5CASE MANAGEMENT

5.1. Diagnosing malaria (2015)

Suspected malaria

The signs and symptoms of malaria are non-specific. Malaria is suspected clinically primarily on the basis of fever or a history of fever. There is no combination of signs or symptoms that reliably distinguishes malaria from other causes of fever; diagnosis based only on clinical features has very low specificity and results in overtreatment. Other possible causes of fever and whether alternative or additional treatment is required must always be carefully considered. The focus of malaria diagnosis should be to identify patients who truly have malaria, to guide rational use of antimalarial medicines.

In malaria-endemic areas, malaria should be suspected in any patient presenting with a history of fever or temperature ≥ 37.5 °C and no other obvious cause. In areas in which malaria transmission is stable (or during the high-transmission period of seasonal malaria), malaria should also be suspected in children with palmar pallor or a haemoglobin concentration of < 8 g/dL. High-transmission settings include many parts of sub-Saharan Africa and some parts of Oceania.

In settings where the incidence of malaria is very low, parasitological diagnosis of all cases of fever may result in considerable expenditure to detect only a few patients with malaria. In these settings, health workers should be trained to identify patients who may have been exposed to malaria (e.g. recent travel to a malaria-endemic area without protective measures) and have fever or a history of fever with no other obvious cause, before they conduct a parasitological test.

In all settings, suspected malaria should be confirmed with a parasitological test. The results of parasitological diagnosis should be available within a short time (< 2 h) of the patient presenting. In settings where parasitological diagnosis is not possible, a decision to provide antimalarial treatment must be based on the probability that the illness is malaria.

In children < 5 years, the practical algorithms for management of the sick child provided by the WHO–United Nations Children’s Fund (UNICEF) strategy for Integrated Management of Childhood Illness (111) should be used to ensure full assessment and appropriate case management at first-level health facilities and at the community level.

Parasitological diagnosis

The benefit of parasitological diagnosis relies entirely on an appropriate management response of health care providers. The two methods used routinely for parasitological diagnosis of malaria are light microscopy and immunochromatographic RDTs. The latter detect parasite-specific antigens or enzymes that are either genus or species specific.

Both microscopy and RDTs must be supported by a quality assurance programme. Antimalarial treatment should be limited to cases with positive tests, and patients with negative results should be reassessed for other common causes of fever and treated appropriately.

In nearly all cases of symptomatic malaria, examination of thick and thin blood films by a competent microscopist will reveal malaria parasites. Malaria RDTs should be used if quality-assured malaria microscopy is not readily available. RDTs for detecting PfHRP2 can be useful for patients who have received incomplete antimalarial treatment, in whom blood films can be negative. This is particularly likely if the patient received a recent dose of an artemisinin derivative. If the initial blood film examination is negative in patients with manifestations compatible with severe malaria, a series of blood films should be examined at 6–12 h intervals, or an RDT (preferably one detecting PfHRP2) should be performed. If both the slide examination and the RDT results are negative, malaria is extremely unlikely, and other causes of the illness should be sought and treated.

This document does not include recommendations for use of specific RDTs or for interpreting test results. For guidance, see the WHO manual Universal access to malaria diagnostic testing (112).

Diagnosis of malaria

In patients with suspected severe malaria and in other high-risk groups, such as patients living with HIV/AIDS, absence or delay of parasitological diagnosis should not delay an immediate start of antimalarial treatment.

At present, molecular diagnostic tools based on nucleic-acid amplification techniques (e.g. loop-mediated isothermal amplification or PCR) do not have a role in the clinical management of malaria.

Where P. vivax malaria is common and microscopy is not available, it is recommended that a combination RDT be used that allows detection of P. vivax (pLDH antigen from P. vivax) or pan-malarial antigens (Pan-pLDH or aldolase).

Light microscopy

Microscopy not only provides a highly sensitive, specific diagnosis of malaria when performed well but also allows quantification of malaria parasites and identification of the infecting species. Light microscopy involves relatively high costs for training and supervision, and the accuracy of diagnosis is strongly dependent on the competence of the microscopist. Microscopy technicians may also contribute to the diagnosis of non-malarial diseases.

Although nucleic acid amplification-based tests are more sensitive, light microscopy is still considered the “field standard” against which the sensitivity and specificity of other methods must be assessed. A skilled microscopist can detect asexual parasites at a density of < 10 per µL of blood, but under typical field conditions, the limit of sensitivity is approximately 100 parasites per µL (113). This limit of detection approximates the lower end of the pyrogenic density range. Thus, microscopy provides good specificity for diagnosing malaria as the cause of a presenting febrile illness. More sensitive methods allow detection of an increasing proportion of cases of incidental parasitaemia in endemic areas, thus reducing the specificity of a positive test. Light microscopy has other important advantages:

• low direct costs, if laboratory infrastructure to maintain the service is available;
• high sensitivity, if the performance of microscopy is high;
• differentiation of Plasmodia species;
• determination of parasite densities – notably identification of hyperparasitaemia;
• detection of gametocytaemia;
• allows monitoring of responses to therapy and
• can be used to diagnose many other conditions.

Good performance of microscopy can be difficult to maintain, because of the requirements for adequate training and supervision of laboratory staff to ensure competence in malaria diagnosis, electricity, good quality slides and stains, provision and maintenance of good microscopes and maintenance of quality assurance (114) and control of laboratory services [94][95].

Numerous attempts have been made to improve malaria microscopy, but none has proven to be superior to the classical method of Giemsa staining and oil-immersion microscopy for performance in typical health care settings (115).

Rapid diagnostic tests

Rapid diagnostic tests (RDTs) are immuno-chromatographic tests for detecting parasite-specific antigens in a finger-prick blood sample. Some tests allow detection of only one species (P. falciparum); others allow detection of one or more of the other species of human malaria parasites (P. vivax, P. malariae and P. ovale) (116) (117)(118). They are available commercially in various formats, e.g. dipsticks, cassettes and cards. Cassettes and cards are easier to use in difficult conditions outside health facilities. RDTs are relatively simple to perform and to interpret, and they do not require electricity or special equipment (119).

Since 2012, WHO has recommended that RDTs should be selected in accordance with the following criteria, based on the results of the assessments of the WHO Malaria RDT Product Testing programme (120):

• For detection of P. falciparum in all transmission settings, the panel detection score against P. falciparum samples should be at least 75% at 200 parasites/µL.
• For detection of P. vivax in all transmission settings the panel detection score against P. vivax samples should be at least 75% at 200 parasites/µL.
• The false positive rate should be less than 10%.
• The invalid rate should be less than 5%.

Current tests are based on the detection of histidine-rich protein 2 (HRP2), which is specific for P. falciparum, pan-specific or species-specific Plasmodium lactate dehydrogenase (pLDH) or pan-specific aldolase. The different characteristics of these antigens may affect their suitability for use in different situations, and these should be taken into account in programmes for RDT implementation. The tests have many potential advantages, including:

• rapid provision of results and extension of diagnostic services to the lowest-level health facilities and communities;
• fewer requirements for training and skilled personnel (for instance, a general health worker can be trained in 1 day); and
• reinforcement of patient confidence in the diagnosis and in the health service in general.

They also have potential disadvantages, including:

• inability, in the case of PfHRP2-based RDTs, to distinguish new infections from recently and effectively treated infections, due to the persistence of PfHRP2 in the blood for 1–5 weeks after effective treatment;
• the presence in countries in the Amazon region of variable frequencies of HRP2 deletions in P. falciparum parasites, making HRP2-based tests not suitable in this region (121);
• poor sensitivity for detecting P. malariae and P. ovale; and
• the heterogeneous quality of commercially available products and the existence of lot-to-lot variation.

In a systematic review (122), the sensitivity and specificity of RDTs in detecting P. falciparum in blood samples from patients in endemic areas attending ambulatory health facilities with symptoms suggestive of malaria were compared with the sensitivity and specificity of microscopy or polymerase chain reaction. The average sensitivity of PfHRP2-detecting RDTs was 95.0% (95% confidence interval [CI], 93.5–96.2%), and the specificity was 95.2% (93.4–99.4%). RDTs for detecting pLDH from P. falciparum are generally less sensitive and more specific than those for detecting HRP2, with an average sensitivity (95% CI) of 93.2% (88.0–96.2%) and a specificity of 98.5% (96.7–99.4%). Several studies have shown that health workers, volunteers and private sector providers can, with adequate training and supervision, use RDTs correctly and provide accurate malaria diagnoses. The criteria for selecting RDTs or microscopy can be found in the WHO Recommended selection criteria for the procurement of malaria rapid diagnostic tests (123).

Diagnosis with either microscopy or RDTs is expected to reduce overuse of antimalarial medicines by ensuring that treatment is given only to patients with confirmed malaria infection, as opposed to treating all patients with fever (124). Although providers of care may be willing to perform diagnostic tests, they do not, however, always respond appropriately to the results. This is especially true when they are negative. It is therefore important to ensure the accuracy of parasite- based diagnosis and also to demonstrate this to users and to provide them with the resources to manage both positive and negative results adequately (112).

Immunodiagnosis and nucleic acid amplification test methods

Detection of antibodies to parasites, which may be useful for epidemiological studies, is neither sensitive nor specific enough to be of use in the management of patients suspected of having malaria (125).

Techniques to detect parasite nucleic acid, e.g. polymerase chain reaction and loop-mediated isothermal amplification, are highly sensitive and very useful for detecting mixed infections, in particular at low parasite densities that are not detectable by conventional microscopy or with RDTs. They are also useful for studies of drug resistance and other specialized epidemiological investigations (126); however, they are not generally available for large-scale field use in malaria- endemic areas, nor are they appropriate for routine diagnosis in endemic areas where a large proportion of the population may have low-density parasitaemia.

These techniques may be useful for population surveys and focus investigation in malaria elimination programmes.

At present, nucleic acid-based amplification techniques have no role in the clinical management of malaria or in routine surveillance systems (127).

5.2. Treating uncomplicated malaria

Definition of uncomplicated malaria

A patient who presents with symptoms of malaria and a positive parasitological test (microscopy or RDT) but with no features of severe malaria is defined as having uncomplicated malaria (see section 7.1 for definition of severe malaria).

Therapeutic objectives

The clinical objectives of treating uncomplicated malaria are to cure the infection as rapidly as possible and to prevent progression to severe disease. “Cure” is defined as elimination of all parasites from the body. The public health objectives of treatment are to prevent onward transmission of the infection to others and to prevent the emergence and spread of resistance to antimalarial drugs.

Incorrect approaches to treatment

Use of monotherapy

The continued use of artemisinins or any of the partner medicines alone will compromise the value of ACT by selecting for drug resistance.

As certain patient groups, such as pregnant women, may need specifically tailored combination regimens, single artemisinin derivatives will still be used in selected referral facilities in the public sector, but they should be withdrawn entirely from the private and informal sectors and from peripheral public health care facilities.

Similarly, continued availability of amodiaquine, mefloquine and SP as monotherapies in many countries is expected to shorten their useful therapeutic life as partner drugs of ACT, and they should be withdrawn wherever possible.

Incomplete dosing

In endemic regions, some semi-immune malaria patients are cured by an incomplete course of antimalarial drugs or by a treatment regimen that would be ineffective in patients with no immunity. In the past, this led to different recommendations for patients considered semi-immune and those considered non-immune. As individual immunity can vary considerably, even in areas of moderate-to-high transmission intensity, this practice is no longer recommended. A full treatment course with a highly effective ACT is required whether or not the patient is considered to be semi-immune.

Another potentially dangerous practice is to give only the first dose of a treatment course to patients with suspected but unconfirmed malaria, with the intention of giving the full treatment if the diagnosis is confirmed. This practice is unsafe, could engender resistance, and is not recommended.

Additional considerations for clinical management

Can the patient take oral medication?

Some patients cannot tolerate oral treatment and will require parenteral or rectal administration for 1–2 days, until they can swallow and retain oral medication reliably. Although such patients do not show other signs of severity, they should receive the same initial antimalarial treatments recommended for severe malaria. Initial rectal or parenteral treatment must always be followed by a full 3-day course of ACT.

Use of antipyretics

In young children, high fevers are often associated with vomiting, regurgitation of medication and seizures. They are thus treated with antipyretics and, if necessary, fanning and tepid sponging. Antipyretics should be used if the core temperature is > 38.5 °C. Paracetamol (acetaminophen) at a dose of 15 mg/kg bw every 4 h is widely used; it is safe and well tolerated and can be given orally or as a suppository. Ibuprofen (5 mg/kg bw) has been used successfully as an alternative in the treatment of malaria and other childhood fevers, but, like aspirin and other non-steroidal anti-inflammatory drugs, it is no longer recommended because of the risks of gastrointestinal bleeding, renal impairment and Reye’s syndrome.

Use of anti-emetics

Vomiting is common in acute malaria and may be severe. Parenteral antimalarial treatment may therefore be required until oral administration is tolerated. Then a full 3-day course of ACT should be given. Anti-emetics are potentially sedative and may have neuropsychiatric adverse effects, which could mask or confound the diagnosis of severe malaria. They should therefore be used with caution.

Management of seizures

Generalized seizures are more common in children with P. falciparum malaria than in those with malaria due to other species. This suggests an overlap between the cerebral pathology resulting from falciparum malaria and febrile convulsions. As seizures may be a prodrome of cerebral malaria, patients who have more than two seizures within a 24 h period should be treated as for severe malaria. If the seizures continue, the airways should be maintained and anticonvulsants given (parenteral or rectal benzodiazepines or intramuscular paraldehyde). When the seizure has stopped, the child should be treated as indicated in section 7.10.5, if his or her core temperature is > 38.5 °C. There is no evidence that prophylactic anticonvulsants are beneficial in otherwise uncomplicated malaria, and they are not recommended.

5.2.3. Dosing of ACTS

ACT regimens must ensure optimal dosing to prolong their useful therapeutic life, i.e. to maximize the likelihood of rapid clinical and parasitological cure, minimize transmission and retard drug resistance.

It is essential to achieve effective antimalarial drug concentrations for a sufficient time (exposure) in all target populations in order to ensure high cure rates. The dosage recommendations below are derived from understanding the relationship between dose and the profiles of exposure to the drug (pharmacokinetics) and the resulting therapeutic efficacy (pharmacodynamics) and safety. Some patient groups, notably younger children, are not dosed optimally with the “dosage regimens recommended by manufacturers, which compromises efficacy and fuels resistance. In these guidelines when there was pharmacological evidence that certain patient groups are not receiving optimal doses, dose regimens were adjusted to ensure similar exposure across all patient groups.

Weight-based dosage recommendations are summarized below. While age-based dosing may be more practical in children, the relation between age and weight differs in different populations. Age-based dosing can therefore result in under- dosing or over-dosing of some patients, unless large, region-specific weight-for-age databases are available to guide dosing in that region.

Factors other than dosage regimen may also affect exposure to a drug and thus treatment efficacy. The drug exposure of an individual patient also depends on factors such as the quality of the drug, the formulation, adherence and, for some drugs, co-administration with fat. Poor adherence is a major cause of treatment failure and drives the emergence and spread of drug resistance. Fixed-dose combinations encourage adherence and are preferred to loose (individual) tablets. Prescribers should take the time necessary to explain to patients why they should complete antimalarial course.

Artemether + lumefantrine

Formulations currently available: Dispersible or standard tablets containing 20 mg artemether and 120 mg lumefantrine, and standard tablets containing 40 mg artemether and 240 mg lumefantrine in a fixed-dose combination formulation. The flavoured dispersible tablet paediatric formulation facilitates use in young children.

Target dose range: A total dose of 5–24 mg/kg bw of artemether and 29–144 mg/ kg bw of lumefantrine

Recommended dosage regimen: Artemether + lumefantrine is given twice a day for 3 days (total, six doses). The first two doses should, ideally, be given 8 h apart.

Table

Factors associated with altered drug exposure and treatment response:

• Decreased exposure to lumefantrine has been documented in young children (<3 years) as well as pregnant women, large adults, patients taking mefloquine, rifampicin or efavirenz and in smokers. As these target populations may be at increased risk for treatment failure, their responses to treatment should be monitored more closely and their full adherence ensured.
• Increased exposure to lumefantrine has been observed in patients concomitantly taking lopinavir- lopinavir/ritonavir-based antiretroviral agents but with no increase in toxicity; therefore, no dosage adjustment is indicated.

Additional comments:

• An advantage of this ACT is that lumefantrine is not available as a monotherapy and has never been used alone for the treatment of malaria.
• Absorption of lumefantrine is enhanced by co-administration with fat. Patients or caregivers should be informed that this ACT should be taken immediately after food or a fat containing drink (e.g. milk), particularly on the second and third days of treatment.

Artesunate + amodiaquine

Formulations currently available: A fixed-dose combination in tablets containing 25 + 67.5 mg, 50 + 135 mg or 100 + 270 mg of artesunate and amodiaquine, respectively

Target dose and range: The target dose (and range) are 4 (2–10) mg/kg bw per day artesunate and 10 (7.5–15) mg/kg bw per day amodiaquine once a day for 3 days. A total therapeutic dose range of 6–30 mg/kg bw per day artesunate and 22.5–45 mg/kg bw per dose amodiaquine is recommended.

Table

Factors associated with altered drug exposure and treatment response:

• Treatment failure after amodiaquine monotherapy was more frequent among children who were underweight for their age. Therefore, their response to artesunate + amodiaquine treatment should be closely monitored.
• Artesunate + amodiaquine is associated with severe neutropenia, particularly in patients co-infected with HIV and especially in those on zidovudine and/or cotrimoxazole. Concomitant use of efavirenz increases exposure to amodiaquine and hepatotoxicity. Thus, concomitant use of artesunate + amodiaquine by patients taking zidovudine, efavirenz and cotrimoxazole should be avoided, unless this is the only ACT promptly available.

Additional comments:

• No significant changes in the pharmacokinetics of amodiaquine or its metabolite desethylamodiaquine have been observed during the second and third trimesters of pregnancy; therefore, no dosage adjustments are recommended.
• No effect of age has been observed on the plasma concentrations of amodiaquine and desethylamodiaquine, so no dose adjustment by age is indicated. Few data are available on the pharmacokinetics of amodiaquine in the first year of life.

Artesunate + mefloquine

Formulations currently available: A fixed-dose formulation of paediatric tablets containing 25 mg artesunate and 55 mg mefloquine hydrochloride (equivalent to 50 mg mefloquine base) and adult tablets containing 100 mg artesunate and 220 mg mefloquine hydrochloride (equivalent to 200 mg mefloquine base)

Target dose and range: Target doses (ranges) of 4 (2–10) mg/kg bw per day artesunate and 8.3 (7–11) mg/kg bw per day mefloquine, given once a day for 3 days

Table

Additional comments:

• Mefloquine was associated with increased incidences of nausea, vomiting, dizziness, dysphoria and sleep disturbance in clinical trials, but these symptoms are seldom debilitating, and, where this ACT has been used, it has generally been well tolerated. To reduce acute vomiting and optimize absorption, the total mefloquine dose should preferably be split over 3 days, as in current fixed-dose combinations.
• As concomitant use of rifampicin decreases exposure to mefloquine, potentially decreasing its efficacy, patients taking this drug should be followed up carefully to identify treatment failures.

Artesunate + sulfadoxine–pyrimethamine

Formulations: Currently available as blister-packed, scored tablets containing 50 mg artesunate and fixed dose combination tablets comprising 500 mg sulfadoxine + 25 mg pyrimethamine. There is no fixed-dose combination.

Target dose and range: A target dose (range) of 4 (2–10) mg/kg bw per day artesunate given once a day for 3 days and a single administration of at least 25 / 1.25 (25–70 / 1.25–3.5) mg/kg bw sulfadoxine / pyrimethamine given as a single dose on day 1.

Table

Factors associated with altered drug exposure and treatment response: The low dose of folic acid (0.4 mg daily) that is required to protect the fetuses of pregnant women from neural tube defects do not reduce the efficacy of SP, whereas higher doses (5 mg daily) do significantly reduce its efficacy and should not be given concomitantly.

Additional comments:

• The disadvantage of this ACT is that it is not available as a fixed-dose combination. This may compromise adherence and increase the risk for distribution of loose artesunate tablets, despite the WHO ban on artesunate monotherapy.
• Resistance is likely to increase with continued widespread use of SP, sulfalene– pyrimethamine and cotrimoxazole (trimethoprim-sulfamethoxazole). Fortunately, molecular markers of resistance to antifols and sulfonamides correlate well with therapeutic responses. These should be monitored in areas in which this drug is used.

Strong recommendation for

Revised dose recommendation for dihydroartemisinin + piperaquine in young children: Children weighing <25kg treated with dihydroartemisinin + piperaquine should receive a minimum of 2.5 mg/kg bw per day of dihydroartemisinin and 20 mg/kg bw per day of piperaquine daily for 3 days.

*unGRADEd recommendation, anticipated to be updated in 2022

Practical Info

Formulations: Currently available as a fixed-dose combination in tablets containing 40 mg dihydroartemisinin and 320 mg piperaquine and paediatric tablets contain 20 mg dihydroartemisinin and 160 mg piperaquine.

Target dose and range: A target dose (range) of 4 (2–10) mg/kg bw per day dihydroartemisinin and 18 (16–27) mg/kg bw per day piperaquine given once a day for 3 days for adults and children weighing ≥ 25 kg. The target doses and ranges for children weighing < 25 kg are 4 (2.5–10) mg/kg bw per day dihydroartemisinin and 24 (20–32) mg/kg bw per day piperaquine once a day for 3 days.

Recommended dosage regimen: The dose regimen currently recommended by the manufacturer provides adequate exposure to piperaquine and excellent cure rates (> 95%), except in children < 5 years, who have a threefold increased risk for treatment failure. Children in this age group have significantly lower plasma piperaquine concentrations than older children and adults given the same mg/kg bw dose. Children weighing < 25 kg should receive at least 2.5 mg/kg bw dihydroartemisinin and 20 mg/kg bw piperaquine to achieve the same exposure as children weighing ≥ 25 kg and adults.

Dihydroartemisinin + piperaquine should be given daily for 3 days.

Table

Factors associated with altered drug exposure and treatment response:

High-fat meals should be avoided, as they significantly accelerate the absorption of piperaquine, thereby increasing the risk for potentially arrhythmogenic delayed ventricular repolarization (prolongation of the corrected electrocardiogram QT interval). Normal meals do not alter the absorption of piperaquine.

As malnourished children are at increased risk for treatment failure, their response to treatment should be monitored closely.

• Dihydroartemisinin exposure is lower in pregnant women.
• Piperaquine is eliminated more rapidly by pregnant women, shortening the post-treatment prophylactic effect of dihydroartemisinin + piperaquine. As this does not affect primary efficacy, no dosage adjustment is recommended for pregnant women.

Additional comments: Piperaquine prolongs the QT interval by approximately the same amount as chloroquine but by less than quinine. It is not necessary to perform an electrocardiogram before prescribing dihydroartemisinin + piperaquine, but this ACT should not be used in patients with congenital QT prolongation or who have a clinical condition or are on medications that prolong the QT interval. There has been no evidence of cardiotoxicity in large randomized trials or in extensive deployment.

Justification

The dosing subgroup reviewed all available dihydroartemisinin-piperaquine pharmacokinetic data (6 published studies and 10 studies from the WWARN database; total 652 patients) (128)(129) and then conducted simulations of piperaquine exposures for each weight group. These showed lower exposure in younger children with higher risks of treatment failure. The revised dose regimens are predicted to provide equivalent piperaquine exposures across all age groups.

Other considerations

This dose adjustment is not predicted to result in higher peak piperaquine concentrations than in older children and adults, and as there is no evidence of increased toxicity in young children, the GRC concluded that the predicted benefits of improved antimalarial exposure are not at the expense of increased risk.

5.2.5. Reducing the transmissibility of treated P. falciparum infections in areas of low-intensity transmission

Strong recommendation for, Low certainty evidence

Reducing the transmissibility of treated P. falciparum infections: In low-transmission areas, give a single dose of 0.25 mg/kg bw primaquine with ACT to patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months) to reduce transmission. G6PD testing is not required.

Practical Info

In light of concern about the safety of the previously recommended dose of 0.75 mg/kg bw in individuals with G6PD deficiency, a WHO panel reviewed the safety of primaquine as a P. falciparum gametocytocide and concluded that a single dose of 0.25 mg/kg bw of primaquine base is unlikely to cause serious toxicity, even in people with G6PD deficiency (138). Thus, where indicated a single dose of 0.25mg/kg bw of primaquine base should be given on the first day of treatment, in addition to an ACT, to all patients with parasitologically confirmed P. falciparum malaria except for pregnant women, infants < 6 months of age and women breastfeeding infants < 6 months of age, because there are insufficient data on the safety of its use in these groups.

Dosing table based on the most widely currently available tablet strength (7.5mg base)

Table

Please refer to the Policy brief on single-dose primaquine as a gametocytocide in Plasmodium falciparum malaria (139).

Evidence To Decision

Benefits and harms

Desirable effects

• Single doses of primaquine > 0.4 mg/kg bw reduced gametocyte carriage at day 8 by around two thirds (moderate-quality evidence).
• There are too few trials of doses < 0.4 mg/kg bw to quantify the effect on gametocyte carriage (low-quality evidence).
• Analysis of observational data from mosquito feeding studies suggests that 0.25 mg/kg bw may rapidly reduce the infectivity of gametocytes to mosquitoes.

Undesirable effects

• People with severe G6PD deficiency are at risk for haemolysis. At this dose, however, the risk is thought to be small; there are insufficient data to quantify this risk.

Certainty of the Evidence

Overall certainty of evidence for all critical outcomes: low.

Preference and values

Justification

GRADE

In an analysis of observational studies of single-dose primaquine, data from mosquito feeding studies on 180 people suggest that adding 0.25 mg/kg primaquine to treatment with an ACT can rapidly reduce the infectivity of gametocytes to mosquitoes.

In a systematic review of eight randomized controlled trials of the efficacy of adding single-dose primaquine to ACTs for reducing the transmission of malaria, in comparison with ACTs alone (136):

• single doses of > 0.4 mg/kg bw primaquine reduced gametocyte carriage at day 8 by about two thirds (RR, 0.34; 95% CI, 0.19–0.59, two trials, 269 participants, high-certainty evidence); and
• single doses of primaquine > 0.6 mg/kg bw reduced gametocyte carriage at day 8 by about two thirds (RR, 0.29; 95% CI, 0.22–0.37, seven trials, 1380 participants, high-certainty evidence).

There have been no randomized controlled trials of the effects on the incidence of malaria or on transmission to mosquitos.

Other considerations

The guideline development group considered that the evidence of a dose– response relation from observational studies of mosquito feeding was sufficient to conclude the primaquine dose of 0.25mg/kg bw significantly reduced P. falciparum transmissibility.

The population benefits of reducing malaria transmission with gametocytocidal drugs such as primaquine require that a very high proportion of treated patients receive these medicines and that there is no large transmission reservoir of asymptomatic parasite carriers. This strategy is therefore likely to be effective only in areas of low-intensity malaria transmission, as a component of elimination programmes.

Remarks

This recommendation excludes high-transmission settings, as symptomatic patients make up only a small proportion of the total population carrying gametocytes within a community, and primaquine is unlikely to affect transmission.

A major concern of national policy-makers in using primaquine has been the small risk for haemolytic toxicity in G6PD-deficient people, especially where G6PD testing is not available.

Life-threatening haemolysis is considered unlikely with the 0.25mg/kg bw dose and without G6PD testing (137).

Rationale for the recommendation: The Guideline Development Group considered the evidence on dose–response relations in the observational mosquito-feeding studies of reduced transmissibility with the dose of 0.25 mg/kg bw and the judgement of the WHO Evidence Review Group (November 2012). Their view was that the potential public health benefits of single low-dose (0.25 mg/kg bw) primaquine in addition to an ACT for falciparum malaria, without G6PD testing, outweigh the potential risk for adverse effects.

5.3. Treating special risk groups

Several important patient sub-populations, including young children, pregnant women and patients taking potent enzyme inducers (e.g. rifampicin, efavirenz), have altered pharmacokinetics, resulting in sub-optimal exposure to antimalarial drugs. This increases the rate of treatment failure with current dosage regimens. The rates of treatment failure are substantially higher in hyperparasitaemic patients and patients in areas with artemisinin-resistant falciparum malaria, and these groups require greater exposure to antimalarial drugs (longer duration of therapeutic concentrations) than is achieved with current ACT dosage recommendations. It is often uncertain how best to achieve this. Options include increasing individual doses, changing the frequency or duration of dosing, or adding an additional antimalarial drug. Increasing individual doses may not, however, achieve the desired exposure (e.g., lumefantrine absorption becomes saturated), or the dose may be toxic due to transiently high plasma concentrations (piperaquine, mefloquine, amodiaquine, pyronaridine). An additional advantage of lengthening the duration of treatment (by giving a 5-day regimen) is that it provides additional exposure of the asexual cycle to the artemisinin component as well as augmenting exposure to the partner drug. The acceptability, tolerability, safety and effectiveness of augmented ACT regimens in these special circumstances should be evaluated urgently.

Large and obese adults

Large adults are at risk for under-dosing when they are dosed by age or in standard pre-packaged adult weight-based treatments. In principle, dosing of large adults should be based on achieving the target mg/kg bw dose for each antimalarial regimen. The practical consequence is that two packs of an antimalarial drug might have to be opened to ensure adequate treatment. For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.

In the past, maximum doses have been recommended, but there is no evidence or justification for this practice. As the evidence for an association between dose, pharmacokinetics and treatment outcome in overweight or large adults is limited, and alternative dosing options have not been assessed in treatment trials, it is recommended that this gap in knowledge be assessed urgently. In the absence of data, treatment providers should attempt to follow up the treatment outcomes of large adults whenever possible.

5.4. Treating uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi

Plasmodium vivax accounts for approximately half of all malaria cases outside Africa (3)(142)(143). It is prevalent in the Middle East, Asia, the Western Pacific and Central and South America. With the exception of the Horn, it is rarer in Africa, where there is a high prevalence of the Duffy-negative phenotype, particularly in West Africa, although cases are reported in both Mauritania and Mali (143). In most areas where P. vivax is prevalent, the malaria transmission rates are low (except on the island of New Guinea). Affected populations achieve only partial immunity to this parasite, and so people of all ages are at risk for P. vivax malaria (143). Where both P. falciparum and P. vivax are prevalent, the incidence rates of P. vivax tend to peak at a younger age than for P. falciparum. This is because each P. vivax inoculation may be followed by several relapses. The other human malaria parasite species, P. malariae and P. ovale (which is in fact two sympatric species), are less common. P. knowlesi, a simian parasite, causes occasional cases of malaria in or near forested areas of South-East Asia and the Indian subcontinent (144). In parts of the island of Borneo, P. knowlesi is the predominant cause of human malaria and an important cause of severe malaria

Of the six species of Plasmodium that affect humans, only P. vivax and the two species of P. ovale (145) form hypnozoites, which are dormant parasite stages in the liver that cause relapse weeks to years after the primary infection. P. vivax preferentially invades reticulocytes, and repeated illness causes chronic anaemia, which can be debilitating and sometimes life-threatening, particularly in young children (146). Recurrent vivax malaria is an important impediment to human and economic development in affected populations. In areas where P. falciparum and P. vivax co-exist, intensive malaria control often has a greater effect on P. falciparum, as P. vivax, is more resilient to interventions.

Although P. vivax has been considered to be a benign form of malaria, it may sometimes cause severe disease (147). The major complication is anaemia in young children. In Papua province, Indonesia (147), and in Papua New Guinea (148), where malaria transmission is intense, P. vivax is an important cause of malaria morbidity and mortality, particularly in young infants and children. Occasionally, older patients develop vital organ involvement similar to that in severe and complicated P. falciparum malaria (149)(150). During pregnancy, infection with P. vivax, as with P. falciparum, increases the risk for abortion and reduces birth weight (151)(140). In primigravidae, the reduction in birth weight is approximately two thirds that associated with P. falciparum. In one large series, this effect increased with successive pregnancies (151).

P. knowlesi is a zoonosis that normally affects long- and pig-tailed macaque monkeys. It has a daily asexual cycle, resulting in a rapid replication rate and high parasitaemia. P. knowlesi may cause a fulminant disease similar to severe falciparum malaria (with the exception of coma, which does not occur) (152)(153). Co-infection with other species is common.

Diagnosis

Diagnosis of P. vivax, P. ovale, and P. malariae malaria is based on microscopy. P. knowlesi is frequently misdiagnosed under the microscope, as the young ring forms are similar to those of P. falciparum, the late trophozoites are similar to those of P. malariae, and parasite development is asynchronous. Rapid diagnostic tests based on immunochromatographic methods are available for the detection of P. vivax malaria; however, they are relatively insensitive for detecting P. malariae and P. ovale parasitaemia. Rapid diagnostic antigen tests for human Plasmodium species show poor sensitivity for P. knowlesi infections in humans with low parasitaemia (154).

Treatment

The objectives of treatment of vivax malaria are twofold: to cure the acute blood stage infection and to clear hypnozoites from the liver to prevent future relapses. This is known as “radical cure”.

In areas with chloroquine-sensitive P. vivax

For chloroquine-sensitive vivax malaria, oral chloroquine at a total dose of 25 mg base/kg bw is effective and well tolerated. Lower total doses are not recommended, as these encourage the emergence of resistance. Chloroquine is given at an initial dose of 10 mg base/kg bw, followed by 10 mg/kg bw on the second day and 5 mg/kg bw on the third day. In the past, the initial 10 mg/kg bw dose was followed by 5 mg/kg bw at 6 h, 24 h and 48 h. As residual chloroquine suppresses the first relapse of tropical P. vivax (which emerges about 3 weeks after onset of the primary illness), relapses begin to occur 5–7 weeks after treatment if radical curative treatment with primaquine is not given.

ACTs are highly effective in the treatment of vivax malaria, allowing simplification (unification) of malaria treatment; i.e. all malaria infections can be treated with an ACT. The exception is artesunate + SP, where resistance significantly compromises its efficacy. Although good efficacy of artesunate + SP was reported in one study in Afghanistan, in several other areas (such as South-East Asia) P. vivax has become resistant to SP more rapidly than P. falciparum. The initial response to all ACTs is rapid in vivax malaria, reflecting the high sensitivity to artemisinin derivatives, but, unless primaquine is given, relapses commonly follow. The subsequent recurrence patterns differ, reflecting the elimination kinetics of the partner drugs. Thus, recurrences, presumed to be relapses, occur earlier after artemether + lumefantrine than after dihydroartemisinin + piperaquine or artesunate + mefloquine because lumefantrine is eliminated more rapidly than either mefloquine or piperaquine. A similar temporal pattern of recurrence with each of the drugs is seen in the P. vivax infections that follow up to one third of acute falciparum malaria infections in South-East Asia.

In areas with chloroquine-resistant P. vivax

ACTs containing piperaquine, mefloquine or lumefantrine are the recommended treatment, although artesunate + amodiaquine may also be effective in some areas.

In the systematic review of ACTs for treating P. vivax malaria, dihydroartemisinin + piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (artemether + lumefantrine, artesunate + amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up (RR, 0.57; 95% CI, 0.40–0.82, three trials, 1066 participants). The half-life of mefloquine is similar to that of piperaquine, but use of dihydroartemisinin + piperaquine in P. vivax mono-infections has not been compared directly in trials with use of artesunate + mefloquine.

Uncomplicated P. ovale, P. malariae or P. knowlesi malaria

Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae.

The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or chloroquine, as for vivax malaria.

Mixed malaria infections

Mixed malaria infections are common in endemic areas. For example, in Thailand, despite low levels of malaria transmission, 8% of patients with acute vivax malaria also have P. falciparum infections, and one third of acute P. falciparum infections are followed by a presumed relapse of vivax malaria (making vivax malaria the most common complication of falciparum malaria).

Mixed infections are best detected by nucleic acid-based amplification techniques, such as PCR; they may be underestimated with routine microscopy. Cryptic P. falciparum infections in vivax malaria can be revealed in approximately 75% of cases by RDTs based on the PfHRP2 antigen, but several RDTs cannot detect mixed infection or have low sensitivity for detecting cryptic vivax malaria. ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.

[3][119][120][120][120][121][122][123][124][124][125][126][127][128]

5.5. Treating severe malaria

Mortality from untreated severe malaria (particularly cerebral malaria) approaches 100%. With prompt, effective antimalarial treatment and supportive care, the rate falls to 10–20% overall. Within the broad definition of severe malaria some syndromes are associated with lower mortality rates (e.g. severe anaemia) and others with higher mortality rates (e.g. acidosis). The risk for death increases in the presence of multiple complications.

Any patient with malaria who is unable to take oral medications reliably, shows any evidence of vital organ dysfunction or has a high parasite count is at increased risk for dying. The exact risk depends on the species of infecting malaria parasite, the number of systems affected, the degree of vital organ dysfunction, age, background immunity, pre-morbid, and concomitant diseases, and access to appropriate treatment. Tests such as a parasite count, haematocrit and blood glucose may all be performed immediately at the point of care, but the results of other laboratory measures, if any, may be available only after hours or days. As severe malaria is potentially fatal, any patient considered to be at increased risk should be given the benefit of the highest level of care available. The attending clinician should not worry unduly about definitions: the severely ill patient requires immediate supportive care, and, if severe malaria is a possibility, parenteral antimalarial drug treatment should be started without delay.

Definitions

Severe falciparum malaria: For epidemiological purposes, severe falciparum malaria is defined as one or more of the following, occurring in the absence of an identified alternative cause and in the presence of P. falciparum asexual parasitaemia.

• Impaired consciousness: A Glasgow coma score < 11 in adults or a Blantyre coma score < 3 in children
• Prostration: Generalized weakness so that the person is unable to sit, stand or walk without assistance
• Multiple convulsions: More than two episodes within 24 h
• Acidosis: A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as respiratory distress (rapid, deep, laboured breathing).
• Hypoglycaemia: Blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL)
• Severe malarial anaemia: Haemoglobin concentration ≤ 5 g/dL or a haematocrit of ≤ 15% in children < 12 years of age (< 7 g/dL and < 20%, respectively, in adults) with a parasite count > 10 000/µL
• Renal impairment: Plasma or serum creatinine > 265 µmol/L (3 mg/dL) or blood urea > 20 mmol/L
• Jaundice: Plasma or serum bilirubin > 50 µmol/L (3 mg/dL) with a parasite count > 100 000/ µL
• Pulmonary oedema: Radiologically confirmed or oxygen saturation < 92% on room air with a respiratory rate > 30/min, often with chest indrawing and crepitations on auscultation
• Significant bleeding: Including recurrent or prolonged bleeding from the nose, gums or venepuncture sites; haematemesis or melaena
• Shock: Compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure < 70 mm Hg in children or < 80 mmHg in adults, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill).
• Hyperparasitaemia: P. falciparum parasitaemia > 10%

Severe vivax and knowlesi malaria: defined as for falciparum malaria but with no parasite density thresholds.

Severe knowlesi malaria is defined as for falciparum malaria but with two differences:

• P. knowlesi hyperparasitaemia: parasite density > 100 000/ µL
• Jaundice and parasite density > 20 000/µL.

Therapeutic objectives

The main objective of the treatment of severe malaria is to prevent the patient from dying. Secondary objectives are prevention of disabilities and prevention of recrudescent infection.

Death from severe malaria often occurs within hours of admission to a hospital or clinic, so it is essential that therapeutic concentrations of a highly effective antimalarial drug be achieved as soon as possible. Management of severe malaria comprises mainly clinical assessment of the patient, specific antimalarial treatment, additional treatment and supportive care.

Clinical assessment

Severe malaria is a medical emergency. An open airway should be secured in unconscious patients and breathing and circulation assessed. The patient should be weighed or body weight estimated, so that medicines, including antimalarial drugs and fluids, can be given appropriately. An intravenous cannula should be inserted, and blood glucose (rapid test), haematocrit or haemoglobin, parasitaemia and, in adults, renal function should be measured immediately. A detailed clinical examination should be conducted, including a record of the coma score. Several coma scores have been advocated: the Glasgow coma scale is suitable for adults, and the simple Blantyre modification is easily performed in children. Unconscious patients should undergo a lumbar puncture for cerebrospinal fluid analysis to exclude bacterial meningitis.

The degree of acidosis is an important determinant of outcome; the plasma bicarbonate or venous lactate concentration should be measured, if possible. If facilities are available, arterial or capillary blood pH and gases should be measured in patients who are unconscious, hyperventilating or in shock. Blood should be taken for cross-matching, a full blood count, a platelet count, clotting studies, blood culture and full biochemistry (if possible). Careful attention should be paid to the patient’s fluid balance in severe malaria in order to avoid over- or under-hydration. Individual requirements vary widely and depend on fluid losses before admission.

The differential diagnosis of fever in a severely ill patient is broad. Coma and fever may be due to meningoencephalitis or malaria. Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness, photophobia or Kernig’s sign), but the patient may be opisthotonic. As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture should be performed to exclude this condition. There is also considerable clinical overlap between septicaemia, pneumonia and severe malaria, and these conditions may coexist. When possible, blood should always be taken on admission for bacterial culture. In malaria-endemic areas, particularly where parasitaemia is common in young age groups, it is difficult to rule out septicaemia immediately in a shocked or severely ill obtunded child. In all such cases, empirical parenteral broad-spectrum antibiotics should be started immediately, together with antimalarial treatment.

Treatment of severe malaria

It is essential that full doses of effective parenteral (or rectal) antimalarial treatment be given promptly in the initial treatment of severe malaria. This should be followed by a full dose of effective ACT orally. Two classes of medicine are available for parenteral treatment of severe malaria: artemisinin derivatives (artesunate or artemether) and the cinchona alkaloids (quinine and quinidine). Parenteral artesunate is the treatment of choice for all severe malaria. The largest randomized clinical trials ever conducted on severe falciparum malaria showed a substantial reduction in mortality with intravenous or intramuscular artesunate as compared with parenteral quinine. The reduction in mortality was not associated with an increase in neurological sequelae in artesunate-treated survivors. Furthermore, artesunate is simpler and safer to use.

Pre-referral treatment options

See recommendation.

Adjustment of parenteral dosing in renal failure or hepatic dysfunction

The dosage of artemisinin derivatives does not have to be adjusted for patients with vital organ dysfunction. However quinine accumulates in severe vital organ dysfunction. If a patient with severe malaria has persisting acute kidney injury or there is no clinical improvement by 48 h, the dose of quinine should be reduced by one third, to 10 mg salt/kg bw every 12 h. Dosage adjustments are not necessary if patients are receiving either haemodialysis or haemofiltration.

Follow-on treatment

The current recommendation of experts is to give parenteral antimalarial drugs for the treatment of severe malaria for a minimum of 24 h once started (irrespective of the patient’s ability to tolerate oral medication earlier) or until the patient can tolerate oral medication, before giving the oral follow-up treatment.

After initial parenteral treatment, once the patient can tolerate oral therapy, it is essential to continue and complete treatment with an effective oral antimalarial drug by giving a full course of effective ACT (artesunate + amodiaquine, artemether + lumefantrine or dihydroartemisinin + piperaquine). If the patient presented initially with impaired consciousness, ACTs containing mefloquine should be avoided because of an increased incidence of neuropsychiatric complications. When an ACT is not available, artesunate + clindamycin, artesunate + doxycycline, quinine + clindamycin or quinine + doxycycline can be used for follow-on treatment. Doxycycline is preferred to other tetracyclines because it can be given once daily and does not accumulate in cases of renal failure, but it should not be given to children < 8 years or pregnant women. As treatment with doxycycline is begun only when the patient has recovered sufficiently, the 7-day doxycycline course finishes after the artesunate, artemether or quinine course. When available, clindamycin may be substituted in children and pregnant women.

Continuing supportive care

Patients with severe malaria require intensive nursing care, preferably in an intensive care unit where possible. Clinical observations should be made as frequently as possible and should include monitoring of vital signs, coma score and urine output. Blood glucose should be monitored every 4 h, if possible, particularly in unconscious patients.

Management of complications

Severe malaria is associated with a variety of manifestations and complications, which must be recognized promptly and treated as shown below.

Immediate clinical management of severe manifestations and complications of P. falciparum malaria

Table

Additional aspects of management

Fluid therapy

Fluid requirements should be assessed individually. Adults with severe malaria are very vulnerable to fluid overload, while children are more likely to be dehydrated. The fluid regimen must also be adapted to the infusion of antimalarial drugs. Rapid bolus infusion of colloid or crystalloids is contraindicated. If available, haemofiltration should be started early for acute kidney injury or severe metabolic acidosis, which do not respond to rehydration. As the degree of fluid depletion varies considerably in patients with severe malaria, it is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit. In high-transmission settings, children commonly present with severe anaemia and hyperventilation (sometimes termed “respiratory distress”) resulting from severe metabolic acidosis and anaemia; they should be treated by blood transfusion. In adults, there is a very thin dividing line between over-hydration, which may produce pulmonary oedema, and under-hydration, which contributes to shock, worsening acidosis and renal impairment. Careful, frequent evaluation of jugular venous pressure, peripheral perfusion, venous filling, skin turgor and urine output should be made.

Blood transfusion

Severe malaria is associated with rapid development of anaemia, as infected, once infected and uninfected erythrocytes are haemolysed and/or removed from the circulation by the spleen. Ideally, fresh, cross-matched blood should be transfused; however, in most settings, cross-matched virus-free blood is in short supply. As for fluid resuscitation, there are not enough studies to make strong evidence-based recommendations on the indications for transfusion; the recommendations given here are based on expert opinion. In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL (haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin, 7 g/100 mL) is recommended. These general recommendations must, however, be adapted to the individual, as the pathological consequences of rapid development of anaemia are worse than those of chronic or acute anaemia when there has been adaptation and a compensatory right shift in the oxygen dissociation curve.

Exchange blood transfusion

Many anecdotal reports and several series have claimed the benefit of exchange blood transfusion in severe malaria, but there have been no comparative trials, and there is no consensus on whether it reduces mortality or how it might work. Various rationales have been proposed:

• removing infected red blood cells from the circulation and therefore lowering the parasite burden (although only the circulating, relatively non-pathogenic stages are removed, and this is also achieved rapidly with artemisinin derivatives);
• rapidly reducing both the antigen load and the burden of parasite-derived toxins, metabolites and toxic mediators produced by the host; and
• replacing the rigid unparasitized red cells by more easily deformable cells, therefore alleviating microcirculatory obstruction.

Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.

Concomitant use of antibiotics

The threshold for administering antibiotic treatment should be low in severe malaria. Septicaemia and severe malaria are associated, and there is substantial diagnostic overlap, particularly in children in areas of moderate and high transmission. Thus broad- spectrum antibiotic treatment should be given with antimalarial drugs to all children with suspected severe malaria in areas of moderate and high transmission until a bacterial infection is excluded. After the start of antimalarial treatment, unexplained deterioration may result from a supervening bacterial infection. Enteric bacteria (notably Salmonella) predominated in many trial series in Africa, but a variety of bacteria have been cultured from the blood of patients with a diagnosis of severe malaria.

Patients with secondary pneumonia or with clear evidence of aspiration should be given empirical treatment with an appropriate broad-spectrum antibiotic. In children with persistent fever despite parasite clearance, other possible causes of fever should be excluded, such as systemic Salmonella infections and urinary tract infections, especially in catheterized patients. In the majority of cases of persistent fever, however, no other pathogen is identified after parasite clearance. Antibiotic treatment should be based on culture and sensitivity results or, if not available, local antibiotic sensitivity patterns.

Use of anticonvulsants

The treatment of convulsions in cerebral malaria with intravenous (or, if this is not possible, rectal) benzodiazepines or intramuscular paraldehyde is similar to that for repeated seizures from any cause. In a large, double-blind, placebo-controlled evaluation of a single prophylactic intramuscular injection of 20 mg/kg bw of phenobarbital to children with cerebral malaria, the frequency of seizures was reduced but the mortality rate was increased significantly. This resulted from respiratory arrest and was associated with additional use of benzodiazepine.

A 20 mg/kg bw dose of phenobarbital should not be given without respiratory support. It is not known whether a lower dose would be effective and safer or whether mortality would not increase if ventilation were given. In the absence of further information, prophylactic anticonvulsants are not recommended.

Treatments that are not recommended

In an attempt to reduce the high mortality from severe malaria, various adjunctive treatments have been evaluated, but none has proved effective and many have been shown to be harmful. Heparin, prostacyclin, desferroxamine, pentoxifylline, low-molecular-mass dextran, urea, high-dose corticosteroids, aspirin anti-TNF antibody, cyclosporine A, dichloroacetate, adrenaline, hyperimmune serum,N-acetylcysteine and bolus administration of albumin are not recommended. In addition, use of corticosteroids increases the risk for gastrointestinal bleeding and seizures and has been associated with prolonged coma resolution times when compared with placebo.

Treatment of severe malaria during pregnancy

Women in the second and third trimesters of pregnancy are more likely to have severe malaria than other adults, and, in low-transmission settings, this is often complicated by pulmonary oedema and hypoglycaemia. Maternal mortality is approximately 50%, which is higher than in non-pregnant adults. Fetal death and premature labour are common.

Parenteral antimalarial drugs should be given to pregnant women with severe malaria in full doses without delay. Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed. If artesunate is unavailable, intramuscular artemether should be given, and if this is unavailable then parenteral quinine should be started immediately until artesunate is obtained.

Obstetric advice should be sought at an early stage, a paediatrician alerted and blood glucose checked frequently. Hypoglycaemia should be expected, and it is often recurrent if the patient is receiving quinine. Severe malaria may also present immediately after delivery. Postpartum bacterial infection is a common complication and should be managed appropriately.

Treatment of severe P. vivax malaria

Although P. vivax malaria is considered to be benign, with a low case-fatality rate, it may cause a debilitating febrile illness with progressive anaemia and can also occasionally cause severe disease, as in P. falciparum malaria. Reported manifestations of severe P. vivax malaria include severe anaemia, thrombocytopenia, acute pulmonary oedema and, less commonly, cerebral malaria, pancytopenia, jaundice, splenic rupture, haemoglobinuria, acute renal failure and shock.

Prompt effective treatment and case management should be the same as for severe P. falciparum malaria (see section 5.5.1). Following parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery.

Please refer to Management of severe malaria - A practical handbook, 3rd edition (160).

5.6. Other considerations in treating malaria

5.7. National adaptation and implementation

These guidelines provide a generic framework for malaria diagnosis and treatment policies worldwide; however, national policy-makers will be required to adapt these recommendations on the basis of local priorities, malaria epidemiology, parasite resistance and national resources.

National decision-making

National decision-makers are encouraged to adopt inclusive, transparent, rigorous approaches. Broad, inclusive stakeholder engagement in the design and implementation of national malaria control programmes will help to ensure they are feasible, appropriate, equitable and acceptable. Transparency and freedom from financial conflicts of interest will reduce mistrust and conflict, while rigorous evidence-based processes will ensure that the best possible decisions are made for the population.

Information required for national decision-making

Selection of first- and second-line antimalarial medicines will require reliable national data on their efficacy and parasite resistance, which in turn require that appropriate surveillance and monitoring systems are in place (see Monitoring efficacy and safety of antimalaria drugs). In some countries, the group adapting the guidelines for national use might have to re-evaluate the global evidence base with respect to their own context. The GRADE tables may serve as a starting-point for this assessment. Decisions about coverage, feasibility, acceptability and cost may require input from various health professionals, community representatives, health economists, academics and health system managers.

Opportunities and risks

The recommendations made in these guidelines provide an opportunity to improve malaria case management further, to reduce unnecessary morbidity and mortality and to contribute to continued efforts towards elimination. Failure to implement the basic principles of combination therapy and rational use of antimalarial medicines will risk promoting the emergence and spread of drug resistance, which could undo all the recent gains in malaria control and elimination.

General guiding principles for choosing a case management strategy and tools

Choosing a diagnostic strategy

The two methods currently considered suitable for routine patient management are light microscopy and RDTs. Different strategies may be adopted in different health care settings. The choice between RDTs and microscopy depends on local circumstances, including the skills available, the patient case-load, the epidemiology of malaria and use of microscopy for the diagnosis of other diseases. When the case-load of patients with fever is high, the cost of each microscopy test is likely to be less than that of an RDT; however, high-throughput, high-quality microscopy may be less operationally feasible. Although several RDTs allow diagnosis of both P. falciparum and P. vivax infections, microscopy has further advantages, including accurate parasite counting (and thus identification of high parasite density), prognostication in severe malaria, speciation of other malaria parasites and sequential assessment of the response to antimalarial treatment. Microscopy may help to identify other causes of fever. High-quality light microscopy requires well-trained, skilled staff, good staining reagents, clean slides and, often, electricity to power the microscope. It requires a quality assurance system, which is often not well implemented in malaria-endemic countries.

In many areas, malaria patients are treated outside the formal health services, e.g. in the community, at home or by private providers. Microscopy is generally not feasible in the community, but RDTs might be available, allowing access to confirmatory diagnosis of malaria and the correct management of febrile illnesses. The average sensitivity of HRP2-detecting RDTs is generally greater than that of RDTs for detecting pLDH of P. falciparum, but the latter are slightly more specific because the HRP2 antigen may persist in blood for days or weeks after effective treatment. HRP2-detecting RDTs are not suitable for detecting treatment failure. RDTs are slightly less sensitive for detecting P. malariae and P. ovale. The WHO Malaria RDT Product Testing programme provides comparative data on the performance of RDT products to guide procurement. Since 2008, 210 products have been evaluated in five rounds of product testing (120)(123).

For the diagnosis of severe malaria, microscopy is preferred, as it provides a diagnosis of malaria and assessment of other important parameters of prognostic relevance in severely ill patients (such as parasite count and stage of parasite development and intra-leukocyte pigment). In severe malaria, an RDT can be used to confirm malaria rapidly so that parenteral antimalarial treatment can be started immediately. Where possible, however, blood smears should be examined by microscopy, with frequent monitoring of parasitaemia (e.g. every 12 h) during the first 2–3 days of treatment in order to monitor the response.

Choosing ACT

In the absence of resistance, all the recommended ACTs have been shown to result in parasitological cure rates of > 95%. Although there are minor differences in the oral absorption, bioavailability and tolerability of the different artemisinin derivatives, there is no evidence that these differences are clinically significant in currently available formulations. It is the properties of the partner medicine and the level of resistance to it that determine the efficacy of a formulation.

Policy-makers should also consider:

• local data on the therapeutic efficacy of the ACT,
• local data on drug resistance,
• the adverse effect profiles of ACT partner drugs,
• the availability of appropriate formulations to ensure adherence,
• cost.

In parts of South-East Asia, artemisinin resistance is compromising the efficacy of ACTs and placing greater selection pressure on resistance to the partner medicines. Elsewhere, there is no convincing evidence for reduced susceptibility to the artemisinins; therefore, the performance of the partner drugs is the determining factor in the choice of ACT, and the following principles apply:

• Resistance to mefloquine has been found in parts of mainland South-East Asia where this drug has been used intensively. Nevertheless, the combination with artesunate is very effective, unless there is also resistance to artemisinin. Resistance to both components has compromised the efficacy of artesunate + mefloquine in western Cambodia, eastern Myanmar and eastern Thailand.
• Lumefantrine shares some cross-resistance with mefloquine, but this has not compromised its efficacy in any of the areas in which artemether + lumefantrine has been used outside South-East Asia.
• Until recently, there was no evidence of resistance to piperaquine anywhere, but there is now reduced susceptibility in western Cambodia. Elsewhere, the dihydroartemisinin + piperaquine combination is highly effective.
• Resistance to SP limits its use in combination with artesunate to the few areas in which susceptibility is retained.
• Amodiaquine remains effective in combination with artesunate in parts of Africa and the Americas, although elsewhere resistance to this drug was prevalent before its introduction in an ACT.

Considerations in use of artemisinin-based combination therapy

Oral artemisinin and its derivatives (e.g. artesunate, artemether, dihydroartemisinin) should not be used alone. In order to simplify use, improve adherence and minimize the availability of oral artemisinin monotherapy, fixed-dose combination ACTs are strongly preferred to co-blistered or co-dispensed loose tablets and should be used when they are readily available. Fixed-dose combinations of all recommended ACT are now available, except artesunate + SP. Fixed-dose artesunate + amodiaquine performs better than loose tablets, presumably by ensuring adequate dosing. Unfortunately, paediatric formulations are not yet available for all ACTs.

The choice of ACT in a country or region should be based on optimal efficacy and adherence, which can be achieved by:

• minimizing the number of formulations available for each recommended treatment regimen
• using, where available, solid formulations instead of liquid formulations, even for young patients.

Although there are some minor differences in the oral absorption and bioavailability of different artemisinin derivatives, there is no evidence that such differences in currently available formulations are clinically significant. It is the pharmacokinetic properties of the partner medicine and the level of resistance to it that largely determine the efficacy and choice of combinations. Outside South-East Asia, there is no convincing evidence yet for reduced susceptibility to the artemisinins; therefore, the performance of the partner drug is the main determinant in the choice of ACT, according to the following principles:

• Drugs used in IPTp, SMC or chemoprophylaxis should not be used as first-line treatment in the same country or region.
• Resistance to SP limits use of artesunate + SP to areas in which susceptibility is retained. Thus, in the majority of malaria-endemic countries, first-line ACTs remain highly effective, although resistance patterns change over time and should be closely monitored.

Choosing among formulations

Use of fixed-dose combination formulations will ensure strict adherence to the central principle of combination therapy. Monotherapies should not be used, except as parenteral therapy for severe malaria or SP chemoprevention, and steps should be taken to reduce and remove their market availability. Fixed-dose combination formulations are now available for all recommended ACTs except artesunate + SP.

Paediatric formulations should allow accurate dosing without having to break tablets and should promote adherence by their acceptability to children. Paediatric formulations are currently available for artemether + lumefantrine, dihydroartemisinin + piperaquine and artesunate + mefloquine.

Other operational issues in managing effective treatment

Individual patients derive the maximum benefit from an ACT if they can access it within 24–48 h of the onset of malaria symptoms. The impact in reducing transmission at a population level depends on high coverage rates and the transmission intensity. Thus, to optimize the benefits of deploying ACTs, they should be available in the public health delivery system, the private sector and the community, with no financial or physical barrier to access. A strategy for ensuring full access (including community management of malaria in the context of integrated case management) must be based on analyses of national and local health systems and may require legislative changes and regulatory approval, with additional local adjustment as indicated by programme monitoring and operational research. To optimize the benefits of effective treatment, wide dissemination of national treatment guidelines, clear recommendations, appropriate information, education and communication materials, monitoring of the deployment process, access and coverage, and provision of adequately packaged antimalarial drugs are needed.

Community case management of malaria

Community case management is recommended by WHO to improve access to prompt, effective treatment of malaria episodes by trained community members living as close as possible to the patients. Use of ACTs in this context is feasible, acceptable and effective (173). Pre-referral treatment for severe malaria with rectal artesunate and use of RDTs are also recommended in this context. Community case management should be integrated into community management of childhood illnesses, which ensures coverage of priority childhood illnesses outside of health facilities.

Health education From the hospital to the community, education is vital to optimizing antimalarial treatment. Clear guidelines in the language understood by local users, posters, wall charts, educational videos and other teaching materials, public awareness campaigns, education and provision of information materials to shopkeepers and other dispensers can improve the understanding of malaria. They will increase the likelihood of better prescribing and adherence, appropriate referral and reduce unnecessary use of antimalarial medicines.

Adherence to treatment

Patient adherence is a major determinant of the response to antimalarial drugs, as most treatments are taken at home without medical supervision. Studies on adherence suggest that 3-day regimens of medicines such as ACTs are completed reasonably well, provided that patients or caregivers are given an adequate explanation at the time of prescribing or dispensing. Prescribers, shopkeepers and vendors should therefore give clear, comprehensible explanations of how to use the medicines. Co-formulation probably contributes importantly to adherence. User- friendly packaging (e.g. blister packs) also encourages completion of a treatment course and correct dosing.