Malaria: an update on management in adults
د. حسين محمد جمعةاختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2010
Key points
Malaria is common.The severity of falciparum malaria is easy to underestimate - patients can deteriorate rapidly despite treatment. You should admit these patients to hospital for treatment. Patients with non-falciparum malaria, however, seldom need admission.
Your choice of drug will depend on where in the world the patient has visited since rates of drug resistance vary from country to country. In a patient with a mild or moderate attack of falciparum malaria, you should consider:
Oral quinine (followed by sulfadoxine-pyrimethamine, doxycycline, or clindamycin)
Atovaquone-proguanil
Artemether-lumefantrine
In a patient with severe or potentially complicated disease you should use parenteral quinine or, preferably, artesunate. Currently, there exists no good manufacturing process for artesunate licensed in the United Kingdom, although it can be obtained from specialist centres. You should give a loading dose if you use quinine.
Clinical tips
Debates about adjunctive treatment, such as exchange transfusion, should never delay you giving an effective antimalarial in sufficient doses to patients with malaria.
Antimalarial drugs are the only interventions that definitely improve outcome.
While people repeatedly exposed to malaria can become semi-immune (so getting less severe attacks of malaria), it is not possible to make accurate judgments about the immune status of individuals from their ethnicity or country of residence. You should assume that all patients presenting in non-endemic countries (such as the United Kingdom) have no immunity.
You should seek up to date advice on the treatment of:
Patients with severe falciparum malaria travelling from South East Asia (where there is multidrug resistant malaria)Pregnant women
You should assume that all falciparum malaria is resistant to chloroquine
Imported vivax malaria that is resistant to chloroquine is still rare. Chloroquine remains the drug of choice for non-falciparum malaria
Chloroquine remains the drug of choice for non-falciparum malaria
Patients treated with quinine are likely to get transient nausea, deafness, and tinnitus. You should warn them about possible side effects prior to treatment.Beware of hypoglycaemia in drowsy or comatose patients, especially when they are pregnant.
What is malaria?
Adisease caused by intracellular Plasmodium parasites. It is acquired when people are bitten by infected Anopheles mosquitoes in malarial areas - in practice almost all tropical countries. Malaria is common, especially in Africa. In some areas, the average inhabitant can have more than three clinical attacks in a year. It can therefore be considerably more common than significant upper respiratory tract infections in the United Kingdom.There are five forms of malaria which cause disease in humans:
• Plasmodium falciparum (common)• Plasmodium vivax (common)
• Plasmodium ovale
• Plasmodium malariae
• Plasmodium knowlesi.
Falciparum is the form which causes almost all life threatening malaria. Vivax malaria is also common. The other forms, however, are relatively rare
Life cycle of plasmodium
Parasites are inoculated and pass to the liver, where they develop over around 10 days before emerging to infect red blood cells and appear as tiny rings.They mature over two to three days (depending on the species).
In falciparum malaria, this takes about 48 hours.
As the parasites mature they begin to sequestrate in the muscle, kidneys, and brain, and therefore disappear from the peripheral blood.
In general, it is the sequestrated forms that cause serious pathology.
The importance of this is that parasite levels can appear low in the peripheral blood, yet the patient can be very sick.
Conversely, a patient can appear to be very well with a high parasite count; the patient is then likely to deteriorate despite treatment.
Plasmodium vivax and ovale (but not falciparum)
lay down hypnozoites in the liver.These are dormant forms that are not treated by conventional drugs such as quinine or chloroquine, and they can reactivate months or, occasionally, years after a successfully treated primary infection.
Gametocytes of all species of plasmodium are also not killed by many conventional drugs, and may persist for several weeks.
Gametocytes on their own are not harmful to humans, and persisting gametocytes do not require prolonged treatment if there are no asexual parasites seen.
Each year, more than a million people die from falciparum malaria, including some in industrialised countries. Virtually all forms of malaria, if treated early enough, can be cured with currently available drugs.
Most deaths from malaria are therefore avoidable and are due to:
Delayed presentation
Delayed diagnosis
Use of ineffective drugs or doses
Doctors underestimating the severity .
In diagnostic testing
Sensitivity
refers to the chance of having a positive test result, given that you have a disease.Specificity
Specificity refers to the chance of having a negative test result, given that you do not have a disease.How do I diagnose it?
Clinical and routine blood tests are insensitive and non-specific. The diagnosis has to be based on blood tests for malaria. Examining blood films remains the gold standard, although this can be supported by additional rapid diagnostic tests. If you suspect that a patient has malaria, you need to check these tests immediately (within a couple of hours); it is dangerous to wait for tests to come back the next day as malaria can deteriorate rapidly in some cases.Rapid diagnostic tests
While rapid diagnostic tests are useful, they should not be used as the sole method of diagnosis because they:Have a false negative rate, especially for non-falciparum malaria
Can give no indication of the parasite count
Can remain positive for days to weeks after successful treatment, so are not useful for follow up.
Evidence for rapid diagnostic tests
Most have been evaluated only for falciparum malaria and have lower sensitivities for the other types of malaria.Rapid diagnostic tests detecting
plasmodial histidine-rich protein 2 (for example, ParaSight F and ICT) have sensitivities ranging from 77% to 99%, and specificities ranging from 83% to 98% for falciparum malaria.
Tests detecting parasite specific lactate dehydrogenase (for example, OptiMAL) have sensitivities of 88.5% to 95%, and specificities of 92% to 100% for P falciparum, measured against high quality microscopy.
Expert microscopy can detect as little as 0.001% parasitaemias (this is the percentage of red cells containing parasites). Rapid diagnostic tests are broadly similar and can detect levels of 0.002% parasitaemia.
Polymerase chain reaction (PCR) can detect lower parasitaemias, but this is not practical or useful for clinical management.
A single negative blood film does not completely rule out the diagnosis of malaria; if in doubt, repeat the test the next day.
There is no role for blind treatment of malaria if diagnostic facilities are available.
It is easy to underestimate the severity of malaria in children and adults. Patients can appear well initially, and then deteriorate rapidly.
Drowsiness, impaired consciousness,
fits,
rapid or laboured breathing,
anaemia, and
disseminated intravascular coagulation all indicate severe disease .
Patients with parasite counts of greater than 2% will usually need parenteral treatment, irrespective of their initial clinical state.
Patients with parasite counts of greater than 5% will almost certainly need parenteral treatment, irrespective of their initial clinical state.
Patients who are pregnant or jaundiced should be treated as potentially complicated cases.
How should I treat it?
Uncomplicated falciparum malaria
Give an effective antimalarial promptly at an appropriate dose and to ensure that patients complete the course.
Drug resistance means that drug combinations are always preferable to a single drug used alone. Examples of such combinations are:
• Quinine plus sulfadoxine-pyrimethamine
• Artemether-lumefantrine
• Atovaquone-proguanil.
Quinine, either for five days or until the parasites have been cleared from the blood, followed by either:
• Sulfadoxine-pyrimethamine for one day
• Doxycycline for seven days
• Clindamycin for three days.
There are no confirmed cases of quinine resistance in Africa. A good alternative regimen, which is a first choice in some centres, is either:
Atovaquone-proguanil for three days
Artemether-lumefantrine for three days (six dose regimen).
Clinical failures can occur with any of these combinations, but failure rates are low if the course is completed.
Special cases
In patients from South East Asia (Thailand, Laos, Burma/Myanmar, Vietnam) there is some evidence of partial quinine resistance, and it may be preferable to use combinations without quinine. There is some evidence of parasite tolerance of artemisinins in Cambodia. This is probably of limited clinical importance at present, provided a combination is used (2009).In pregnant women, quinine is advised because its side effect profile in pregnancy is known. It is generally safe, although it increases the risk of hypoglycaemia and may induce labour. The usual practice is to extend the course of quinine to seven days and to not give a second drug.
Doxycycline is contraindicated in pregnancy. There are insufficient data on atovaquone-proguanil to advise its use in pregnancy. There are concerns about using artemether in the first trimester of pregnancy and thus it should be avoided, unless there is a clear reason to recommend it (such as drug resistance in South East Asia or severe disease), until more data are available.
Side effects
Nausea, mild deafness, and mild tinnitus (cinchonism) occur almost invariably in patients taking quinine. These are reversible when the patient stops the drug. Quinine can induce cardiac arrhythmias in people with a pre-existing cardiac condition, although this does not happen commonly at doses used in oral treatment.Sulfadoxine-pyrimethamine, in common with other sulphur containing drugs, can cause skin rashes, and rare cases of Stevens-Johnson syndrome have been reported.
Doxycycline can cause gastritis, skin rashes, and all of the problems associated with broad spectrum antibiotics.
Clindamycin is associated with an increased risk of a patient developing infections with Clostridium difficile.
Evidence
Quinine became established as the gold standard therapy for falciparum malaria before the development of modern trial methods. No placebo controlled studies were performed, and none would now be ethical. Many studies compare new therapies against quinine, and its continuing effectiveness has been repeatedly demonstrated.Dose
Quinine 600 mg (adults) three times a day for five days or until the parasites have cleared from the peripheral blood, followed by either of the regimens below:Sulfadoxine-pyrimethamine three tablets once only
Doxycycline 100 mg daily for seven days
Combined with clindamycin 450 mg three times a day for three days.
Atovaquone-proguanil (Malarone)
Has a slightly higher failure rate than quinine, but it is reported to be slightly better tolerated. The evidence, however, is weak. There is currently no part of the world that has specific problems with atovaquone-proguanil resistance. Where patients have been taking prophylaxis with atovaquone-proguanil, it is not the best choice for treatment because there is a risk that the malaria parasite will be resistant.Side effects
Gastritis and nausea are relatively common.
Dose
Atovaquone-proguanil four tablets once daily for three days in adults
Side effects
Atovaquone-proguanil is generally well tolerated.
Evidence
No significant difference was seen between six dose artemether-lumefantrine and artesunate-mefloquine in a recent study from Laos.The six dose regimen has been less well studied than the four dose regimen, but the former appears to be significantly more effective.
Dose
For adults, four tablets (each comprising 20 mg artemether and 120 mg lumefantrine) followed by a further four tablets at eight hours, and then twice daily for two days.
Non-falciparum malaria
When a diagnosis of malaria caused by P vivax, P ovale, or P malariae is made, the key is to be completely sure that the patient does not in fact have malaria caused by P falciparum or a mixed infection. This is an easy mistake to make, especially in laboratories that rarely see malaria.The following scenarios should raise questions about the diagnosis:
A very sick patientA very high parasite count
A patient arriving from Africa (where falciparum malaria constitutes over 95% of cases).
Non-falciparum malaria seldom leads to death, and patients can almost always be treated as outpatients.
Almost all parasites are chloroquine sensitive and thus chloroquine remains the drug of choice to treat acute infection.
True vivax resistance to chloroquine has been reported, especially in Indonesia, but it remains extremely rare in travellers.
Vivax and ovale malaria lay down hypnozoites in the liver, which can cause a relapse after months or, occasionally, years. Hypnozoites are not reliably killed by chloroquine, or indeed by any of the other drugs used to treat the acute infection.
Only one drug, primaquine - which has been demonstrated to work against hypnozoites ("radical cure") - is licensed in Europe.
Tafenoquine, a new drug, probably also works against hypnozoites, but it is not licensed for this indication. Primaquine and, probably, tafenoquine can cause significant haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Chloroquine
Chloroquine works rapidly and reliably where there is no resistance, is safe in usual doses, and is well tolerated. It is considered safe in pregnancy and in children.Side effects
Chloroquine can cause gastritis and mild abdominal pain. It can also cause itching in some Africans (the mechanism of this is unknown).
Evidence
Chloroquine became established as the standard therapy for non-falciparum malaria before the development of modern trial methods. Randomised placebo controlled trials have not been done and would now be unethical. Case series suggest that chloroquine remains highly effective (greater than 98% cure rates).Dose
Chloroquine 600 mg orally, then 300 mg at six hours, 24 hours, and 48 hoursPrimaquine (for radical cure of hypnozoites)
Primaquine needs a prolonged course of treatment (14 days)
Primaquine, along with tafenoquine, is contraindicated in people with G6PD deficiency, in whom it can cause significant haemolysis, and it should not be prescribed before a G6PD test has been performed
Primaquine is contraindicated in pregnant women
Evidence
There is general agreement about the efficacy of primaquine, and studies have illustrated increases in relapse rates with decreased dosage regimens or with increasing primaquine resistance. There is clear evidence that treatment for fewer than 14 days is suboptimal.
Dose
Primaquine 15 mg daily for 14 days (increased to 15 mg twice daily if primaquine resistant P vivax is a possibility).Severe falciparum malaria
Adults with severe malaria may develop any combination of the following:• Cerebral malaria (strictly an unrousable coma, although any neurological symptoms should be treated as such)
• Renal failure
• Acute respiratory distress syndrome
• Disseminated intravascular coagulation
• Significant anaemia.
In practice, in Western high intensity settings deaths occur due to cerebral malaria (usually within the first 48 hours) or acute respiratory distress syndrome (which can come on later, even once the parasites have cleared).
Renal failure can be managed by haemofiltration or dialysis in this setting. Always check for hypoglycaemia if patients are drowsy, unconscious, or fitting.
The key intervention (and the only one for which there is strong evidence) is to give an effective antimalarial at an adequate dose parenterally. All other decisions are secondary.
The current options are:
• Quinine (intravenous)
• Artesunate (intravenous).
The artemisinins reduce parasite counts faster, and there is now good evidence from Asia that they reduce mortality in adults with severe malaria compared with quinine.
This finding may be specific to adults in Asia because of some degree of drug resistance present in the population of South East Asia which is not found in Africa - where most cases of severe malaria originate. But, where reliable sources of well manufactured artesunate are available, this is the drug of choice in adults with severe malaria.
Quinine remains a good drug to treat severe malaria if it is what is available. Debates about which drug to give should never delay you giving one of them in adequate doses.
There are a few situations where artesunate clearly has the edge:
• Patients from South East Asia might have relatively quinine resistant malaria, so an artemisinin is preferable
• Quinine is proarrhythmogenic, so artesunate should be considered in all patients with a cardiac condition.
• Artesunate reduces parasite counts faster, so is preferable in patients with a parasite count of greater than 10%.
There are a few situations where artesunate clearly has the edge:
It is not clear what effect exchange transfusion has on blood concentrations of artemisinins, so using both artesunate and exchange transfusion may be counterproductive.
Side effects
The side effects of intravenous quinine are the same as for oral quinine, with the addition of arrhythmias and hypoglycaemia. Artesunate is generally well tolerated, although its effects in the first trimester of pregnancy are still being assessed.Evidence
Quinine became established as the gold standard therapy for severe malaria before the development of modern trial methods. Randomised placebo controlled trials have not been done and would now be unethical.Loading doses of quinine have been demonstrated (in one systematic review of four randomised controlled trials) to reduce parasite and fever clearance times. Although there was a trend towards decreased mortality, this failed to reach statistical significance. There was no apparent effect on coma recovery time, neurological sequelae, or seizures.
Faster parasite clearance has been seen with artesunate, but there were no differences in fever clearance time, coma recovery, neurological sequelae, or mortality in one study. A more recent study from Asia showed a clear survival benefit for artesunate when compared to quinine.
Dose
Quinine:
10 mg/kg (max 700 mg) IV twice daily (loading dose = 20 mg/kg (max 1400 mg))
Artesunate:
2.4 mg/kg IV loading, then 1.2 mg/kg IV twice daily (to a total of 600 mg)
Adjunctive therapy
Various adjunctive treatments have been tried. Few of these, if any, work, and some are harmful. Among the commonly considered treatments, steroids and mannitol have been shown not to work in cerebral malaria.The role of exchange transfusion remains controversial. There is contradictory trial evidence and, in practice, it is unlikely that further trials will ever settle this question. Nobody would advise exchange transfusion for a parasitaemia of less than 10%. At high parasite counts, the evidence is mixed; most centres with expertise in malaria consider doing an exchange transfusion if parasite counts are greater than 20%, but some centres never use them. In practice, there is general agreement that the effect is marginal at best in most cases.
Prophylactic anticonvulsants used to be given to patients with cerebral malaria but, although this does reduce the risk of fits, a trial of phenobarbitone (in children) suggested an excess mortality. Now they are generally reserved for patients who are actively fitting.
Haemofiltration will need to be considered in acute renal failure. Renal failure secondary to malaria (which is usually not due primarily to prerenal failure but to the direct effects of parasites in the kidney) virtually invariably resolves completely, although this can take days and, occasionally, weeks.
Patients whose blood pressure drops may have coexisting Gram negative sepsis and should be considered for broad spectrum antibiotics. Malaria itself almost never causes major haemodynamic collapse directly.
Pulmonary oedema can be treated with diuretics, but these may be ineffective in malaria induced renal failure. In these cases, haemofiltration will be needed.
The most concerning complication in adults, which develops after the first 24 hours, is acute respiratory distress syndrome. The treatment is as for all other causes of acute respiratory distress syndrome. There is weak evidence that heavy hydration increases the risk of acute respiratory distress syndrome; patients need to be adequately hydrated, but "running patients wet" is not advised by most centres with expertise in malaria.
Evidence
Steroids
One systematic review examined two randomised controlled trials comparing dexamethasone with placebo in severe cerebral malaria. There were no differences in mortality, but there was increased gastrointestinal bleeding and seizures in the dexamethasone groups.
Mannitol
One systematic review failed to identify any randomised or quasi-randomised controlled trials. Mannitol has been demonstrated to control intracranial pressure in children with cerebral malaria, but the effects on morbidity or mortality are unclear.Exchange transfusion
There are no suitable randomised controlled trials on exchange transfusion for analysis. A systematic review of case control studies found variable efficacy, but no influence on mortality overallProphylactic anticonvulsants
One systematic review of three randomised controlled trials comparing phenobarbitone with placebo (no treatment) demonstrated fewer convulsions, but increased mortality, in the phenobarbitone group. Trials of different doses and anticonvulsants are awaited.When should I seek specialist advice from a tropical centre?
Tropical centres are always happy to give advice on the management of severe malaria or multidrug resistant malaria of any sort. We strongly recommend that you seek advice for patients with severe malaria who:• Are pregnant
• Are from (or have been to) South East Asia, where there is drug resistance
• Are elderly
• Have pre-existing medical problems (especially cardiac).
Although most malaria presents within the first month after arriving from an endemic country it can present up to a year later for falciparum malaria and longer still for non-falciparum malaria.
South East Asia is the region of the world with the greatest concentration of drug resistant malaria.
There is insufficient evidence to recommend atovaquone-proguanil in the first trimester of pregnancy.
Quinine is a safe choice, although none of the drugs are ideal in pregnancy.
Because there is debate at present about the safety of artemisinins in early pregnancy, unless there is a clear reason why they are the best choice, you should not give them to women in the first trimester of pregnancy. The exception is in women from South East Asia, where relative quinine resistance alters the risk-benefit balance.
Malaria, and to a lesser extent quinine, substantially increase the risk of hypoglycaemia.
Chloroquine resistant vivax malaria occurs, but is sufficiently rare that chloroquine remains the drug of choiceOver 95% of malaria cases in people travelling from Africa take the falciparum form, and vivax malaria is rare, so beware of reports of vivax malaria from Africa.
Rapid breathing is a worrying sign in malaria and may indicate pulmonary oedema or acidosis in children, or acute respiratory distress syndrome in adults.
Thrombocytopenia occurs in most cases of malaria and correlates poorly with severity.
A parasite count >2% is an indication for parenteral treatment according to UK guidelines, but in most cases does not suggest severe malaria. Patients can have severe malaria with low parasite counts.In adults from Asia, artemisinins undoubtedly have the edge over quinine. Since there are no data on this in adults from Africa and in children from any area, nobody would claim quinine is better.
Which one of the following statements about severe malaria is correct?
a.Quinine gives better clinical outcomes than artesunate
b.
Renal failure should be treated with repeated fluid challenges
c.
Shock suggests a coexisting Gram negative sepsis
• a : Quinine gives better clinical outcomes than artesunate
• In adults from Asia, artemisinins undoubtedly have the edge over quinine. Since there are no data on this in adults from Africa and in children from any area, nobody would claim quinine is better.• b : Renal failure should be treated with repeated fluid challenges It is worth trying a fluid challenge to exclude prerenal failure, but most renal failure in malaria in adults is caused by parasites and not by dehydration, and there is a danger of overhydration with repeated fluid challenges.
• c : Shock suggests a coexisting Gram negative sepsis
• Malaria alone seldom leads to haemodynamic dysfunction.
a.
Artesunate should be the drug of choice
b.
Exchange transfusion is essential
c.
Adding exchange transfusion to artemisinins gives twice the benefit
Which one of the following statements about the treatment of a patient with a parasite count >20% is correct?
a : Artesunate should be the drug of choice
Artesunate reduces parasite counts more rapidly than other drugs and its survival advantage in adults who have severe falciparum malaria with hyperparasitaemia is convincing.b : Exchange transfusion is essential
Exchange transfusion should be considered, but it is not essential, and many would not recommend it at all.
c : Adding exchange transfusion to artemisinins gives twice the benefit
The use of both exchange transfusion and artesunate in patients is not recommended. We have no idea of the effect of exchange transfusion on drug levels of artesunate, although it has been proved to have little effect on quinine, which has a substantial volume of distribution.
Tinnitus is a common, almost invariable, effect of quinine. It is almost always reversible.
Full blown cinchonism, manifesting as vomiting and instability, is sometimes an indication for decreasing the dosage, but not for stopping treatment.
Liver hypnozoites occur only in the vivax and ovale types of malaria.
P malariae may cause chronic disease, but it does not lay down hypnozoites.
The only currently licensed drug for radical cure of liver hypnozoites is primaquine. Chloroquine does not kill hypnozoites. Liver hypnozoites may cause relapses months to years later if they are not eradicated.
Complications, especially acute respiratory distress syndrome, may occur even after the parasites have been eradicated.
Patients with parasite counts >5% need intravenous treatment regardless of their clinical state.
Falciparum malaria is resistant to chloroquine.
Rapid diagnostic tests• can remain positive for days to weeks after successful treatment, so they are not useful for testing whether the patient has been cured.
• Rapid diagnostic tests give no indication of the parasite count.
• Rapid diagnostic tests have a clinically significant false negative rate, especially for non-falciparum malaria.
