Background
Each year one to two million people die from malaria, with half of these deaths occurring among children infected with the Plasmodium falciparum malaria parasite in sub-Saharan Africa (Wyler 1992; WHO 2000). Cerebral malaria is the commonest fatal syndrome of P. falciparum malaria, and mortality can be as high as 50% (WHO 2000). Death and sequelae occur even in people treated with antimalarial drugs, and researchers are exploring the effects of adding treatments to the main antimalarial regimens in an effort to reduce mortality.
Iron chelation is one potential adjuvant treatment. The biological rationale for iron chelation is that malaria parasites require iron to reproduce, so drugs that withhold available iron from the malaria parasite could inhibit its reproduction rate (Wyler 1992; Mabeza 1996). Other indirect evidence of a potential effect comes from experimental studies that suggest iron supplementation exacerbates malaria infection (Murray 1975; Oppenheimer 1984), and observational studies that have led the authors to conclude that iron deficiency is protective (Murray 1978; Raventos 1982). Theory also suggests that iron-chelation therapy may accelerate coma recovery by inhibiting iron-induced damage to brain cells, thus protecting against damage to the central nervous system (Mabeza 1996).
Desferrioxamine (DFO) is the standard iron-chelating agent in clinical use. It works by entering malaria parasites and combining (chelating) with available iron (Hider 1994; Lytton 1994; Mabeza 1996). It is generally regarded as a safe drug despite known adverse effects (eg neutropenia, haematological toxicity, transient headaches, dizziness, myalgia, and malaise) and reports of serious auditory and visual neurotoxicities in long-term therapy (Olivieri 1996). However, it is considered of little use in most malarious areas because it is expensive, has to be given intravenously, and penetrates infected red blood cells slowly (Wyler 1992; Hershko 1994).
Other iron-chelating agents are being considered, such as the orally active deferiprone. However, before iron-chelating agents are used as adjuvant treatments for malaria, it is important to assess that their antimalarial action is complementary and not antagonistic to standard therapy. In vitro and animal experiments suggest that iron-chelating agents and artemisinin-class antimalarial drugs might be less effective when used simultaneously (Meshnick 1993). Therefore, studies of iron chelator and artemisinin drugs used together will be carefully scrutinized to detect any inhibitory effects of the iron chelator on the action of artemisinin.
Objectives
To evaluate iron-chelating agents alone or combined with standard antimalarial drugs for treating P. falciparum malaria.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials.
Types of participants
Adults and children with P. falciparum malaria confirmed by a blood slide.
Types of interventions
- Iron-chelating agents versus placebo.
- Iron-chelating agents plus antimalarial drugs versus antimalarial drugs alone.
Types of outcome measures
- Death.
- Coma recovery (time to recover consciousness).
- Persistent seizures (more than three).
- Parasite clearance time (time to 50% clearance).*
- Parasite clearance at day three.*
- Parasitaemia (parasite concentration).*
- Adverse effects: local effects (at site of injection/infusion); systemic effects (toxic effects, nausea, visual disturbance, headache, abdominal pain, other).*
*Measures used for people with asymptomatic malaria.
Search methods for identification of studies
We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
We searched the following databases using the search terms and strategy described in Table 1: Cochrane Infectious Diseases Group Specialized Register (May 2007); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2007, Issue 2); MEDLINE (1966 to May 2007); EMBASE (1980 to May 2007); and LILACS (1982 to May 2007). We also searched the metaRegister of Controlled Trials (mRCT) using 'malaria' and 'chelat*' as search terms.
We checked the reference lists of all studies identified by the above methods. We also contacted experts and individuals actively involved in malaria research for additional references and unpublished studies, and asked external referees to check the completeness of the search strategy and identify additional unpublished, ongoing, or planned trials.
Data collection and analysis
Selection of studies
We independently assessed the full text of all potentially relevant trials and applied the inclusion criteria. Any disagreement about inclusion of trials was resolved by discussion.
Data extraction and management
H Smith extracted data from the included trials. We contacted trial authors requesting original data; one author supplied a comprehensive account of his studies allowing some quantitative analysis.
Assessment of risk of bias in included studies
We independently assessed the risk of bias in the trials. We assessed the generation of allocation sequence and allocation concealment to be adequate, inadequate, or unclear (Jüni 2001). We classified blinding as double, single, or not blinded, and described who was blinded where this information was available. We considered the inclusion of all randomized participants in the analysis as adequate if greater than 90%, inadequate if less than 90%, or unclear.
Data synthesis
We used Review Manager 5 to analyse data. We assessed the estimates of effect using risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and presented both with 95% confidence intervals (CI). We pooled data using a fixed-effect model. We stratified the results by malaria severity − severe malaria, asymptomatic malaria, and symptomatic malaria.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Eligibility
Seven trials involving 570 participants met the inclusion criteria (see 'Characteristics of included studies'). Thuma 1998b reported two cross-over trials, which we treated as two separate trials (Thuma 1998b-i; Thuma 1998b-ii). Thuma 1998a, conducted at two centres in Zambia, was treated as one for the analysis. One trial was published in reported in two articles with no cross-referencing (Gordeuk 1992b). Four studies were excluded for the reasons given in the 'Characteristics of excluded studies'.
Location
Mohanty 2002 was conducted in India, and the other trials were conducted in Zambia.
Participants
Thuma 1998a and Gordeuk 1992b looked specifically at children less than six years old with cerebral malaria. Mohanty 2002 studied people aged 13 to 84 years with P. falciparum infection and fever. Thuma 1998b-i, Thuma 1998b-ii, Gordeuk 1992a, and Gordeuk 1993 included adults with asymptomatic P. falciparum infection; Thuma 1998b-i and Thuma 1998b-ii included adult males only.
Interventions
Four trials compared DFO with placebo. In the two trials in children with cerebral malaria (Gordeuk 1992b; Thuma 1998a), DFO (100 mg/kg/day intravenously for 72 hours) or placebo was added to standard therapy with quinine. Quinine dosage was the same in both trials, but Thuma 1998a gave an initial loading dose of 20 mg/kg. Gordeuk 1992a and Gordeuk 1993, which studied people with asymptomatic malaria, compared DFO (100 mg/kg/day) and placebo (normal saline) administered by continuous subcutaneous infusion over 72 hours via battery-operated pumps.
Three trials compared deferiprone with placebo. Thuma 1998b-i and Thuma 1998b-ii were cross-over trials, but we used only the results from the initial trial periods for the purpose of this review. The intervention group in the Thuma 1998b-i received deferiprone (75 mg/kg/day) divided into doses given every eight hours for an initial 72-hour period. In Thuma 1998b-ii, deferiprone (100 mg/kg/day) was administered every six hours for 96 hours. The participants in Mohanty 2002 received either deferiprone (75 mg/kg/day orally in doses every 12 hours) plus standard quinine and doxycycline therapy or placebo capsules plus the same antimalarial therapy.
Outcome measures
All of the prespecified outcome measures were reported on by at least one of the trials. We also added persistent seizures (more than three) and parasitaemia (parasite concentration) because the included trials provided useful information on these outcome measures.
Gordeuk 1992b and Thuma 1998a reported median time to coma recovery; they treated the data as continuous and implied a skewed data set, which meant that we could not include these in meta-analyses. We contacted the trial authors, and Thuma 1998a provided the mean and standard deviation for survivors; the mean was less than the standard deviation in each treatment group, thus confirming the skewed nature of the data. Time to coma recovery constitutes time-to-event data and should be analysed as such. To pool the results from both trials requires log-hazard ratios, which give a measure of treatment effect. We contacted the trial authors for this information when the review was first prepared (1999), but we have not received these additional data.
Gordeuk 1992b and Thuma 1998a both reported parasite clearance rate rather than clearance time, and it is unclear how the 'rates' were calculated.
Trials of DFO versus placebo in asymptomatic persons and deferiprone versus placebo reported mean (and standard error of the mean) parasite concentration only.
Risk of bias in included studies
One trial used an adequate method (random-number table) to generate the allocation sequence (Mohanty 2002). The method was unclear in the other trials despite purporting to be randomized.
Three trials reported adequate measures to conceal allocation. Participants in Gordeuk 1992b and Thuma 1998a were randomized centrally by pharmacy staff, and Mohanty 2002 used serial numbering. The other four trials did not mention procedures to conceal allocation.
All trials were reported as double blind and used a placebo. Three trials reported that only the pharmacist knew the code to treatment allocation (Thuma 1998a; Thuma 1998b-i; Thuma 1998b-ii), but this was only discovered after communication with the trial author .
The inclusion of all randomized participants in the analysis was adequate in six trials: it was 100% in five trials (Gordeuk 1992a (for the initial period of this cross-over trial analysed in this review); Gordeuk 1992b; Gordeuk 1993; Thuma 1998a; Mohanty 2002); and 92.3% in Thuma 1998b-i. Thuma 1998b-ii included 83.3%, which we consider inadequate, after two participants in this trial of 12 participants withdrew for personal reasons.
Effects of interventions
1. DFO versus placebo (plus standard antimalarial regimen): severe malaria
Gordeuk 1992b and Thuma 1998a compared DFO (100 mg/kg/day) with placebo (both in addition to a standard antimalarial drugs) for children less than six years old.
Death
Both trials reported on deaths, and Thuma 1998a was stopped early on the recommendation of the safety and data monitoring committee since more were reported in the DFO group. While trials stopped early can sometimes introduce bias if due to a trend in the results of a spurious study, in this trial, however, the risk of death was significantly increased in the DFO group (RR 1.70, 95% CI 1.00 to 2.89; 352 participants, Analysis 1.1), therefore systematic error is unlikely. Overall, the pooled estimate indicates an increased risk of death in the DFO group (435 participants, 2 trials, Analysis 1.1), but this is not statistically significant.
Coma recovery
Both trials reported the estimated median time to recovery and rate of recovery (see Table 2). This suggests that the trialists treated time to coma recovery as a continuous variable rather than using survival data methods; and we have not received details of any time-to-event analyses from the trial authors. Gordeuk 1992b reported an estimated median time to recovery of 20.2 hours (41 participants) in the DFO group and 43.1 hours (42 participants) in the placebo group (P = 0.38). The rate of recovery of consciousness was 1.3 times faster in the DFO group in Gordeuk 1992b and an estimated 1.2 times faster in the DFO group in Thuma 1998a.
Persistent seizures
The risk of experiencing persistent seizures was significantly lower with DFO (RR 0.80, 95% CI 0.67 to 0.95; 334 participants, 1 trial, Analysis 1.2); data provided by the Thuma 1998a authors upon request.
Parasite clearance
The rate was two times faster with DFO than in the placebo group (95% CI 1.2 to 3.6) in Gordeuk 1992b (see Table 3). In contrast, it was faster in the placebo group in Thuma 1998a (see Table 3), but this difference was not statistically significant. It is unclear how the trialists calculated these rates.
Parasite clearance at day three
There was no statistically significant difference in the number of participants with parasite clearance at day three (300 participants, 1 trial, Analysis 1.3); data provided by the Thuma 1998a authors upon request.
Adverse effects
Gordeuk 1992b stated explicitly that no toxic reaction or side effect could be attributed to DFO. Paresis was observed in two surviving children at the time of discharge, but both were in the placebo group.
The Thuma 1998a trial author provided additional data on a range of adverse effects. There were two adverse effects that the trial authors (and external referees) thought were most likely to be directly attributable to DFO treatment, but there was no statistically significant difference compared with placebo: phlebitis (inflammation of the vein wall) (344 participants, 1 trial, Analysis 1.4); and recurrent hypoglycaemia (334 participants, 1 trial, Analysis 1.5).
2. DFO versus placebo: asymptomatic malaria
Gordeuk 1992a and Gordeuk 1993 compared DFO (100 mg/kg/day) with placebo in adults with asymptomatic P. falciparum. Both trials administered treatments via subcutaneous infusion over 72 hours.
Parasitaemia
Gordeuk 1992a reported significant decreases in geometric mean concentrations of parasites in both the DFO group (P = 0.0001; 12 participants) and placebo group (P = 0.002; 12 participants) during the initial trial period (see Table 4). The magnitude of the decline in mean parasite concentration with DFO treatment was significantly greater than the decline with placebo (P = 0.005).
Gordeuk 1993 reported that mean parasite concentrations decreased significantly in the DFO group (P < 0.001; 16 participants; see Table 4). Notably, during the week following administration of DFO or placebo (days three to 10), parasite concentrations remained significantly lower in those who received DFO (P = 0.009), but mean parasitaemia did not change significantly.
Adverse effects
Gordeuk 1992a noted that no toxicity was detected during the DFO infusions (see Table 5). Participants reported mild swelling and pain at the site of needle insertion in 22/25 subcutaneous administrations of DFO, but only in 10/25 administrations of placebo − a statistically significant difference (P < 0.05). Gordeuk 1993 did not report any local or systemic adverse effects, despite reporting that participants were examined and questioned regarding adverse effects twice a day (see Table 5).
3. Deferiprone versus placebo: asymptomatic persons
Thuma 1998b-i and Thuma 1998b-ii compared deferiprone (75 mg/kg/day or 100 mg/kg/day respectively) with placebo in adult males with asymptomatic P. falciparum.
Parasitaemia
Neither trial reported a significant decrease in parasite concentration in either the deferiprone or placebo groups (see Table 6).
Adverse effects
Both trials used open questioning of participants to identify possible adverse effects during the study period. Details of five adverse effects were provided. Overall, there was no statistically significant difference (after the trial authors applied the Bonferroni correction) in the number of participants in the two groups experiencing abdominal pain (44 participants, 2 trials, Analysis 2.1), dizziness (44 participants, 2 trials, Analysis 2.3), myalgia (20 participants, 1 trial, Analysis 2.4), and malaise (24 participants, 1 trial, Analysis 2.5), but the sample sizes were small. There was, however, a significant increase in the number of participants with headache in the DFO group (RR 8.00, 95% CI 1.08 to 59.05; 44 participants, Analysis 2.3).
4. Deferiprone versus placebo (plus standard antimalarial regimen): symptomatic persons
Mohanty 2002 compared deferiprone (75 mg/kg/day) with placebo (both groups also received a standard antimalarial regimen) in 45 participants aged 13 to 84 years with P. falciparum infection and fever.
Death
There was no statistically significant difference in the number of deaths between the two groups (45 participants, Analysis 3.1).
Coma recovery time
Participants in the deferiprone group recovered from coma faster that those in the placebo group (MD -27 h, 95% CI -34.20 to -19.80; 45 participants, Analysis 3.1).
Parasite clearance time
Mean time to parasite clearance was significantly faster in the deferiprone group (MD -24 h, 95% CI -35.27 to -12.73; 45 participants, Analysis 3.3).
Adverse effects
The trial authors stated explicitly that deferiprone was reasonably well tolerated in the dose given and had no adverse effects. They also noted that agranulocytosis (a known adverse effect of deferiprone) was not observed during the study.
Discussion
Strength of evidence
We identified only seven trials of iron-chelating agents used in conjunction with standard antimalarial drugs (three trials) or as single agents (four trials). The strength of evidence is affected by the small sample sizes used; any effect would have to be dramatic to detect a difference between the treatment groups. Concealment of allocation was inadequate in four of the included trials, which increases the likelihood of selection bias and exaggerated estimates of treatment effects (Schulz 1995). Poor graphical presentation of continuous data meant interpretation of results for some outcomes was difficult.
Is death less likely in those treated with iron-chelating agents?
The available evidence from one trial of people with severe malaria suggests that DFO is harmful (Thuma 1998a), while the other trial suggests there is no adverse or beneficial effect of DFO (Gordeuk 1992b). To address the inconsistent evidence of the effect of DFO on death will require further large randomized trials of people, but justification for such trials will depend on a belief of potential benefit from iron-chelating agents.
One trial of deferiprone found fewer deaths in the deferiprone group (Mohanty 2002), but the difference was not statistically or clinically significant because of the small number of study participants.
Does adjunctive iron-chelation therapy shorten coma recovery time?
It is inappropriate to comment on the effect of DFO on coma recovery since the available results were reported as continuous data. In one trial of deferiprone for people with symptomatic malaria, coma recovery was significantly faster in the deferiprone group (Mohanty 2002).
Are persistent seizures less likely with adjunctive DFO treatment?
The results from one trial indicate that adjunctive DFO treatment has a significant association with a reduction in the incidence of persistent seizures in children less than six years old with severe malaria (Thuma 1998a).
Do iron-chelating agents have an effect on parasitaemia?
The results are inconclusive for people with severe malaria. Trialists need to report parasitaemia effects in a consistent way to allow data to be pooled.
In trials of DFO alone versus placebo in people with asymptomatic malaria, means and standard error of the means were reported for parasite concentration. The evidence indicates that participants treated with DFO experienced a significant decrease in mean parasite concentration compared to those taking placebo or no treatment.
Two trials of deferiprone in people with asymptomatic malaria reported means and standard error of the means for parasite concentrations. The results showed no evidence of an effect on parasitaemia. To detect even a 40% reduction in parasites would require at least eight participants in each arm of the 75 mg/kg trial and 11 in each arm of the 100 mg/kg trial (Thuma 1998b-i; Thuma 1998b-ii). The actual numbers used were much smaller. The investigators proposed that, given the low numbers, it is possible the antimalarial effect of deferiprone was not found due to a type II error.
In one trial of deferiprone in people with P. falciparum infection and fever (Mohanty 2002), mean time to parasite clearance was significantly faster in the deferiprone group, but it is difficult to determine clinical significance from the small number of study participants.
What are the adverse effects associated with iron-chelating agents?
Hypoglycaemia, phlebitis, and swelling and pain at the site of needle insertion were observed in the DFO trials. All these effects were more common in the participants treated with DFO, but due to the small numbers randomized in the trials we cannot comment on the clinical significance of these results. It should be noted that in one trial, Gordeuk 1992a, participants were questioned regarding adverse effects twice daily, but facilities for thoroughly assessing auditory and visual neurotoxicities were not available. Such effects have been detected in patients receiving long-term DFO therapy (Olivieri 1996), but the trial authors suggested the short-term nature of this trial probably lessens the risk of such complications. Therefore, until further trials can confirm that neurological adverse effects are not associated with DFO therapy, adverse effect data should be regarded as incomplete and interpreted with caution.
Headaches and dizziness occurred more frequently in those receiving deferiprone compared to placebo. Abdominal pain, myalgia, and malaise did not differ significantly between the treatment groups. Neutropenia has been observed in other studies of deferiprone (75 to 100 mg/kg/day or more), but only in iron-overloaded patients over a long period (Berdoukas 1993). Another adverse effect associated with deferiprone is haematological toxicity, which may be idiosyncratic (Thuma 1998b-i; Thuma 1998b-ii). No data were available for these effects in trials of deferiprone in malaria, which signifies the need to confirm (in future trials) whether or not persons treated with this iron-chelating agent are likely to experience such effects.
Applicability
Trials of iron-chelating agents as adjunctive treatments for malaria were prompted by the fact that cerebral malaria remains a major cause of death in African children despite treatment with standard antimalarial drugs. All trials included in this review, except one small trial in India, were conducted in Zambia. This limits our ability to comment on the wider relevance of iron-chelating agents to populations in other malarious areas.
Trials of DFO in malaria do show positive (but not statistically significant) results; however, it may not be the ideal iron-chelating agent for use in malaria. Parenteral administration is required due to the poor absorption of DFO, so its use is unlikely in uncomplicated malaria or areas where equipment is not readily available. The drug is also expensive and requires continuous administration for optimal effectiveness, limiting its use in most malarious areas of Africa and Asia.
Authors' conclusions
Implications for practice There are insufficient data to draw conclusions about the effect of the DFO or deferiprone iron-chelating agents. |
Implications for research In view of the tendency in one trial for DFO to be associated with more deaths, and given the paucity of recent trials in this area (most recent trial published in 2002) and other priorities in malaria treatment research, new trials in this area are unlikely and we do not plan to update this review. |
Acknowledgements
We thank D Lalloo, H McIntosh, M Molyneux, and P Winstanley for helpful comments; and PE Thuma for kindly supplying original data. This document is an output from a project funded by the Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
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What's new
Last assessed as up-to-date: 16 February 2003.
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History
Protocol first published: Issue 2, 1999
Review first published: Issue 4, 1999
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Contributions of authors
We independently applied inclusion criteria, assessed trial methodological quality, and extracted data. H Smith entered data into Review Manager, analysed the data, and co-wrote the review. M Meremikwu helped analyse the data and co-wrote the review.
Declarations of interest
None known.
Sources of support
Internal sources
- Liverpool School of Tropical Medicine, UK.
External sources
- Department for International Development (UK), UK.
- European Commission (Development Directorate XII, Grant IC 18 CT 96 0086), Belgium.
Index terms
Medical Subject Headings (MeSH)
Antimalarials [*therapeutic use]; Chemotherapy, Adjuvant; Iron Chelating Agents [*therapeutic use]; Malaria, Cerebral [drug therapy]; Malaria, Falciparum [drug therapy]; Randomized Controlled Trials as Topic
MeSH check words
Adult; Child; Humans
* Indicates the major publication for the study