Antimalarial drugs given at regular intervals for preventing clinical malaria and severe anaemia in preschool children

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the benefits and harms of giving drugs at regular intervals to prevent malaria in preschool children living in areas where malaria is endemic.

Background

Malaria is a parasitic disease common in tropical and subtropical areas of the world. The disease is caused by Plasmodium parasites and is transmitted to humans by the bite of infected female anopheline mosquitoes. People who live in or visit areas where malaria commonly occurs (endemic areas) are at the risk of becoming infected. Infected people may show no sign of illness (asymptomatic) or may develop fever, chills, malaise and headache (symptomatic malaria). The severity of infection varies from mild (uncomplicated) to life threatening (severe or complicated). Among the four human species of malaria parasites, Plasmodium falciparum is the main species that causes severe malaria, and is most frequently encountered in subSaharan Africa. People with severe malaria become very ill, may develop severe anaemia, convulsions, or become unconscious, and in some cases the disease is fatal. Severe malaria is more likely to occur in people who lack or have low immunity to malaria (WHO 2000).

People develop natural immunity to malaria following several infections. Those who live in areas where there is no malaria are not exposed and lack this natural immunity. Children living in areas where malaria is endemic will have acquired natural immunity to malaria by the time they are between 7 and 10 years (Branch 1998, Warrell 2001). Preschool children (below five years) living in malarious areas have inadequate immunity to malaria, and this explains why most of the one million malaria deaths that occur each year in endemic areas of subSaharan Africa occur in this age group (Snow 1999).

The major goal of the global malaria control effort is to reduce the number of people dying from malaria. The key strategies currently promoted by the World Health Organization (WHO 1999) for the control of malaria are: early diagnosis with prompt treatment of affected people; use of insecticide-treated nets; and taking antimalarial drugs regularly to prevent or suppress malaria (chemoprophylaxis). Early diagnosis with prompt treatment is not always possible because of limited access to health care in many malaria endemic areas. Insecticide-treated nets are effective in reducing malaria deaths (Lengeler 2002), and are widely promoted by the World Health Organization (WHO) as part of the RollBack Malaria initiative. However, they are not widely available to the majority of those at risk of dying from malaria because of poverty and logistic problems (Goodman 1999, WHO 1999).

The WHO recommend that those at high risk of dying from malaria should use multiple preventive measures (WHO 1993). Experts recommend that people who are not immune visiting an area with malaria, and pregnant women living in areas with malaria, should take regular malaria chemoprophylaxis in addition to any other preventive measure they may be using (Shanks 1995, Chulay 1998). Evidence from two Cochrane reviews show that chemoprophylaxis reduces the risk of malaria in non-immune adult travellers (Croft 2002), and in pregnant women living in malaria endemic areas (Garner 2002). Although preschool children living in malarious areas are also at high risk of dying from malaria the WHO does not recommend malaria chemoprophylaxis for this age group (Goodman 1999).

Malaria chemoprophylaxis entails giving daily or weekly preventive doses (usually smaller than therapeutic doses) of antimalarial drugs to people over a prolonged period (Croft 2002). Intermittent presumptive treatment involves giving full therapeutic doses of an antimalarial at specified time points to cure malaria during vulnerable periods such as infancy (Schellenberg 2001) or pregnancy (Verhoeff 1998). This review will address both regimens of giving drugs to prevent malaria.

There are fears that giving chemoprophylaxis to preschool children would prevent them from developing natural immunity to malaria, and therefore make them more vulnerable to severe malaria when they grow older (WHO 1993). Research has shown that young African children who received malaria chemoprophylaxis for a long time had lower levels of malaria antibodies than their counterparts, but there is no evidence that this increased the risk of dying from malaria later in life (Otoo 1988).

There are also concerns that the widespread use of antimalarial drugs for chemoprophylaxis in young children could increase the incidence of malaria parasite resistance to these drugs (WHO 1990, WHO 1993). High rates of parasite resistance to antimalarial drugs make malaria control difficult and ineffective in many endemic areas (White 1999). Inappropriate use of antimalarial drugs is known to increase the incidence of drug resistance (Peters 1998, Nuwaha 2001). Some researchers have shown that giving intermittent presumptive treatment to infants attending routine immunization clinics helps to ensure that drugs are used appropriately (Schellenberg 2001). Such an approach minimizes underdosing and improves adherence, which reduces the likelihood of drug resistance developing.

Antimalarial drugs commonly used for chemoprophylaxis are chloroquine, proguanil, atovaquone-proguanil, mefloquine, doxycycline, sulfadoxine-pyrimethamine, and pyrimethamine-dapsone. Some of these drugs are expensive, and there is concern that the universal implementation of routine malaria chemoprophylaxis for young children in endemic areas may not be sustainable due to logistic difficulties and high operational costs (Goodman 1999). There are also concerns that giving these antimalarial drugs regularly for prolonged periods of time would increase the incidence of adverse drug effects. These may be reduced with the intermittent presumptive treatment approach given that the period and frequency of administration are reduced.

Despite the concerns regarding the safety and sustainability of this intervention, several researchers have reported that giving chemoprophylaxis to young children in endemic African communities reduces malaria attacks, prevents anaemia, and reduces mortality (Menon 1990, Schellenberg 2001). The uncertainties about the potential benefits and harms of giving malarial chemoprophylaxis or intermittent presumptive treatment routinely to all young children living in endemic areas make it necessary to review available evidence on this intervention strategy.

Objectives

To evaluate the benefits and harms of giving drugs at regular intervals to prevent malaria in preschool children living in areas where malaria is endemic.

Criteria for considering studies for this review

Types of studies

Randomized and quasi-randomized controlled trials.

Types of participants

Children aged five and under living in an area where malaria is endemic.

Types of intervention

Intervention: Antimalarial drugs given at regular intervals. This includes regimens described as "prophylaxis" and "intermittent treatment".
Control: Placebo or no preventive intervention.

Types of outcome measures

PRIMARY
Incidence of clinical malaria episodes.
Incidence of severe anaemia.

SECONDARY
Proportion admitted to hospital for any cause.
Proportion that received any blood transfusion.
Proportion with malaria parasitaemia (whether symptomatic or asymptomatic).
All-cause mortality (death from any cause).
Proportion with enlarged spleen.
Proportion that need second-line antimalarial drug.
Mean haemoglobin (or haematocrit).

ADVERSE EVENTS
Proportion with any adverse event.
Proportion with severe adverse events: life threatening; leading to admission in hospital; or discontinuation of drug.

We will also look for these outcomes after stopping prophylaxis or intermittent presumptive treatment in the short term (0 to 6 months) and long term (6 months to 2 years).

Search strategy for identification of studies

See: Unavailable search strategy

We will attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).

We will use the following terms to search trial registers and electronic databases: malaria; prophylaxis; prevention; chemoprophylaxis; chemoprevention; intermittent treatment; presumptive treatment; anti-malarial drugs; antimalarial agents; antimalarials; infant; and child.

We will search the Cochrane Infectious Diseases Group (CIDG) specialized trials register for relevant trials (May 2002) . Full details of the CIDG methods and the journals hand searched are published in The Cochrane Library in the section on Collaborative Review Groups.

We will search The Cochrane Controlled Trials Register, published on The Cochrane Library (Issue 2, 2002). This contains mainly reference information to randomized controlled trials and controlled clinical trials in health care.

We will search the following electronic databases using the topic search terms in combination with the search strategy developed by the Cochrane Collaboration and detailed in the Cochrane Reviewer's Handbook (Clarke 2001):
(1) MEDLINE (1966 to May 2002);

(2) EMBASE (1988 to March 2002);

(3) LILACS (La Literatura Latinoamericana y del Caribe de Informacion en Ciencias de Salud) database (http://www.bireme.br; April 2002).

We will contact researchers to help identify additional published, unpublished, and ongoing trials.

We will contact pharmaceutical companies to supply information on trials relevant to this review.

We will also check the reference lists of all the trials identified by the above methods.

Methods of the review

STUDY SELECTION
Both reviewers (Martin Meremikwu and Aika Omari) will go through all results of the literature search for potentially relevant trials. We will obtain the full reprints or reports for all potentially relevant trials.

Both reviewers will independently assess identified potentially relevant trials for inclusion using an eligibility form based on the inclusion criteria specified in the protocol. We will resolve disagreements through discussion, and when necessary, by consulting a member of the Cochrane Infectious Diseases Group editorial team.

ASSESSMENT OF THE METHODOLOGICAL QUALITY OF INCLUDED TRIALS
Both reviewers will independently assess the methodological quality of each trial using the following criteria:

(1) Concealment of allocation: 'adequate' if participants and investigators enrolling participants did not foresee assignment; 'unclear' if the authors failed to report the procedure used to conceal allocation; and 'inadequate' if authors reported an approach that could not be considered adequate.

(2) Generation of allocation sequence: 'adequate' if the method described is suitable to prevent selection bias (such as computer generated random numbers, table of random numbers, drawing lots, or tossing a coin); 'unclear' if method is not described but trial is described as "randomized"; and 'inadequate' if sequences could be related to prognosis (eg, case record number, date of birth, day, month, or year of admission).

(3) Blinding: double blind; single blind; or open.

(4) Inclusion of all randomized participants in analysis: 'adequate' if at least 90% of the randomized participants are included and kept in their original groups for the analysis of primary outcomes; and 'inadequate' if more 10% were not included in an intention-to-treat analysis of the primary outcome.

DATA EXTRACTION
Both reviewers will independently extract data from the included trials using a data extraction form. We will resolve disagreements through discussion, and when necessary, by consulting a member of the the Cochrane Infectious Diseases Group editorial team. We will contact trial authors to supply incomplete data.

DATA ANALYSIS
We will use Review Manager (Version 4.1) for data analysis. We will compute Relative Risk with 95% confidence intervals for binary data. We will calculate weighted mean differences for normally distributed continuous data. We will present skewed data in tables only. We plan to present intention-to-treat analysis if the authors accounted for all randomized participants, otherwise we will present as per protocol analysis.

We will consider the existence of heterogeneity by visually examining the forest plot and by using the Chi-square test for heterogeneity with a 10% level of statistical significance. If heterogeneity is detected but it is considered appropriate to combine the trials, we will use a random effect model.

We will explore heterogeneity using the following subgroups:

(1) age at onset of chemoprophylaxis - during infancy (below 12 months) compared to after infancy (12 months to five years);
(2) type of antimalarial drug used;
(3) dosage regimen - continuous compared to intermittent;
(4) hypo-meso areas (spleen and parasite rates 50% or less in children aged 2 to 9 years) compared with hyper-holoendemic areas (spleen and parasite rates > 50% in children aged 2 to 9 years; parasite rate > 75% in infants 0 to 11 months; spleen rate > 25% in adults) (Wellcome Trust 1991);
(5) levels of adherence to the antimalarial drug
(a) intermittent regimen: those that had two or more doses compared with those that had only one dose;
(b) weekly regimen: those that had at least 75% adherence compared with those that had less than 75%.

We will perform meta-regression where adequate data are available.

We will examine funnel plots for asymmetry using Review Manager (Version 4.1). Asymmetry of funnel plot may be caused by factors such as publication bias, heterogeneity, and poor methodological quality.

Potential conflict of interest

We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (eg, employment, consultancy, stock ownership, honoraria, expert testimony).

Acknowledgements

This protocol was developed during the Mentorship Programme organized by the Cochrane Infectious Diseases Group in November 2001. The Department for International Development (UK) supports this programme through the Effective Health Care Alliance Programme at the Liverpool School of Tropical Medicine.

Notes

CO-REVIEWER CONTACT ADDRESS:

Dr Aika A A Omari
Research Associate
International Health Research Group
Liverpool School of Tropical Medicine
Pembroke Place
Liverpool L3 5QA
UK
Telephone: +44 (0)151 708 9393 extension: 3202
Facsimile: +44 (0) 151 707 1203
E-mail: aika@liv.ac.uk

Search strategy for MEDLINE (OVID)

1. exp Malaria/ or malaria.mp.
2. exp Chemoprevention/ or chemoprevention.mp.
3. chemoprophylaxis.mp.
4. prophylaxis.mp.
5. intermittent treatment.mp.
6. prevention.mp.
7. presumptive treatment.mp.
8. 2 or 3 or 4 or 5 or 6 or 7
9. 1 and 8
10. exp Antimalarials/
11. antimalaria$.mp.
12. 10 or 11
13. 8 or 12
14. exp Infant/ or infant.mp.
15. exp Child/ or child.mp.
16. 14 or 15
17. 13 and 16
18. limit 17 to human


Search strategy for EMBASE (OVID)

1. exp Malaria/ or malaria.mp.
2. exp Chemoprophylaxis/ or chemoprophylaxis.mp.
3. chemoprevention.mp.
4. prophylaxis.mp.
5. intermittent treatment.mp.
6. prevention.mp.
7. presumptive treatment.mp.
8. 2 or 3 or 4 or 5 or 6 or 7
9. 1 and 8
10. exp Antimalarial Agent/
11. antimalaria$.mp.
12. 10 or 11
13. 9 or 12
14. exp Infant/ or infant.mp.
15. exp Child/ or child.mp.
16. 14 or 15
17. 13 and 16
18. limit 17 to human

Sources of support

External sources of support

  • Department for International Development UK

Internal sources of support

  • University of Calabar NIGERIA

  • Liverpool School of Tropical Medicine UK

Ancillary