Malaria continues to be a major global health problem, with over 40% of the world’s population – more than 2400 million people – exposed to varying degrees of malaria risk in some 100 countries.
Malaria is an important cause of morbidity and mortality in children and adults in tropical countries.
Mortality, currently estimated at over a million people per year, has risen in recent years, probably due to increasing resistance to the various anti-malarial medicines.
Effective Malaria Control requires an integrated approach comprising of prevention measures including IPT and the use of ITNs, ITMs, LLINs, vector control and early treatment with effective anti-malarials.
The affordable and widely available anti-malarial chloroquin that was in the past a mainstay of malaria control is now ineffective in most Falciparum Malaria endemic areas, and resistance to sulfadoxine–pyrimethamine is also increasing rapidly in some of various countries. The discovery and development of the artemisinin derivatives in China, have provided a new class of highly effective antimalarials, and have already transformed the chemotherapy of malaria.
Artemisinin-based combination therapies (ACTs) are now generally considered as the best current treatment for uncomplicated Falciparum Malaria.
Malaria - Introduction
Malaria is caused by infection of red blood cells with protozoan parasites of
the genus Plasmodium.
The parasites are inoculated into the human host by a feeding female anopheline mosquito.
The four Plasmodium species that infect humans are P. falciparum, P. vivax,
P. ovale and P. malariae.
The initial symptoms of malaria are nonspecific and similar to the symptoms of a minor systemic viral illness.
Symptoms comprise of : headache, lassitude, fatigue, abdominal discomfort and muscle and joint aches, followed by fever, chills, perspiration, anorexia, vomiting and worsening malaise. This is the typical picture of uncomplicated malaria. Residents of endemic areas are often familiar with this combination of symptoms, and frequently self-diagnose.
Malaria is therefore frequently over-diagnosed on the basis of symptoms alone. This is often the case during the first month of winter which coincides with influenza outbreaks. Malaria cases reported during this period are also known as “winter malaria”. Low slide positivity rate for malaria during these periods is evidence that these cases could be as a result of over-diagnosis of malaria.
Malaria – Introduction..continued
Infection with P. vivax and P. ovale can be associated with well-defined malarial paroxysms, in which fever spikes, chills and rigors occur at regular intervals. At this stage, with no evidence of vital organ dysfunction, the case-fatality rate is low provided prompt and effective treatment is given.
On the other hand, if ineffective drugs are given or treatment is delayed in Falciparum malaria, the parasite burden continues to increase and may result in severe malaria. The patient may progress from having minor symptoms to having severe disease within a few hours. This usually manifests with one or more of the following complications: coma (cerebral malaria), metabolic acidosis, severe anemia, hypoglycemia and, in adults, acute renal failure or acute pulmonary edema.
At this stage, mortality in people receiving treatment has risen to 15–20%.
If untreated, severe malaria is almost always fatal.
Treatment of Uncomplicated Malaria (Objectives)
The objective of treating uncomplicated malaria is to cure the infection. This
is important as it will help prevent progression to severe disease (complicated
malaria) and prevent additional morbidity associated with treatment failure.
Cure of the infection means eradication from the body of the infection that caused the illness. In treatment evaluations in all settings, emerging evidence indicates that it is necessary to follow patients for long enough to document cure.
The public health goal of treatment is to reduce transmission of the infection to others, i.e. to reduce the infectious reservoir.
A secondary but equally important objective of treatment is to prevent the
emergence and spread of resistance to anti-malarials. Tolerability, the adverse
effect profile and the speed of therapeutic response are also important
Treatment of Severe Malaria (Objectives)
The primary objective of anti-malarial treatment in severe malaria is to prevent death.
inappropriate utilization of available resources through unnecessary treatment of
patients without parasitaemia and thus results to an unsustainable intervention.
In addition to cost savings, parasitological diagnosis has the following
Improved patient care in parasite-positive patients owing to greater certainty that the patient has malaria.
Identification of parasite-negative patients in whom another diagnosis
must be sought.
3. Prevention of unnecessary exposure to anti-malarials, thereby reducing
side-effects, drug interactions and selection pressure.
4. Improved health information.
5. Confirmation of treatment failures.
Parasitological Diagnosis … continued
The two methods in use for parasitological diagnosis are light microscopy and Rapid Diagnostic Tests (RDTs).
Light microscopy has the advantage of low cost and high sensitivity and specificity when used by well trained staff.
2.RDTs for detection of parasite antigen are generally more expensive, but the prices of some of these products have recently decreased to an extent that makes their deployment cost-effective in some settings. Their sensitivity and specificity are variable, and their vulnerability to high temperatures and humidity is an important constraint.
Despite these concerns, RDTs make it possible to expand the use of
confirmatory diagnosis. Deployment of these tests, as with microscopy, must be
accompanied by quality assurance. Practical experience and operational
evidence from large-scale implementation are limited and, therefore, their
introduction should be carefully monitored and evaluated.
(less than 2 hours) of the patient presenting. If this is not possible the patient
must be treated on the basis of a clinical diagnosis.
Examination of slides-Thin
Case Management Sub Committee Meeting
24th May 2006
Case Management Sub Committee Meeting
24th May 2006
Malaria parasite species identification
In areas where two or more species of malaria parasites are common, only a parasitological method will permit a species diagnosis. Where mono-infection with P. vivax is common and microscopy is not available, it is recommended that a combination RDT which contains a pan-malarial antigen is used.
Alternatively, RDTs specific for falciparum malaria may be used, and treatment for vivax malaria given only to cases with a negative test result but a high clinical suspicion of malaria. Where P. vivax, P.malariae or P.ovale occur almost always as a co-infection with P. falciparum, an RDT detecting P. falciparum alone is sufficient. Anti-relapse treatment with primaquine should only be given to cases with confirmed diagnosis of vivax malaria.
(2) In the rare event that a mutant parasite that is resistant to one of the drugs arises de novo during the course of the infection, the parasite will be killed by the other drug. This mutual protection is thought to prevent or delay the emergence of resistance.
To realize the two advantages, the partner drugs in a combination must be independently effective.
The possible disadvantages of combination treatments are the potential for increased risk of adverse effects and the increased cost.
Artemisinin-based Combination Therapy (ACT)
Artemisinin and its derivatives (artesunate, artemether, artemotil,
dihydroartemisinin) produce rapid clearance of parasitaemia and rapid
resolution of symptoms. They reduce parasite numbers by a factor of
approximately 10 000 in each asexual cycle, which is more than other current
antimalarials (which reduce parasite numbers 100- to 1000-fold per
Artemisinin and its derivatives are eliminated rapidly. When given in
combination with rapidly eliminated compounds (tetracyclines, clindamycin),
a 7-day course of treatment with an artemisinin compound is required; but
when given in combination with slowly eliminated antimalarials, shorter
courses of treatment (3 days) are effective. The evidence of their superiority
in comparison to monotherapies has been clearly documented.
Non-Artemisinin based Combination Therapy
Non-artemisinin based combinations (non-ACTs) include:-
sulfadoxine–pyrimethamine with chloroquine (SP+CQ) or
However, the prevailing high levels of resistance have
compromised the efficacy of these combinations. There is no
convincing evidence that SP+CQ provides any additional
benefit over SP, so this combination is not recommended;
SP+AQ can be more effective than either drug alone, but
The following ACTs are currently recommended (alphabetical order):
• artesunate + amodiaquine,
• artesunate + mefloquine,
• artesunate + sulfadoxine–pyrimethamine.
Note: amodiaquine + sulfadoxine–pyrimethamine may be considered as an interim option where ACTs cannot be made available, provided that efficacy of both is high.
Recommended Second-line Anti-malarial Treatments
On the basis of the evidence from current practice and the consensus opinion of the Guidelines Development Group, the following second-line treatments are recommended, in order of preference:
Alternative ACT known to be effective in the region,
Artesunate + tetracycline or doxycycline or clindamycin,
Quinine + tetracycline or doxycycline or clindamycin.
The alternative ACT has the advantages of simplicity, and where available, co-formulation to improve adherence. The 7-day quinine regimes are not well tolerated and adherence is likely to be poor if treatment is not observed.
Treatment In Specific Populations And Situations
First trimester: quinine + clindamycin to be given for 7 days.
ACT should be used if it is the only effective treatment available.
Second and third trimesters: ACT known to be effective in the
country/region or artesunate + clindamycin to be given for 7 days
or quinine + clindamycin to be given for 7 days.
Treatment In Specific Populations And Situations
Lactating women should receive standard anti-malarial
treatment (including ACTs) except for tetracyclines and
dapsone, which should be withheld during lactation.
Important: These severe manifestations can occur singly or, more commonly, in
combination in the same patient.
Recommendations For Management Of Severe Malaria
Severe malaria is a medical emergency. After rapid clinical assessment and
confirmation of the diagnosis, full doses of parenteral antimalarial treatment should
be started without delay with whichever effective antimalarial is first available.
Artesunate 2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended choice in low transmission areas or outside malaria endemic areas
2. For children in high transmission areas, the following antimalarial medicines are recommended as there is insufficient evidence to recommend any of these antimalarial medicines over another for severe malaria:
– artesunate 2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h,then once a day;
– artemether 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day;
– quinine 20 mg salt/kg bw on admission (i.v. infusion or divided i.m. injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour.
Treatment Of Malaria Caused By P. Vivax, P. Ovale Or P. Malariae
about 40% of malaria cases worldwide . It is prevalent in endemic areas in the Middle
East, Asia, Oceania and Central and South America. In most areas where P. vivax is
prevalent, malaria transmission rates are low, and the affected populations therefore
achieve little immunity to this parasite. Consequently, people of all ages are at risk.
The other two human malaria parasite species P. malariae and P. ovale are generally
less prevalent but are distributed worldwide especially in the tropical areas of Africa.
Among the four species of Plasmodium that affect humans, only P. vivax and P. ovale
form hypnozoites, parasite stages in the liver that can result in multiple relapses of
infection, weeks to months after the primary infection. Thus a single infection causes
repeated bouts of illness. This affects the development and schooling of children and
debilitates adults, thereby impairing human and economic development in affected
populations. The objective of treating malaria caused by P. vivax and P. ovale is to cure
both the blood stage and the liver stage infections, and thereby prevent both relapse
and recrudescence.This is called radical cure.
Diagnosis Of P. Vivax Malaria
Diagnosis of P. vivax malaria is based on
Although rapid diagnostic testsbased on
immunochromatographic methods are available for
the detection of non-falciparum malaria, their
sensitivities below parasite densities of 500/μl are
low. Their high cost is an impediment to their
widespread use in endemic areas.
Recommendations On The Treatment Of Uncomplicated Vivax Malaria
Chloroquine 25 mg base/kg bw divided over 3 days, combined with primaquine 0.25 mg base/kg bw, taken with food once daily for 14 days is the treatment of choice for chloroquine-sensitive infections. In Oceania and South-East Asia the dose of primaquine should be 0.5 mg/kg bw.
Amodiaquine (30 mg base/kg bw divided over 3 days as 10 mg/kg bw single daily doses) combined with primaquine should be given for chloroquine-resistant vivax malaria.
In moderate G6PD deficiency, primaquine 0.75 mg base/kg bw should be given once a week for 8 weeks. In severe G6PD deficiency, primaquine should not be given.
Where ACT has been adopted as the first-line treatment for P. falciparum malaria, it may also be used for P. vivax malaria in combination with primaquine for radical cure. Artesunate +sulfadoxine-pyrimethamine is the exception as it will not be
effective against P. vivax in many places.
Treatment of Severe Vivax Malaria
P. Vivax malaria is considered to be a benign malaria, with a very low
case-fatality ratio, it may still cause a severe and debilitating febrile illness.
It can also very occasionally result in severe disease as in falciparum malaria.
Severe Vivax malaria manifestations that have been reported are:
Severe anaemia and acute pulmonary oedema are not uncommon.
The underlying mechanisms of severe manifestations are not well understood.
Prompt and effective treatment and case management should be the same as
for severe and complicated falciparum malaria
Treatment Of Malaria Caused By P. Ovale And P. Malariae
P. ovale and P. malariae to antimalarials infections caused by these
two species are considered to be generally sensitive to chloroquin.
P. malariae should be treated with the standard regimen of chloroquin
as for vivax malaria, but it does not require radical cure with
primaquine as no hypnozoites are formed in infection with this
P.ovale mainly occurs in areas of high stable transmission where the
risk of re-infection is high. In such settings, primaquine treatment is
Mixed Malaria Infections
Mixed malaria infections are common. Mixed infections are underestimated by routine microscopy.
Cryptic P. falciparum infections can be revealed in approximately 75% of cases by the RDTs based on the histidine-rich protein 2 (HRP2) antigen, but such antigen tests are much less useful (because of their lower sensitivity) in detecting cryptic vivax malaria.
ACTs are effective against all malaria species and are the treatment of choice.
should be used for treatment as they are highly effective against all malaria species.
In areas with pure vivax epidemics, and where drug resistance has not been reported, chloroquin is the most appropriate drug once the cause of the epidemic has been established.
Use Of Gameto-cytocidal Drugs To Reduce Transmission
ACTs reduce gametocyte carriage markedly, and therefore reduce transmission.
This is very valuable in epidemic control.
In circumstances where an ACT is not used, a single oral dose of primaquine of
0.75 mg base/kg bw (45 mg base maximal for adults) combined with a fully
effective blood schizonticide could be used to reduce transmission provided
that it is possible to achieve high coverage (>85%) of the population infected with malaria. This strategy has been widely used in South-East Asia and South
America, although its impact has not been well documented. The single
primaquine dose was well tolerated and prior testing for G6PD deficiency was not required.
There is no experience with its use in Africa, where there is the highest prevalence of G6PD deficiency in the world. Primaquine should not be given in pregnancy.
Mass treatment (mass drug administration) of all or a large section of the population (whether symptoms are present or not) has been carried out in the past, usually in conjunction with insecticide residual spraying, as a way of controlling epidemics. Analysis of mass drug administration projects during the period 1932–1999 did not draw definitive conclusions . Many projects were unsuccessful, although a reduction in parasite prevalence and some transient reduction in mortality and morbidity occurred in some cases. Reduced transmission was seen only in one study, in Vanuatu, where the population concerned was relatively small, well defined and controlled.
There is no convincing evidence for the benefits of mass treatment.
Mass treatment of symptomatic febrile patients is considered appropriate in epidemic and complex emergency situations. Whenever this strategy is adopted, a full treatment course should be given.
References Used For The Purpose Of This Presentation
WHO Guidelines For The Treatment Of Malaria. WHO/HTM/MAL/2006.1108.
Management Of Severe Malaria -A Practical Handbook -Second edition.