Background
The global burden and impact of severe malaria
The pathobiology of severe and cerebral malaria
Primary treatment of severe and cerebral malaria
The role of adjunctive therapy in severe malaria treatment
Search methodology
Author, year, country, references | Antimalarial | Adjuvant therapy | Dosage and route | Study design | Type of malaria | Ages | Sample size | Outcome |
---|---|---|---|---|---|---|---|---|
Immunomodulation | ||||||||
Warrell et al. 1982, Thailand, [31] | IV quinine | Dexamethasone | IV; children 0.6 mg/kg at the start followed by 7 doses of 0.2 mg/kg at 6-h intervals; adults 0.5 mg/kg at the start followed by 7 doses of 10 mg each (total duration of treatment 48 h) | RCT, DB, PC | CM | 6–70 years | 100 | Failed to decrease mortality. Increased risk of adverse events (prolonged coma, pneumonia and gastrointestinal bleeding) |
Hoffman et al. 1988, Indonesia, [32] | IV quinine | Dexamethasone | IV; initial dose, 3 mg/kg; total, 11.4 mg/kg per 48 h | RCT, DB, PC | CM | 1.5–42 years | 38 | No differences in mortality, parasite and fever clearance times or incidence of complications |
Taylor et al. 1992, Malawi, [34] | IV quinine | Immunoglobulin (IFAT antimalarial Ab) | IV; 400 mg/kg over 3 h | RCT, DB, PC | Coma | 1–12 years | 31 | Increased mortality but not statistically significant. No differences in parasite and fever clearance times or incidence of complications |
Havlik et al. 2005, Thailand, [36] | IV artesunate | Curdlan sulphate | IV; 4 mg/kg over 30 min/8 h (adjusted dose according to APTT) | RCT, DB, PC | SM but not CM (Phase IIB); SM and CM (Phase IIC) | 12–60 years | Phase IIB: 44; Phase IIC: 26 | No differences in mortality or parasite clearance times. Trend to improve duration of coma and fever clearance time |
van Hensbroek et al. 1996, The Gambia, [37] | IM quinine and IM artemether ± oral pyrimethaminesulfadoxine | anti-TNF mAb | IV; 5 mg/kg over 15 min | RCT, DB, PC | CM | 1–9 years | 624 | No differences in mortality, coma recovery or complications. Lower fever clearance time. Trend towards faster parasite clearance time. Higher rate of neurological sequelae |
Di Perri et al. 1995, Burundi, [38] | IV quinine | Pentoxifyline | IV; 10 mg/kg/24, 72 h | RCT | CM | < 14 years | 56 | Lower mortality not statistically significant. Significant reduction in coma recovery |
Das et al. 2003, India, [39] | IV quinine | Pentoxifylline | IV; 10 mg/kg/24, 72 h | RCT | CM | > 18 years | 52 | Improved mortality, not statistically significant. Significant reduction in coma recovery time |
Hemmer et al. 1997, Germany, [40] | 1. IV quinine + doxycycline; 2. oral mefloquine or halofantrine | Pentoxifylline | IV; 5 mg/kg/24 h for 5 days | RCT, DB, PC | UM and CM | 22–69 years | 51 | No differences in mortality, clinical outcomes or laboratory parameters. More side effects |
Looareesewam et al. 1998, Thailand, [41] | IV artesunate | Pentoxifylline | IV; low (0.83 mg/kg/h) or high (1.67 mg/kg/h) over 72 h | RCT, DB, PC | SM | 16–60 years | 45 | No significant differences in fever and parasite clearance time or in clinical outcomes |
Lell et al. 2005, Kenya, [42] | IV quinine | Pentoxifylline | IV; 10 mg/kg/24 h for 72 h | RCT, DB, PC | CM | 9 month–8 years | 15 | Higher mortality. No difference in coma recovery, incidence of complications or neurological sequelae. Trend to faster fever and parasite clearance times |
Decreasing procoagulant effects | ||||||||
Hemmer et al. 1991, Germany, [52] | 1. IV quinine + oral doxycycline or oral mefloquine; 2. IV quinine + oral doxycycline | Heparin or acetylsalicylic acid (ASA) | IV: Heparin 70 U/kg/day SC. for 5 days; ASA 500 mg on days 0, 2, 4 | RCT | SM | > 14 years | 97 | No difference in fever, parasite clearance, or time to discharge |
Decreasing cytoadherence and sequestration | ||||||||
Maude et al. 2014, Bangladesh, [57] | IV artesunate | Levamisole | Oral, 150 mg, single dose | RCT, OL | SM | 21–45 years | 56 | No differences in mortality, parasite clearance time, ‘sequestration ratio’ or normalization of plasma lactate |
Improving liver function | ||||||||
Treeprasertsuk et al. 2009, Thailand, [80] | IV artesunate | Ursodeoxycholic acid | IV; 750 mg/day, 2 weeks | RCT, DB, PC | SM with jaundice | > 15 years | 80 | Safe, but no differences between liver test, fever and parasite clearance times |
Restricting iron availability | ||||||||
Gordeauk et al. 1992, Zambia, [81] | IV quinine +oral pyrimethaminesulfadoxine | Deferoxamine | IV; 100 mg/kg/day over 72 h | RCT, DB, PC | CM | 20–54 months | 83 | Lower mortality, not statistically significant. Faster coma recovery time and parasite clearance time |
Thuma et al. 1998, Zambia, [82] | IV quinine | Deferoxamine | IV; 100 mg/kg/day over 72 h | RCT, PC | CM | < 6 years | 352 | Non-significant trend to faster recovery from coma. No statistical differences in mortality |
Mohanty et al. 2002, India, [83] | IV quinine and oral doxycycline | Deferiprone | Oral; 75 mg/kg/day in 12 hourly divided doses over 10 days | RCT, DB, PC | SM | 13–84 years | 45 | Faster fever, parasite clearance and coma recovery time. No differences in mortality |
Prevention of seizures | ||||||||
White et al. 1988, Thailand, [85] | IV quinine | Phenobarbital | IM; 3.5 mg/kg, single dose | RCT, DB, PC | CM | 6–78 years | 48 | Fewer convulsions |
Crawley et al. 2000, Kenya, [86] | IV quinine | Phenobarbital | IM; 20 mg/kg, single dose | RCT, DB, PC | CM | 19–65 months | 340 | Fewer convulsions. Higher mortality |
Decreasing intracranial pressure | ||||||||
Namutangula et al. 2007, Uganda, [91] | IV quinine | Mannitol | IV; 1 g/kg | RCT, DBO, PC | CM | 6–60 months | 156 | Did not significantly reduce time taken to regain consciousness, sit unsupported, or mortality |
Mohanty et al. 2011, India, [92] | Mannitol | IV; 1.5 g/kg over 15 min, followed by 0.5 g/kg every 8 h until the patient regained consciousness or for a maximum period of 72 h | RCT, OL, PC | CM with brain swelling | 25–31 years | 61 | Trend towards higher mortality in mannitol group. Mannitol prolonged coma recovery | |
Fluid resuscitation | ||||||||
Maitland et al. 2005, Kenya, [97] | IV quinine | Human albumin/saline | IV; 20 mL/kg of either 4.5% human albumin solution or 0.9% saline vs control (fluids maintenance group) | RCT, OL | SM with either moderate and severe acidosis | > 1 years | 150 | Safe and resulted in significantly lower mortality. Acidosis did not improve |
Akech et al. 2006, Kenya, [98] | IV quinine | Human albumin/gelofusine | IV; 20–40 mL/kg of either 4.5% human albumin solution or gelofusine | RCT, OL | SM | > 3 years | 88 | Trend to lower mortality, not statistically significant with albumin. No difference between shock and acidosis recovery. Higher neurological sequelae with albumin group |
Fluid resuscitation | ||||||||
Maitland et al. 2011, Uganda, Kenya, Tanzania, [99] | IV quinine | Human albumin/saline | 20 mL/kg of either 4.5% human albumin solution or 0.9% saline vs (fluids maintenance group) | RCT, OL | SM | 2 month–12 years | 1793 SM cases out of 3123 total sample size | Higher mortality in children treated with bolus |
Decreasing oxidative stress | ||||||||
Watt et al. 2002, Thailand, [105] | IV artesunate | N-Acetylcysteine | IV; 300 mg/kg over 20 h | RCT, DB, PC | SM | > 18 years | 30 | Faster normalization of lactate levels and Glasgow Coma Score |
Treeprasertsuk et al. 2003, Thailand, [106] | IV artesunate | N-Acetylcysteine | IV, oral: 3 different regimes | RCT, PC | SM | 14–16 years | 108 | No differences in mortality, fever and parasite clearance time. No differences in adverse events between groups |
Charunwatthana et al. 2009, Bangladesh, Thailand, [107] | IV artesunate | N-Acetylcysteine | IV; 300 mg/kg over 20 h | RCT, DB, PC | SM | 30–39 years | 108 | No differences in clearance of elevated plasma lactate levels, coma recovery times, mortality, fever clearance time, and complications or adverse events |
Correcting lactic acidosis | ||||||||
Khrisna et al. 1994, Thailand, [112] | IV quinine | Dichloroacetate | IV; 46 mg/kg, single dose | not stated | SM | > 14 years | 45 | Decreased lactate concentrations. No evidence of toxicity. Mortality, incidence of complications and clinical/parasitological measures of recovery did not differ |
Correcting lactic acidosis | ||||||||
Khrisna et al. 1995, Ghana, [113] | IM quinine | Dichloroacetate | IV; 50 mg/kg, single dose | RCT, OL, PC | SM | 1.5–12 years | 18 | Decreased lactate concentrations. No differences in mortality, fever or parasite clearance times |
Khrisna et al. 1996, Thailand, [114] | IV quinine | Dichloroacetate | IV; 46 mg/kg single dose | RCT, OL, PC | SM | > 14 years | 20 | No differences in mortality, greater decrease in lactate concentrations |
Agbenyega et al. 2003, Ghana, [115] | IV quinine | Dichloroacetate | IV; 50 mg/kg, single dose | RCT, DB, PC | SM | 1–12 years | 124 | Significantly reduced the concentration of blood lactate |
Increasing NO availability | ||||||||
Hawkes et al. 2015, Uganda, [119] | IV artesunate | Nitric Oxide | inhaled, 80 ppm | RCT, B, PC | SM | 1–10 years | 180 | No differences in levels of Ang-2. No differences in mortality, recovery rates or parasite clearance time |
Mwanga-Amumpaire et al. 2015, Uganda, [120] | IV artesunate | Nitric Oxide | inhaled, 80 ppm | RCT, OL, PC | CM | 2 month–2 years | 92 | Did not increase Ang-1, did not reduce mortality rate. Similar clinical outcomes and neurological sequelae between groups |
Adjunctive therapy for the treatment of severe and cerebral malaria in humans
Immunomodulation
Corticosteroids
Intravenous immunoglobulin
Curdlan sulfate
Anti-TNF therapy
Charcoal
PPAR-gamma agonists
Decreasing procoagulant effects
Decreasing cytoadherence and sequestration
Reduction of parasite biomass
Improving anaemia and liver function
Restricting iron availability
Prevention of seizures
Decreasing intracranial pressure
Fluid resuscitation
Decreasing oxidative stress
Correcting lactic acidosis
Reduced nitric oxide bioavailability
Novel strategies for adjunctive therapy delivery (preclinical murine models)
Author, year, reference | Adjuvant Therapy | Route of administration | Outcome of treatment administered after neurological symptoms |
---|---|---|---|
Inmunomodulation | |||
Waknine-Grinberg et al. 2013, [124] | Glucocorticosteroids in liposomes | i.v. injection | Improved survival, prevented ECM symptoms, improved clinical scores |
Dende et al. 2015, [127] | Curcumin | oral gavage | Improved survival, reduced parasitemia |
Neuroprotection | |||
Dai et al. 2012, [129] | Lithium chloride | injection (route not described) | Prevention of cognitive and motor deficits. Reduced long-term motor coordination impairment. No effect on survival or parasitemia |
Cabrales et al. 2010, [130] | Nimodipine | i.p. injection | Improved survival, improved motor score, reduced pial vasoconstriction |
Martins et al. 2013, [132] | Nimodipine | s.c. osmotic pumps | Improved survival, reduced BBB dysfunction, reduced inflammation |
Delivering gaseous signaling | |||
Orjuela-Sanchez et al. 2013, [133] | Glyceryl trinitrate | Transdermal patch | Improved survival, reversal of pial arteriolar vasoconstriction |
Improving endothelial function | |||
Higgins et al. 2016 [140] | Recombinant human Ang-1 | s.c. injection | Improved survival, prevents worsening of clinical outcomes, reduced cerebrovascular leak |
Wilson et al. 2013, [141] | Atorvastatin | i.p. injection | Improved survival, reduced systemic and cerebral inflammation, reduces endothelial activation and reduced cerebrovascular leak |
Dwivedi H et al. 2016, [145] | Vitamin D | i.m. injection | Improved survival, reduced cerebrovascular leak, reduced inflammation |