,” which is typically 6–12 days for P. falciparum; 8–12 days for P. vivax and P. ovale; and 12–16 days for P. malariae. The period between the infective bite and the appearance of clinical symptoms is called the incubation period. Delayed primary attacks by some P. vivax strains may occur 6–12 months after exposure. Gametocytes usually appear in the bloodstream within 3 days of overt parasitemia with P. vivax and P. ovale, and after about 10 days with P. falciparum. Unlike P. vivax and P. ovale, relapses do not occur with falciparum or malariae malaria. Reappearance of P. falciparum (recrudescence) occurs due to inadequate treatment or infection with drug-resistant strains. With P. malariae, low levels of erythrocytic parasites may persist for many years, to be activated at some future time to a level that may result again in clinical illness.

Induced malaria refers to infection that is passed directly from one individual to another through contaminated blood or blood products, injection equipment, or organ transplant. Congenital malaria refers to infection passed from mother to infant in utero. Pregnant women in endemic areas, especially primi- and secundigravidae, are at increased risk of infection with P. falciparum and vivax malaria due to partial loss of immunity during pregnancy. In areas of intense transmission, P. falciparum may infect the placenta and contribute to low birth-weight as well as maternal anemia. In low transmission areas, pregnant women are at high risk of severe falciparum malaria, abortion and premature delivery. Vivax malaria in pregnancy in these areas has been associated with maternal anemia and low birthweight.

Incubation periods

The incubation period is approximately 9–14 days for P. falciparum; 12–18 days for P. vivax and P. ovale; and 18–40 days for P. malariae. Some strains of P. vivax, mostly from temperate areas, may have an incubation period of 6–12 months. With infection through blood transfusion, incubation periods depend on the number of parasites infused and are usually short, but may range up to 2 months. Because there is no liver stage with transfusion-transmitted malaria, vivax or ovale relapses cannot occur. Suboptimal suppression from suboptimal prophylaxis may result in prolonged incubation periods.

Period of communicability

Humans may infect mosquitoes as long as infective gametocytes are present in the blood; this varies with parasite species and with response to therapy. Untreated or insufficiently treated patients may be a source of mosquito infection for several years in malariae, up to 5 years in vivax, and generally not more than 1 year in falciparum malaria; the mosquito remains infective for life. Transfusional transmission may occur as long as asexual forms remain in the circulating blood (with P. malariae, up to 40 years or longer). Stored blood can remain infective for at least a month.

Susceptibility

Susceptibility is universal except in humans with specific genetic traits. Clinical disease is present but often attenuated in adults in highly endemic communities who have acquired partial immunity following repeated exposure to infective anophelines over many years. Most indigenous populations of West Africa show a natural resistance to infection with P. vivax, which is associated with the absence of the Duffy antigen on their erythrocytes. Persons with the inherited sickle cell trait (heterozygotes) show relatively low parasitemia when infected with P. falciparum, and thus are relatively protected from severe disease. Homozygotes suffering from sickle cell disease are at increased risk of severe or fatal falciparum malaria, especially anemia. Other genetic traits that may modify disease expression include other hemoglobinopathies (HbC, HbE), thalassemias, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. HIV-infected immunosuppressed persons living in endemic areas appear to be at increased risk of more frequent and higher density infections, and may show decreased response to antimalarial therapy.

Methods of control

The control of malaria in endemic areas is based on early, effective treatment of all cases and a selection of preventive measures appropriate to the local situation.

Prompt and effective treatment of all cases is essential in order to reduce the risk of severe disease and prevent death. In areas of low transmission, this will also help reduce transmission. In areas of intense transmission, where children are the main risk group, formal health services may not be sufficiently accessible; in these situations, community-based treatment programs may increase access. The increasing problems of drug resistance highlight the importance of selecting a locally effective drug. For falciparum malaria, it is now recommended to use artemisinin-based combination therapy, to protect against the development of resistance and thus achieve rapid and effective cure and prolong the useful life of the treatments used.

A confirmatory diagnosis by microscopy or using a Rapid Diagnostic Test is recommended before treatment. However, in high transmission areas young children (under five years of age) with fever or a history of fever and no other obvious cause are often treated presumptively. P. falciparum malaria is the most likely cause of their illness and there is as yet no evidence to show that a young child with a negative parasitological diagnosis should not be treated. Similarly, starting treatment on clinical grounds can be justifiable for non-immune travelers.

  1. Preventive measures:
    • Local community measures in endemic areas

      1. Insecticide-treated mosquito nets (ITNs) are the most universally useful measure for the prevention of malaria. Although people may go to bed after mosquitoes have started biting, the partial protection is still useful; children, who are usually the most susceptible, generally go to bed earlier. If ITN coverage in a community is very high, a community-level or mass effect may be seen, whereby even those who do not have or sleep under ITNs are relatively protected. The use of mosquito nets has been uncommon or absent among most affected populations, but recently, availability, distribution, and coverage have increased in many countries. The nets must be carefully tucked under the sleeping mattress or mat. Conventional ITNs have to be systematically re-treated after 3 washes or at least once a year, which can be quite difficult to achieve; recently, long-lasting insecticidal nets (LLINs) incorporating or coated with pyrethroid insecticides during manufacture have obviated the need for re-treatment of nets, and these are now the preferred products; estimated life span of these nets is 2–5 years. Information on WHO-recommended nets can be found at: http://www.who.int/whopes/en/

        In order to obtain the best benefit of this highly cost-effective intervention, information on how nets should be used and maintained must be communicated to the people who will be using them. Other long-lasting nets, including some treated with two insecticides to prevent the development of resistance, are under development.

      2. Indoor residual spraying with insecticides (IRS) is another preventive method, targeting adult mosquitoes. IRS is most effective where mosquitoes rest indoors on sprayable surfaces, where people are exposed in or near the home, and when it is applied before the transmission season or period of peak transmission. Coverage rates in the target area must be high: in contrast to ITNs, IRS is a community public health intervention and not a personal protection measure. The susceptibility of vectors to the insecticide applied must be ascertained. When correctly applied on the basis of epidemiological and entomological data, IRS is very effective in reducing transmission by reducing the survival of malaria vectors entering houses or sleeping units. The most important constraints are operational: IRS requires a complex logistical effort involving teams of sprayers that need to be moved from community to community, and a certain number of households must be covered in a given time period. Thus, IRS becomes increasingly difficult in areas with low or very high human density, and where terrain is difficult. In addition, previous experience has shown that IRS, which may need to be carried out up to twice a year depending on the insecticide chosen and the transmission pattern, may become less popular over time: after repeated spray operations, community acceptance of intervention decreases. There are currently 12 insecticides recommended by WHO for IRS. The choice of insecticide is guided by insecticide susceptibility and vector behavior, safety for humans and the environment, efficacy, and cost-effectiveness. DDT is still needed and used for disease vector control because of its efficacy and operational feasibility. The use of DDT for IRS is closely monitored in the context of the Stockholm Convention on Persistent Organic Pollutants, which bans the use of DDT except for public health purposes. For further information on this, please consult: http://www.who.int/malaria/ddtandmalariavectorcontrol.html

      3. Control of larval stages by elimination of mosquito breeding sites—for example, by filling and draining, or by increasing the speed of water flow in natural or artificial channels—is of limited use in most areas where malaria transmission persists today. Similarly, chemical and biological control methods (bacterial larvicides, larvivorous fish) applied to impounded water bodies may be difficult to implement in rural areas; however, some success with these methods has recently been documented in urban African settings, and such methods may be useful adjuncts in situations such as arid, coastal and urban areas, or to maintain low receptivity of areas where malaria elimination has been achieved.

      4. Intermittent preventive treatment with a full curative dose of an effective antimalarial at predefined intervals during the 2nd and 3rd trimester of pregnancy is a highly effective measure for reducing the malaria burden among pregnant women in areas of stable, moderate to intense P. falciparum transmission. This is promoted in Africa, but is of limited use in other parts of the world where transmission is often unstable and of low intensity. ITNs or LLINs should also be made available to pregnant women in endemic areas to help reduce the deleterious effects of malaria in pregnancy.

      5. In epidemic-prone areas, malaria surveillance should be based on weekly reporting and combined with monitoring of locally important factors regarding the genesis of epidemics, such as meteorological and environmental conditions and human population movements. The case definition for surveillance recommended within the national malaria control program should be used. As a minimum, laboratory test-confirmed cases must be distinguished from non-confirmed (probable) cases.

    • Personal protective measures and treatment for non-immune travelers

      Because of the severity of malaria, increasing risks for non-immune travelers, and the large number of such travelers who visit endemic regions, personal protective measures taken by travelers are of utmost importance and are presented in detail.

      Physicians should realize that all people who visit an endemic area during the transmission season and who are exposed to mosquito bites between dusk and dawn are at risk of developing clinical malaria. Falciparum malaria may be fatal if treatment is delayed beyond 24 hours after the onset of clinical symptoms. Falciparum malaria is part of the differential diagnosis in all cases of unexplained fever starting at any time between 7 days after the first possible exposure to malaria and 3 months (or, rarely, later) after the last possible exposure. All non-immune persons, but especially young children, pregnant women, people living with HIV/AIDS, the immunosuppressed, and the elderly, are highly susceptible to development of severe and complicated malaria when infected. Ask for a travel history.

      Travelers to malarious areas must realize that protection from biting mosquitoes is of paramount importance; no antimalarial prophylactic regimen can give complete protection, but such regimens do reduce the risk of fatal disease; prophylaxis with antimalarial drugs should not automatically be prescribed for all travelers to malarious areas; and “standby” emergency self-treatment is recommended when a febrile illness occurs in a falciparum malaria area where professional medical care is not readily available.

      • Measures to reduce the risk of mosquito bites include the following:
        • Avoid being outdoors between dusk and dawn, when anopheline mosquitoes commonly bite. Wear long-sleeved clothing and long trousers when going out at night. The thickness of the material used for protective clothing is critical.

        • Systematic use of insect repellent on exposed skin as well as clothing (especially socks and trousers). Choose a repellent containing DEET (N,N-diethyl-m-toluamide), IR3535® (3-[N-acetyl-N-butyl]-aminopropionic acid ethyl ester), or Bayrepel®/Picaridin® (1-piperidinecarboxylic acid, 2-(2-hydroxyethyl), 1-methylpropylester). Repellents should be used in strict accordance with the manufacturers' instructions, and dosage must not be exceeded, especially for young children and pregnant women.

        • Stay in a well-constructed building, if possible air-conditioned, in the most developed part of town.

        • Use screens over doors and windows; if no screens are available, close windows and doors at night.

        • Use a mosquito net over the bed, with edges tucked in under the mattress; ensure that the net is not torn and that there are no mosquitoes inside it; sleep in the middle of the bed, avoiding contact between body and net. Use an ITN or LLIN to increase protection.

        • Use anti-mosquito sprays or insecticide dispensers (mains- or battery-operated) that contain tablets impregnated with pyrethroids in bedrooms at night (or mosquito coils if there is no electricity and batteries are unavailable). Different protective measures should be used in combination, especially when staying in areas where there is intense malaria transmission.


      • People who are or will be exposed to mosquitoes in malarious areas should know the four principles—the ABCD—of malaria protection:
        • Be Aware of the risk, the incubation period, the possibility of delayed onset, and the main symptoms.

        • Avoid being Bitten by mosquitoes, especially between dusk and dawn.

        • Take antimalarial drugs (Chemoprophylaxis) when appropriate, to prevent infection developing into clinical disease.

        • Immediately seek Diagnosis and treatment if a fever develops one 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.

          The risk of malaria infection varies among countries and between different areas of each country. For more information, see the country list in WHO's annually updated publication International Travel and Health, which can be found at:
          Depending on the malaria risk in the area visited, the recommended prevention method may be mosquito bite prevention only, or mosquito bite prevention in combination with chemoprophylaxis. Alternatively, in rural areas with multidrug-resistant malaria and only a very low risk of P. falciparum infection, mosquito bite prevention can be combined with standby emergency treatment.


      • Pregnant travelers must be advised of the following:
        • Malaria during pregnancy increases the risk of maternal death, miscarriage, stillbirth, low birthweight and neonatal death.

        • Pregnant travelers should not visit malarious areas unless this is absolutely necessary.

        • Pregnant women have been shown to be particularly susceptible to mosquito bites. Extra diligence is needed in using measures to protect against mosquito bites.

        • There is very limited information on the safety and efficacy of most antimalarials in pregnancy, particularly during the first trimester. There is no prophylactic or treatment regimen that is effective and safe for pregnant women in areas of multidrug-resistant malaria.

        • Prophylaxis with chloroquine (with or without proguanil) can be safely prescribed, including during the first 3 months of pregnancy, but its use is now very limited. Mefloquine prophylaxis may be given during the second and third trimesters, but there is limited information on its safety during the first trimester. Doxycycline is contraindicated during pregnancy. Atovaquone–proguanil has not been sufficiently investigated to be prescribed in pregnancy. In light of the danger of malaria to mother and fetus, experts increasingly agree that travel of pregnant women to a chloroquine-resistant P. falciparum area during the first trimester of pregnancy should be avoided or delayed at all costs; if this is truly impossible, good preventive measures should be taken, including prophylaxis with mefloquine where this is indicated.

        • Medical help should be sought immediately if malaria is suspected; standby emergency treatment should be taken only if no medical help is immediately available. Medical help must be sought as soon as possible after standby treatment (see 9AII5 and 9AII6).

        • Women of childbearing age should preferably avoid pregnancy until 3 months after they have stopped mefloquine prophylaxis, and for 1 week after doxycycline, and 3 weeks after atovaquone-proguanil. If pregnancy occurs during antimalarial prophylaxis, this is not considered to be an indication for pregnancy termination.


      • Parents of young children must be advised of the following:
        • Falciparum malaria in a young child may be rapidly fatal. Early symptoms are atypical and difficult to recognize, and life-threatening complications can occur within hours of the initial symptoms. In infants, fever may be absent.

        • Babies and young children should not be taken to areas with risk of falciparum malaria. If travel cannot be avoided, children must be very carefully protected with preventive measures.

        • Chemoprophylaxis dosage schedules for children should be based on body weight. Long-term travelers and expatriates should adjust the chemoprophylaxis dosage according to the increasing weight of the growing child.

        • Chloroquine (5 mg base/kg/week in one dose; or 10 mg base/kg/week divided into 6 daily doses) and proguanil (3 mg/kg/day) are safe, but their use is now very limited. Mefloquine (5 mg/kg/week) may be given to infants of more than 5 kg body weight. Atovaquone–proguanil (in pediatric tablets) is generally not recommended for prophylaxis in children who weigh less than 11 kg, because of limited data; in the USA and Belgium it is given for prophylaxis in infants of more than 5 kg body weight. Doxycycline cannot be used in children less than eight years of age.

        • All antimalarial drugs should be kept out of the reach of children and stored in childproof containers: chloroquine is particularly toxic in case of overdose.


      • Chemoprophylaxis: Before travel, the most appropriate chemoprophylactic antimalarial drug(s) (if any) for the destination(s) should be prescribed in the correct dosages.

        • In areas with only very limited risk of malaria transmission, chemoprophylaxis may not be indicated, as the risk of side effects associated with antimalarials may outweigh the potential benefits. Travelers should, however, always be aware of the possibility of malaria if they develop a febrile disease.

        • In areas where only P. vivax malaria occurs, and those rare places where P. falciparum remains fully sensitive to chloroquine, chemoprophylaxis with chloroquine (5 mg base/kg/week in one dose; or 10 mg base/kg/week divided into 6 daily doses) on its own can be used.

        • In areas with risk of P. vivax and P. falciparum malaria transmission, and emerging chloroquine resistance, chloroquine chemoprophylaxis should be combined with proguanil (3 mg/kg/day).

        • In areas with high risk of P. falciparum malaria and reported antimalarial drug resistance, the chemoprophylaxis choices are atovaquone–proguanil (adult dose: 250 mg atovaquone plus 100 mg proguanil daily), doxycycline (1.5 mg/kg/day), or mefloquine (5 mg/kg/week). This choice also applies to areas with moderate/low P. falciparum risk and reported high levels of drug resistance. The selection depends on the reported resistance pattern in the area to be visited, the contraindications of the various drugs, and personal preferences. Annually updated information on recommended prophylaxis options is available from WHO at:
        • Antimalarials that have to be taken daily (atovaquone-proguanil, chloroquine, doxycycline, proguanil) should be started the day before arrival in the risk area. Weekly chloroquine should be started 1 week before arrival. Mefloquine should preferably be started 2–3 weeks before departure, to achieve higher pre-travel blood levels and to allow side effects to be detected before travel so that possible alternatives can be considered.

        • All prophylactic drugs should be taken with unfailing regularity for the duration of the stay in the malaria risk area, and should be continued for 4 weeks after the last possible exposure to infection, since parasites may still emerge from the liver during this period. The single exception is atovaquone–proguanil, which can be stopped 1 week after return because of its effect on early liver-stage parasites. Premature interruption of the daily atovaquone-proguanil prophylaxis regimen may lead to loss of this causal prophylactic effect, in which case atovaquone-proguanil prophylaxis should also be continued for 4 weeks upon return.

        • All antimalarial drugs have specific contraindications and possible side effects. Serious adverse events—defined as constituting an apparent threat to life, requiring or prolonging hospitalization, or resulting in persistent or significant disability or incapacity—are rare, and normally only identified in post-marketing surveillance once a drug has been in use for some time. Severe neuropsychiatric disturbances (seizures, psychosis, encephalopathy) occur in approximately 1 in 10 000 travelers receiving mefloquine prophylaxis, and have also been reported for chloroquine at a similar rate. The risk of serious adverse reactions can be reduced by carefully observing the contraindications for each drug. A traveler who develops severe side-effects to an antimalarial should stop taking the drug and seek immediate medical attention.

      • Standby emergency treatment (SBET): The most important factors that determine the survival of patients with falciparum malaria are early diagnosis and immediate treatment. Non-immune individuals exposed to or infected with malaria should obtain prompt medical attention when malaria is suspected. A minority will be exposed to a high risk of infection while at least 12–24 hours away from competent medical attention. WHO recommends that prescribers issue antimalarial medicines to be carried for self-administration by persons who may be in such exposed situations. Also, in light of the spread of counterfeit medicines, some travelers may opt to buy a reserve antimalarial treatment before departure, so that they can be confident of drug quality should they become ill.

        Persons prescribed standby treatment must receive precise instructions on recognition of symptoms, when and how to take treatment, the complete treatment regimen to be taken, possible side-effects, and action to be taken in the event of drug failure. They must be made aware that self-treatment is a temporary measure and medical advice is to be sought as soon as possible. If several people travel together, the individual dosages for SBET should be specified. Weight-based dosages for children need to be clearly indicated.

      • Treatment upon return:

        The following antimalarials are suitable for treatment of uncomplicated falciparum malaria in travelers returning to non-endemic countries:
        • Artemether–lumefantrine (adult dose, 4 tablets twice a day for 3 days).

        • Atovaquone–proguanil (15/6 mg/kg, usual adult dose, 4 tablets once a day for 3 days).

        • Quinine (10 mg salt/kg bw every 8 h) plus doxycycline (3.5 mg/kg bw once a day) or clindamycin (10 mg/kg bw twice a day); all drugs to be given for 7 days. Doxycycline cannot be used during pregnancy and in children less than eight years of age.


        The treatment for vivax and ovale malaria in travelers is with chloroquine (25 mg base/kg bw divided over 3 days), combined with primaquine (usual dose 0.25 mg base/kg bw, taken with food once daily for 14 days). For travelers returning from Oceania and southeast Asia the dose of primaquine should be 0.5 mg/kg bw. In moderate G6PD deficiency, primaquine 0.75 mg base/kg bw should be given once a week for 8 weeks. In severe G6PD deficiency, primaquine should not be given. Primaquine is contraindicated during pregnancy and in young infants. Late onset vivax or ovale malaria may occur from the development of intrahepatic parasites after chemoprophylaxis is discontinued. Malariae malaria in travelers can be treated with chloroquine (25 mg base/kg bw divided over 3 days).

        Returning travelers with severe falciparum malaria should be managed in an intensive care unit. Parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available:
        • Artesunate (first choice) (2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day).

        • Artemether (3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day).

        • Quinine (20 mg salt/kg bw on admission (i.v. infusion or divided i.m. injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour).


        If these medicines are not available, use parenteral quinidine with careful clinical and electrocardiographic monitoring.

  2. Control of patient, contacts and the immediate environment:
    1. In non-endemic areas, report to local health authority: Obligatory case report as a Disease under Surveillance by WHO, Class 1 (see Reporting), preferably limited to smear confirmed cases; Class 3 (reporting of probable and confirmed cases) is the more practical procedure in endemic areas.

    2. Isolation: For hospitalized patients, blood precautions. In non-endemic areas where malaria transmission is possible, patients should be in mosquito-proof areas from dusk to dawn, until microscopy shows that they have no gametocytes in the blood.

      Blood donations

      In non-endemic areas, blood donors should be questioned for a history of malaria or a history of travel to, or residence in, a malarious area. In many non-endemic areas, travelers who have not taken antimalarial drugs and who have been free of symptoms may donate blood 6 months after return from an endemic area. In some others, travelers to an area with malaria are deferred from donating blood for 1 year after their return; former residents of malaria-risk areas are deferred for 3 years; and persons diagnosed with malaria cannot donate blood for 3 years after treatment, during which time they must have remained free of symptoms of malaria. Immigrants or visitors from areas where P. malariae malaria is or has been endemic may be a source of transfusion-induced infection for many years. Such areas include malaria endemic countries of the Americas, tropical Africa, the southwestern Pacific, and south and southeast Asia.

    3. Concurrent disinfection: Not applicable.

    4. Quarantine: Not applicable.

    5. Immunization of contacts: Not applicable.

    6. Investigation of contacts and source of infection: Determine history of previous infection or of possible exposure. If a history of sharing needles is obtained from the patient, investigate and treat all persons who shared the equipment. In transfusion-induced malaria, all donors must be located and their blood examined for malaria parasites and for antimalarial antibodies; parasite-positive donors must receive treatment. Malaria cases in non-endemic areas are usually imported, but some cases with no travel history have been reported in recent years: some of these events are believed to have been caused by infected mosquitoes air-transported from an endemic area; in other situations, infected migrants from endemic areas to non-malarious areas have been the source for outbreaks of local transmission where competent vectors are present. If the area is receptive to malaria (competent vectors present), persons living in the same community as well as health services should be advised about the risk of malaria; people developing malaria-like symptoms must be examined by microscopic examination of blood smears or rapid diagnostic tests. The flight range of anopheline mosquitoes may reach 2 km, but in most cases it is only a few hundred meters. Vector control should only be considered if several cases occur in a small area. Malaria outbreaks in receptive areas can also be triggered by a heavy influx of seasonal laborers and/or immigrants from nearby endemic countries. In the USA, several cases of locally-acquired malaria have occurred since the mid-1980s after importation of infection in humans or mosquitoes.

    7. Specific treatment for all forms of malaria:
      • P. falciparum in almost all endemic areas of the world is resistant to chloroquine, and in most areas to sulfadoxine-pyrimethamine (which was initially used to replace chloroquine). Identifying suitable antimalarial drug policies poses a major challenge to national programs in endemic countries. WHO now recommends that P. falciparum endemic countries with chloroquine resistance adopt artemisinin-based combination therapy (ACT). ACTs are highly effective, providing a greater than 90% cure rate in almost all situations. There are four ACT regimens currently recommended for use and the choice of the ACT depends on the efficacy of the non-artemisinin partner medicine in that particular area or country:
        • Artemether-lumefantrine (adult dose, 4 tablets twice a day for 3 days).

        • Artesunate plus mefloquine (4 mg/kg bw of artesunate given once a day for 3 days and 25 mg base/kg bw of mefloquine usually split over 2 or 3 days).

        • Artesunate plus amodiaquine (4 mg/kg bw of artesunate and 10 mg base/kg bw of amodiaquine, given once a day for 3 days).

        • Artesunate plus sulfadoxine-pyrimethamine (4 mg/kg bw of artesunate given once a day for 3 days and a single administration of sulfadoxine-pyrimethamine (25/1.25 mg base/kg bw) on day 1.


        In addition to improving efficacy, the use of combination therapy will help delay the emergence of drug resistance to the non-artemisinin partner medicine in the combination.
        Alternatives to ACTs for the treatment of uncomplicated P. falciparum malaria would be a combination of oral quinine (30 mg salt/kg/day in 3 divided doses for 7 days) together with either oral doxycycline (2 mg/kg once a day, maximal 100 mg/dose) or tetracycline (5 mg/kg/dose, maximal 250 mg/dose, 4 times a day for 7 days) or clindamycin (10 mg/kg bw twice a day). If the patient is pregnant or under 8 years of age, doxycycline and tetracycline are contraindicated, and quinine should be given with clindamycin.

      • For P. falciparum infections acquired in areas of multidrug resistance (southeast Asia, Amazon Basin), ACT treatment with artesunate+mefloquine or artemether-lumefantrine is recommended. Artemether-lumefantrine tablets contain 20mg artemether and 120 mg of lumefantrine. Adult dosage: 6 doses given over 3 days (4 tablets each at 0 hours, 8 hours, 24 hours, 36 hours, 48 hours, and 60 hours). Pediatric dosage by weight: 5–14 kg 1 tablet at same time intervals, 15–24 kg 2 tablets at same time intervals, 25–34 kg 3 tablets at same time intervals, >34 kg adult regimen). Artemether-lumefantrine is not yet available in the United States.

      • Severe falciparum malaria is a medical emergency. After rapid clinical assessment and confirmation of the diagnosis, full doses of parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available. In low transmission areas or outside malaria endemic areas the recommended choice is artesunate 2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day. For children in high transmission areas, any of the following antimalarial medicines can be used:
        • Artesunate (2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day).

        • Artemether (3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day).

        • Quinine (20 mg salt/kg bw on admission (i.v. infusion or divided i.m. injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour).


        Details on the management of severe malaria can be found in: Management of severe malaria—a practical handbook (WHO, Geneva, 2000), available at:
      • For P. vivax infections the recommended treatment is chloroquine (25 mg base/kg divided over 3 days) combined with primaquine to prevent relapses that occur as a result of the late development of intrahepatic stages. Primaquine can produce hemolysis, especially in those with G6PD deficiency; patients should be tested for G6PD deficiency before primaquine is given. In areas where re-infection is very frequent, the risks of widespread use of primaquine may exceed the benefits. The decision to administer primaquine is made on an individual basis, after consideration of the potential risk of adverse reactions. A dose of 0.25 mg base/kg/day taken with food for 14 days (15 mg base or 26.3 mg of primaquine phosphate for the average adult) is often effective. Larger daily doses (30 mg base) are generally required for use in the southwestern Pacific and for some strains from southeast Asia and South America. In moderate G6PD deficiency, primaquine, 0.75 mg base/kg, may be given once weekly for 8 doses (45 mg base or 79 mg primaquine phosphate for the average adult). Primaquine should not be administered during pregnancy, in young infants, and in severe G6PD deficiency. In areas where confirmed chloroquine-resistant P. vivax infections have been reported, any of the recommended ACTs can be given, with the exception of artesunate plus sulfadoxine-pyrimethamine; quinine and artemether-lumefantrine are possible alternatives.

      • For prevention of relapses in mosquito-acquired P. vivax and P. ovale infections, administer primaquine, as described above, after testing for G6PD deficiency to prevent drug-induced hemolysis. Primaquine is not required in the treatment of induced malaria (e.g. transfusion), since no liver phase occurs.

      • P. malariae infections can be treated with chloroquine (25 mg base/kg bw divided over 3 days).

        WHO recommendations, products and drug policies can be found online at:
        US guidelines may differ and can be found at:


  3. Epidemic measures: Determine the nature and extent of the epidemic situation. Malaria epidemics must be controlled through rapid and vigorous action and effective treatment of all cases; in confirmed P. falciparum epidemics where a large part of the population is infected, mass fever treatment, based only on clinical grounds (fever) without laboratory confirmation of diagnosis, may be necessary to cope with the patient load. In falciparum malaria epidemics the inclusion of an anti-gametocyte drug like primaquine in a single adult dose of 30–45 mg may be considered, but possible benefits must be weighed against possible side-effects in G6PD-deficient persons. As soon as possible, full coverage vector control measures should be instituted. Usually, indoor residual spraying is preferred because of its rapid effect; this may be followed by the use of ITNs or LLINs and anti-larval measures.

  4. Disaster implications: Disasters in endemic areas may lead to malaria epidemics, often as a result of population movements, ecological changes favoring vector breeding, breakdown of health services, crowding of people in poorly-constructed housing or the existence of a large number of people without adequate housing, creating high-risk, high-exposure situations. In complex emergencies in Africa, malaria has presented with an epidemic pattern, taking an extraordinarily high toll among children, and often adults. At such times the drug resistance situation often turns out to be worse than had been assumed from national data, and therefore artemether-lumefantrine, to which parasites from most parts of the world are still sensitive, is recommended for use as the first-line medicine. Control priorities are early effective treatment and vector control; the latter is usually only possible after the acute emergency is over, and focuses on personal protection with ITNs or LLINs for high risk groups, combined with indoor residual spraying where feasible. In densely populated refugee camps, space spraying may be effective in the emergency phase; environmental measures may be relevant later. In areas of intense transmission in Africa, intermittent preventive treatment in pregnancy should be provided as soon as antenatal care services have been established or re-established. Health education on a continuous basis, as in any context, is required to support these interventions and promote better malaria control.

    More information can be found at:
  5. International measures:
    1. Important international measures include the following:
      • Disinsectization of aircraft before boarding passengers or in transit, using a residual spray application of an effective insecticide.

      • Disinsectization of aircraft, ships and other vehicles on arrival if the health authority at the place of arrival has reason to suspect importation of malaria vectors.

      • Enforcing and maintaining rigid anti-mosquito sanitation within the mosquito flight range of all ports and airports.


    2. In special circumstances, screen and treat potentially infected migrants, refugees, seasonal workers and persons taking part in periodic mass movement before their arrival in an area or country where malaria has been eliminated. Arrange housing of such populations as much as possible in non-receptive areas, and/or in well-constructed, screened housing that prevents mosquito entry. Primaquine, 30–45 mg base (0.5–0.75 mg/kg), given as a single dose, renders the gametocytes of P. falciparum non-infectious, but possible benefits must be weighed against possible side-effects in G6PD-deficient persons.

    3. As one of the world's major global public health problems, malaria is a disease under surveillance by WHO. It is addressed by the global Roll Back Malaria Initiative, the United Nations' Millennium Development Goals, the Global Fund to fight AIDS, Tuberculosis and Malaria, UNICEF, the US President's Malaria Initiative, the World Bank Booster Program, and other partners. National health administrations in endemic countries are expected to notify WHO annually of the following:

ICD-9

084

ICD-10

B50
B54

Authors

[CCDM19: K. Mendis, A. Rietveld, L. Slutsker]
[CCDM18: A. Schapira]

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