Malaria

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Malaria should always be managed in conjunction with an infectious diseases specialist. Local guidelines will usually have contact details for advice. Most guidelines are similar, but they will vary to some degree depending on which drugs are licensed or available. The following section is predominantly based on guidelines from the Centers for Disease Control and Prevention (CDC), as well as the World Health Organization (WHO).[49][104]

Overview of management

Treatment will depend on the infecting species, the appearance of the blood smear (% parasitemia, presence of schizonts), and the clinical status of the patient.

Consideration should be given to the likely susceptibility of the parasite to the treatment used, based on known epidemiology relating to the geographic area where the infection was acquired.
Specific treatment for malaria should not be given until infection has been confirmed, except in exceptional circumstances.
Consequently, the goal of therapy is to eradicate infection; to reduce the risk of complications by reducing the parasite load as quickly as possible; and, in endemic areas, to avoid selecting resistance by using multiple agents.

Artemisinin derivatives such as artesunate and artemether are extracts of the qinghao plant (Artemisia annua). They have a rapid-onset therapeutic effect by clearing parasites from the blood, and are currently the most effective antimalarial drugs known. In order to prevent late recrudescences and emergence of resistance, they must be used in combination with another drug;[105] oral monotherapy is not recommended.[106]

Artemisinin-based combination therapy (ACT) also reduces gametocyte carriage and thereby lowers the risk of transmission, which is important in endemic regions.[107]
There is evidence that they are safe and effective for uncomplicated malaria in endemic areasin both pregnant and nonpregnant individuals, and in nonimmune travelers.[108][109]
There is also strong evidence to support the use of intravenous artesunate over intravenous quinine for severe malaria.[49] [ ]
There have been reports of severe, often delayed, hemolysis in returning travelers treated with artemisinins.[110][111][112] Based on this finding, European centers have suggested monitoring hemoglobin levels for 4 weeks in patients treated with intravenous artesunate.[113]

Plasmodium falciparum malaria is potentially fatal if not treated promptly, as life-threatening complications can develop quickly in patients who initially appear well, and even short delays increase morbidity and mortality.[39] This is especially the case in certain risk groups including nonimmune travelers, pregnant women, children, and older adults.[16][40][41]

Most authorities recommend that travelers withP falciparum malaria should be hospitalized for treatment.
Several observational studies conducted in centers with a special interest suggested that falciparum malaria can be managed on an outpatient basis, though specific criteria for safe outpatient management in a nonexpert setting are unclear.[114][115][116][117]
Where outpatient management is planned, daily review with slide microscopy has been suggested.[113]

Patients with uncomplicated malaria can be treated effectively with oral antimalarial therapy, but parenteral therapy is recommended if signs of severe malaria are present, or if the patient is unable to tolerate oral therapy. Supportive care is an important aspect of therapy, and a period in an intensive care unit is often necessary in cases of severe malaria.

Nonfalciparum malaria, caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, or Plasmodium knowlesi, is rarely life-threatening and can usually be managed on an outpatient basis unless comorbidities are present or parasite density is high (P knowlesi). In infection with P vivax or P ovale, glucose-6-phosphate dehydrogenase (G6PD) levels should be checked, as primaquine or tafenoquine therapy will be necessary to eradicate hypnozoite forms, and hemolysis may occur in patients who are deficient in G6PD.

If the species cannot be identified, the patient should be treated as for P falciparum infection.[104]

General approach to the management of severe malaria

Severe malaria is almost always caused by falciparum infection. However, severe nonfalciparum infection is also possible. Patients are classified as having severe malaria if they meet certain criteria.[49] See the Criteria section for more information. Treatment of severe malaria is the same, regardless of species.[104]

Patients with severe disease should be treated aggressively with parenteral antimalarial therapy and transferred to the intensive care unit for intensive monitoring and support.[38]

Parenteral therapy precludes poor absorption and reduces the parasite load as quickly as possible.
Exchange transfusion for very high parasitemia is controversial and is not generally recommended.
Delays in antimalarial therapy may increase morbidity and mortality.[39]
Specific parenteral antimalarial regimens are detailed below.

Supportive therapy is vital and is aimed at correcting the above-mentioned complications. This includes careful fluid management, often with renal support; airway protection; control of seizures; and transfusion of blood products. Hypoglycemia may be worsened by quinine-induced hyperinsulinemia, so should be monitored closely.

Uncomplicated P falciparum infection: nonpregnant

Chloroquine resistance is widespread in most regions of the world. Therefore, one of the following oral regimens supported by the CDC or the WHO is recommended for chloroquine-resistant regions:[49][104]

ACT for 3 days; availability varies, but the following regimens are recommended:
- artemether/lumefantrine
- dihydroartemisinin (also known as artenimol) plus piperaquine [ ]
- artesunate plus mefloquine [ ]
- artesunate plus amodiaquine
- artesunate plus sulfadoxine/pyrimethamine
- artesunate plus pyronaridine

quinine (for 3-7 days, depending on location) plus 1 of the following: doxycycline or tetracycline or clindamycin (for 7 days)
atovaquone/proguanil (for 3 days)
mefloquine (for 2 doses)

Mefloquine-based regimens should be used only if the other options are not available due to an increased rate of adverse effects and concerns about longer-lasting or permanent neuropsychiatric complications.[118]

The CDC recommends treatment with chloroquine (preferred) or hydroxychloroquine for chloroquine-sensitive regions.[104] The WHO also recommends ACT as an option.[49] There have been no reports of clinically significant chloroquine resistance in infections acquired in parts of Central America (west of Panama Canal), Haiti and the Dominican Republic, and some parts of the Middle East.

Evidence for regimens

Despite the WHO recommending the ACT options above equally, there is some evidence from African studies that dihydroartemisinin plus piperaquine reduces the overall rates of treatment failure when compared with artemether/lumefantrine, although failure rates in general are low (i.e., <5%).[119] [ ] Resistance to dihydroartemisinin plus piperaquine has been reported in Southeast Asia and East Africa.[120][121] Prolongation of the QTc interval and tachycardia are frequent adverse effects associated with the use of piperaquine-containing combinations, and these drugs are contraindicated in patients with a history (or family history) of sudden cardiac death. However, one large systematic review found that sudden unexplained death caused by repolarization-related tachyarrhythmia after treatment with a standard 3-day course of dihydroartemisinin plus piperaquine is very rare, and the risk is not higher than the baseline rate for sudden cardiac death in the general population ages <35 years.[122]
Also, a retrospective comparative analysis in Sweden found a high rate of symptomatic late treatment failures with artemether/lumefantrine in nonimmune adults, particularly men. The efficacy of this drug was found to be 94.7%, compared with 99.5% for other oral regimens in this study.[123] A case of treatment failure with artemether/lumefantrine has been reported in a UK patient from Uganda; the presence of pfk13 mutations were documented.[124]
One Cochrane review of five randomized controlled trials with 5711 participants across Africa and Asia found that pyronaridine/artesunate was as efficacious or better than existing ACTs for uncomplicated P falciparum malaria, with a less than 5% failure rate at days 28 and 42.[125] [ ]
One Cochrane review found that atovaquone/proguanil is effective against uncomplicated P falciparum malaria, but treatment failure exceeded 5% in some studies.[126]

Primaquine (low-transmission areas)

In low-transmission areas, the WHO recommends giving a single low dose of primaquine with ACT to reduce transmission, to all patients with parasitologically confirmed P falciparum malaria except pregnant women, infants ages <1 month, and women breast-feeding infants ages <1 month. Testing for G6PD deficiency is not required in these patients.[49] This regimen is thought to rapidly reduce the infectivity and number of gametocytes available to mosquitoes, and at a population level is a useful component of pre-elimination or elimination programs.
One study found that a single low dose of primaquine, when used as a gametocytocide, was unlikely to cause serious toxicity, even in patients with G6PD deficiency.[127] One Cochrane review found that a single low dose of primaquine (added to ACT) is as effective as higher doses and reduces the infectiousness of people to mosquitoes at days 3-4 and 8. [ ] There was no evidence of increased hemolysis at this dose; however, it should be noted that very few patients with G6PD deficiency were included in the trials. It is unclear whether this would reduce malaria transmission in communities.[128]

Complicated P falciparum infection (or any other species): nonpregnant

Severe malaria is a medical emergency. Admission to an intensive care unit should be considered. Patients with hyperparasitemia, jaundice, anemia, and renal impairment do not necessarily require intensive care; however, such features are often associated with other complications. Some patients may be able to be managed on an experienced floor or high dependency unit. The decision to admit to intensive care should be discussed with an infectious diseases specialist. Treatment of severe malaria is the same, regardless of species.[104]

Recommended regimen for severe disease

Parenteral artesunate should be given until the patient is able to take oral treatment (but for at least 24 hours) and parasitemia has fallen to <1% (usually a minimum of 3 doses is suggested), followed by a suitable oral regimen (e.g., ACT; atovaquone/proguanil; quinine plus doxycycline or clindamycin).[49][104] Mefloquine is generally not recommended for follow-on treatment of severe malaria due to the increased risk of post-malaria neurologic syndrome.
Intravenous artesunate is the recommended first-line treatment in the US as the previous first-line treatment, intravenous quinidine, has now been discontinued. Intravenous artesunate is approved by the Food and Drug Administration and is commercially available.[129] CDC: how to acquire IV artesunate in the United States Opens in new window

Alternative regimens if preferred regimen unavailable

The WHO recommends intramuscular artemether in preference to quinine if parenteral artesunate is not available.[49]

In areas where parenteral artesunate is not available, a single dose of rectal artesunate may be considered in children ages <6 years for prereferral treatment, but the child should be referred immediately to an appropriate facility for further care. Rectal artesunate is not recommended in older children and adults.[130]

One Cochrane review found that artemether is more effective than quinine in children and adults with severe malaria, and is inferior to artesunate in adults. This review therefore supports current WHO recommendations.[131]

In low-transmission areas, the WHO recommends giving a single low dose of primaquine with ACT to reduce transmission, to all patients with parasitologically confirmed P falciparum malaria except for pregnant women, infants ages <1 month, and women breast-feeding infants ages <1 month.[49]

Nonfalciparum infection: nonpregnant

The majority of nonfalciparum infections are uncomplicated.

P malariae, P ovale, or P knowlesi infection should be treated with oral chloroquine (preferred) or oral hydroxychloroquine, as no widespread evidence of chloroquine resistance has been reported with these species. ACT is a suitable alternative. Treatment of P vivax depends on whether it is chloroquine-sensitive or resistant.[49][104]

P knowlesi, which is found in parts of Southeast Asia, replicates every 24 hours; therefore, rapid diagnosis and prompt treatment of infection is essential.[132] Hospitalization should be considered in patients with P knowlesi infection to monitor for clinical response and parasitemia due to the risk of complications.[104]

Treatment (or prophylactic) failure with chloroquine for P vivax malaria has been observed in at least 24 countries, particularly in Indonesia and Papua New Guinea.[133] Patients who do not respond to standard treatment with chloroquine (or who are in chloroquine-resistant regions) should use one of the following alternative oral regimens:[49][104]

ACT [ ] [ ]
Quinine plus 1 of the following: doxycycline or tetracycline or clindamycin (for 7 days)
Atovaquone/proguanil (for 3 days)
Mefloquine (if no other options)

Nonfalciparum infection: antirelapse treatment

Treatment for the acute phase of P vivax and P ovale malaria should be followed by antirelapse therapy to eliminate the hypnozoite stages that are dormant within the liver. Treatment options include primaquine or tafenoquine. Tafenoquine has a longer half-life and duration of action compared with primaquine and has the advantage of single-dose administration.[49][104]

Primaquine

Primaquine is recommended for the prevention of relapse in patients with uncomplicated P vivax or P ovale malaria.[49][104] It is recommended in all children and adults, except for pregnant women, infants ages <1 month, women breastfeeding infants ages <1 month, and people with G6PD deficiency.[49][104]
Primaquine may be used in combination with any of the drugs recommended for the treatment of the acute phase of infection.[49][104]
The recommended treatment course is 7-14 days, depending on the dose and regimen selected. The hypnozoiticidal activity of primaquine is predominantly a function of the total dose administered. One Cochrane review found no difference in efficacy between the higher dose 7-day course and the standard dose 14-day course in G6PD-normal patients.[134]
A higher total dose is recommended in Africa, South-East Asia, and Oceania; whereas, a lower total dose may be used in areas on the Indian subcontinent and the Americas.[49]
The most common adverse effect is gastrointestinal upset, which can be minimized if taken with food.
Determination of G6PD status using a suitable test is required to guide the safe administration of primaquine.[49][104]

Tafenoquine

Tafenoquine is recommended as an alternative to primaquine for the prevention of relapse. While the CDC recommends use for either P vivax or P ovale malaria, the WHO currently only recommends use in patients with P vivax malaria in South America. The recommended treatment course is a single dose.[49][104]
Tafenoquine is only recommended for use in patients who are receiving treatment with chloroquine (or hydroxychloroquine) for the treatment of the acute phase of infection. It is not recommended for patients who are receiving ACT.[49][104]
The CDC recommends use in adolescents ages ≥16 years and adults, while the WHO recommends use in children ages ≥2 years. It is not recommended in pregnant or breastfeeding women.[49][104]
The specific brand of tafenoquine recommended for antirelapse treatment in the US is Krintafel® (the Arakoda® brand is only licensed for malaria chemoprophylaxis).[104] Tafenoquine is not approved for use in Europe as yet.
One randomized, placebo-controlled study found no clinically meaningful benefit with a single dose of tafenoquine coadministered with dihydroartemisinin/piperaquine compared with dihydroartemisinin/piperaquine alone for radical cure of P vivax infection.[135] However, combination treatment with chloroquine was found to be better than chloroquine alone for P vivax relapse infection.[136]
Tafenoquine has been associated with methemoglobinemia, psychiatric adverse effects, and hypersensitivity reactions. Due to its long half-life, adverse effects may be delayed in onset and/or duration. It should not be used in patients with a history of a psychotic disorder.
Qualitative or semiquantitative determination of G6PD activity is required before administration of tafenoquine.[49][104]

One Cochrane review found moderate-certainty evidence that a single dose of tafenoquine prevents relapse of P vivax malaria in adults compared with no antihypnozoite treatment, and that there is probably little or no difference between tafenoquine and primaquine in preventing relapses.[137]

Patients with G6PD deficiency who are not expected to tolerate either drug should continue on weekly chloroquine prophylaxis for one year from the acute infection.[104]

G6PD deficiency testing

Primaquine and tafenoquine may cause hemolytic anemia in patients with G6PD deficiency; therefore, patients must be screened prior to starting therapy. The G6PD status of patients should be used to guide administration of either drug for preventing relapse.[49]

There are over 180 different genetic G6PD variants that are found commonly in tropical areas, with gene frequencies ranging between 3% and 30%.[127] The extent of hemolysis depends on the degree of G6PD deficiency, as well as the dose and duration of exposure. Two of the most prevalent G6PD variants are the Mediterranean variant (found in Europe, west and central Asia, and north India) that is associated with the most profound deficiencies, and the African A-variant (found in Sub-Saharan Africa and in African-Americans) associated with the mildest.[127]
The WHO recommends the following tests to inform administration of specific treatment regimens to prevent relapses of P vivax and P ovale malaria.[49]
- Qualitative near-patient G6PD tests: G6PD nondeficient patients can receive the lower dose 7-day course (3.5 mg/kg total dose) or the standard dose 14-day course (7 mg/kg total dose) of primaquine.
- Semiquantitative near-patient G6PD tests: only those with ≥70% G6PD activity should receive the higher dose 7-day course (7 mg/kg total dose) of primaquine, or the single dose of tafenoquine. Other primaquine regimens are recommended in patients with >30% to <70% G6PD activity (i.e., the standard dose 14-day course or the lower dose 7-day course).
Radical cure primaquine regimens have been used in those with P vivax malaria and mild G6PD variants. As hemolysis is self-limiting, reticulocytosis following each dose compensates for hemolysis and the progressively younger red-cell population becomes increasingly resistant to the drug’s hemolytic effects. Radical cure primaquine regimens are currently only recommended in patients presenting with P vivax or P ovale malaria. However, there is emerging evidence that they may be effective in patients presenting with uncomplicated P falciparum malaria in areas where both species are circulating. In one open-label randomized trial, high-dose short-course primaquine reduced the risk of subsequent P vivax parasitemia within 63 days by five-fold.[138]
Primaquine and tafenoquine should not be used in pregnancy in case there is undetected G6PD deficiency in the fetus, which can result in hemolysis.[49][139]

Overview of management in pregnancy

Treatment of malaria in pregnancy must be managed together with an infectious diseases specialist.

Pregnant women are at increased risk for severe malaria, anemia, and death. Infected red cells sequester in the placenta, disrupting the nutritional exchange between mother and fetus. Adverse effects on fetal outcome include increased risk of abortion, stillbirth, and low birth weight.[140][141][142]
Pregnant women with malnutrition (defined as low mid-upper arm circumference or low body mass index) and malaria appear to be at an increased risk of having a baby with low birth weight compared with women who are well nourished and not infected; however, no synergistic relationship between malaria and malnutrition was found, suggesting these two factors act independently to influence fetal growth.[143]

There is insufficient information on the safety, efficacy, and pharmacokinetics of most antimalarial agents in pregnancy, particularly use during the first trimester.[49][104]

Drugs that are considered safe to use in pregnancy include ACT, quinine, clindamycin, chloroquine, and hydroxychloroquine.
Primaquine and tafenoquine should be avoided due to risk of hemolysis as a result of undetected G6PD deficiency in the fetus.[144]
Atovaquone/proguanil is not recommended for use, due to a lack of safety data in pregnancy.
Tetracyclines are not recommended in pregnancy.
Although the CDC recommends pregnant women of all gestational ages can be treated with mefloquine, the WHO recommends mefloquine only in the second and third trimesters and in combination with an artemisinin derivative.

Choice of regimen depends on the trimester of pregnancy and whether the infection is complicated or uncomplicated.

Uncomplicated infection: pregnant

The CDC recommends the following options for uncomplicated infection, regardless of species, in all trimesters of pregnancy:[104]
- Chloroquine-resistant: artemether/lumefantrine; quinine plus clindamycin; or mefloquine (if no other options due to concerns about longer-lasting or permanent neuropsychiatric complications)
- Chloroquine-sensitive: chloroquine or hydroxychloroquine (or one of the options for chloroquine-resistant if these drugs are not available)
The WHO recommends ACT in all trimesters of pregnancy, regardless of species.[49]
- Low-certainty evidence suggests that ACT may be used to treat uncomplicated falciparum malaria in the first trimester of pregnancy. The WHO strongly recommends artemether/lumefantrine. There is insufficient evidence to make a recommendation for the routine use of other ACT in the first trimester. However, artesunate plus amodiaquine, artesunate plus mefloquine, or dihydroartemisinin plus piperaquine may be considered if artemether/lumefantrine is not recommended, or it is not available. There are no data on artesunate plus pyronaridine. ACT containing sulfadoxine/pyrimethamine is contraindicated in the first trimester.[49][145]
- Current evidence suggests that ACT may also be used safely to treat uncomplicated falciparum malaria in the second and third trimesters of pregnancy.[49][146][147][148][149]
- Experience with artemisinin-derivatives in the second and third trimesters is reassuring, with no adverse effects reported in mothers or babies.[150][151][152][153] In particular, dihydroartemisinin plus piperaquine and artemether/lumefantrine have better safety and side-effect profiles compared with other ACTs. Dihydroartemisinin plus piperaquine has also been used in trial settings as intermittent preventive treatment in pregnant women in line with WHO policy for high-transmission settings with excellent efficacy and safety profiles.
- The most effective dosing of ACT combinations in pregnancy remains uncertain. Lower total drug concentrations of ACT are achieved when compared with nonpregnant women and lower efficacy has been reported in some settings.[141] Increased volume of distribution and other physiologic changes that occur in pregnancy alter drug metabolism, thus prospective pharmacokinetic studies are needed to improve treatment.
Patients with P vivax or P ovale infection should be maintained on chloroquine prophylaxis once weekly until after delivery.[49]

Complicated infection: pregnant

Pregnant patients with severe disease should be transferred to the intensive care unit for intensive monitoring and support.[38]

Severe malaria should be initially treated aggressively with parenteral therapy. Parenteral artesunate is the treatment of choice for severe malaria in all trimesters of pregnancy.[49][104] A suitable oral follow-on regimen can then be used. The WHO recommends intramuscular artemether if parenteral artesunate is not available.[49]

Recurrent falciparum malaria

Recurrence of P falciparum malaria can occur from either treatment failure or reinfection. Treatment failure may be due to drug resistance or inadequate treatment exposure (e.g., vomiting dose, suboptimal dose, poor adherence). Treatment failure should be confirmed parasitologically, with microscopy or lactate dehydrogenase (LDH)-based rapid diagnostic tests, if possible. Recurrence of fever and parasitemia within 28 days of treatment is usually due to treatment failure, and an alternative ACT that is known to be effective in the region is recommended. Recurrence after 28 days may be due to either treatment failure or new infection, and a first-line ACT is recommended. However, reuse of mefloquine within 60 days of the first treatment is associated with an increased risk of neuropsychiatric events, and a regimen that does not contain mefloquine should be used.[49] Retreatment with the same ACT showed similar efficacy to an alternative ACT or quinine plus clindamycin in a phase III randomized controlled trial.[154]

A specialist should be consulted for guidance on treating these patients.

Artemisinin resistance and ACT failure

Clinical artemisinin resistance is defined as delayed parasite clearance following treatment with an ACT. This does not necessarily lead to treatment failure unless there is resistance to the partner drug in the combination. Mutations in PfKelch13 (K13) are associated with artemisinin resistance and their detection is used as a surveillance tool, globally.[155]

Artemisinin resistance has emerged in all countries of the Greater Mekong subregion, and more recently in Rwanda and Uganda. K13 mutations are emerging and spreading in the eastern part of sub-Saharan Africa. Parasites with K13 mutations have been detected in multiple countries, including Eritrea, Rwanda, Uganda, Ethiopia, Somalia, South Sudan, Sudan, and the United Republic of Tanzania. K13 mutations have been described in parasites in Guyana and Papua New Guinea. However, current evidence suggests artemisinin resistance has not taken hold in these countries. Resistance to piperaquine is widespread in much of Southeast Asia, associated with plasmepsin II/III copy number and P falciparum chloroquine resistance transporter (pfcrt) mutations. To date, a molecular marker for resistance to lumefantrine has not been identified, although there is a weak association of reduced efficacy of artemether/lumefantrine with P falciparum multidrug resistance 1 gene (pfmdr1) copy number. Strategies under evaluation to mitigate the threat of artemisinin resistance include multiple first-line therapies and triple ACT regimens.

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