Table 1 Characteristics of included studies

Krishna 1994 [23]

Prosp

The Gambia; IPD; Research institute

1.5–12 years

115

18.3%

P. falciparum-positive blood film and one or more of the following features: BCS ≤2, parasitemia >100000/μL with 15%, or shock

Other causes of fever or altered consciousness (excluded by examination of blood culture and cerebrospinal fluid)

Included: hyperlactatemia, hypoglycemia, coma (BCS ≤2) Excluded: parasitemia, TNF, IL-1α

English 1996 [16]

Prosp

Kenya; pediatric ward

mean age:31 months

350

8.6%

P. falciparum and one or more of the following clinical symptoms: coma, prostration, hyperparasitaemia, respiratory distress

NR

Included: respiratory distress, deep breathing, nasal flaring, acidosis, chest indrawing

English 1997 [17]

Prosp

Kenya; pediatric ward

mean age 31 months

306

8.0%

P. falciparum and one or more of the following clinical syndromes: coma, prostration, hyperparasitaemia, respiratory distress

Death prior to admission assessment

Included: coma score Excluded: respiratory distress, acidosis, hyperparasitemia and prostration, respiratory distress and cerebral malaria

Assimadi 1998 [24]

Prosp

Togo; pediatric ward

0–15 years

549

18.9%

WHO (1995) criteria of severe malaria

NR

Included: renal failure, circulatory collapse, abnormal hemorrhage, jaundice, choluria, prostration, impaired consciousness, respiratory distress, hypoglycemia, convulsions, coma score, severe anemia, acidosis

Modiano 1998 [25]

Prosp

Burkina Faso; pediatric ward

6 months to 15 years

800

13.8%

WHO definition of severe malaria

Other detectable infections or causes

Included: prostration, coma, convulsions, anemia, hypoglycemia, pulmonary edema/respiratory distress, spontaneous bleeding, renal failure

Varandas 2000 [26]

RCT

Mozambique; pediatric ward

6–72 months

559

3.6%

Criteria for cerebral malaria: coma without a directional response to a painful stimulus 6 h after the last convulsion, clear CSF, parasitemia or positive PCR to P. falciparum; other forms of severe malaria: WHO criteria (1990) and confirmed by parasitemia

Children with a history of measles or measles vaccination in the 4 weeks preceding admission, clinical signs of vitamin A deficiency, signs of kwashiorkor or marasmus or other severe diseases

Included: age, respiratory distress on admission, acidotic breathing on admission, inability to localize painful stimulus on admission, convulsions before admission Excluded: maternal education, poor housing, loss of consciousness before admission, convulsions on admission, not-transfused children

Gérardin 2002 [27]

Prosp

Senegal; pediatric ward

0–15 years

215

12.1%

2000 WHO definition of severe malaria

NR

Included: thrombocytopenia Excluded (no differentiation between severe malaria and malaria): light cerebral disorder, cerebral malaria, convulsions, respiratory distress, severe anemia, jaundice, acidosis, hyperparasitemia, hemoglobinuria, renal failure (abnormal bleeding/collapse/pulmonary edema)

Imbert 2003 [28]

Prosp

Senegal; pediatric ward

<15 years

311

9.0%

P. falciparum trophozoites, WHO criteria of severe malaria

Simple malaria cases

Included: impaired consciousness, coma, respiratory distress, convulsions, jaundice, severe anemia, hyperparasitemia, hypoglycemia, prostration, hemoglobinuria, renal failure, shock, abnormal hemorrhage, pulmonary edema, pupillary anomalies, thrombocytopenia, leukocytosis, co-infection, hyperpyrexia Excluded: acidosis

Maitland 2003 [29]

Retro

Kenya; pediatric high-dependency unit

75% <36 months

515

12.8%

P. falciparum, and one or more of the following: prostration, coma, prolonged or recurrent seizures, respiratory distress, circulatory collapse, anemia, jaundice

NR

Included: impaired consciousness, acidosis, severe anemia, jaundice, hypoglycemia, sex, age, wasting, shock, deep breathing, convulsions Excluded: hypoglycemia

Mockenhaupt 2004 [30]

Prosp

Ghana; pediatric ward

6–102 months

285

11.2%

asexual P. falciparum parasitemia, and one or more of the following WHO (2000) criteria: severe anemia, prostration, respiratory distress, multiple convulsions, impaired consciousness, hemoglobinuria, clinical jaundice, circulatory collapse, abnormal bleeding, pulmonary edema

NR

Included: severe anemia, prostration, respiratory distress, convulsions, impaired consciousness, jaundice, circulatory collapse, hemoglobinuria, coma (BCS ≤2), hyperparasitemia, hypoglycemia, hyperlactatemia, hyperpyrexia

Dzeing-Ella 2005 [31]

Prosp

Gabon; tertiary referral center

0–10 years

576

8.9%

Age 0–10 years, more than two asexual forms of P. falciparum on blood film and one or more of the following features: BCS ≤2, convulsions, hyperlactatemia, hypoglycemia, severe anemia

Alternative diagnosis made clinically or by investigation (e.g., CSF examination, chest radiography, blood culture)

Included: coma, respiratory distress, severe anemia, hypoglycemia, hyperlactatemia, convulsions, sex

Gay-Andrieu 2005 [32]

Prosp

Niger; pediatric ward

3–60 months

114

21.0%

P. falciparum and at least one of the following clinical or biological criteria: coma (BCS ≤2), impaired consciousness (BCS >2 and <5), repeated convulsions, prostration, respiratory distress, jaundice, metabolic acidosis, severe anemia, hyperparasitemia, microscopic haemoglobinuria, renal failure, collapse, abnormal bleeding or pulmonary edema

NR

Included: coma, impaired consciousness, convulsions, respiratory distress, severe anemia, hypoglycemia, hyperparasitemia

Maitland 2005 [33]

RCT

Kenya; pediatric high-dependency unit

median age 2.8 years

150

0.1%

Clinical feature of severe malaria (i.e., prostration, coma, or respiratory distress), and P. falciparum parasitemia and metabolic acidosis (base deficit >8 mmol/L) and Hb >50 g/L

Pulmonary edema, edematous malnutrition, papilledema

Included: acidosis

Zeidan 2005 [34]

Prosp, cx

Sudan; IPD

<15 years

543

2.6%

Identification of P. falciparum in blood film and presence of any of combined complications of change of behaviors, confusion or drowsiness, altered consciousness or coma, convulsions, hypoglycemia, acidosis, difficulty in breathing, pulmonary edema, oliguria, acute renal failure, severe anemia (hematocrit <20%, Hb <6 g/dL), haemoglobinuria, jaundice, tendency to bleed, and generalized weakness rendering the patient unable to walk or sit up without assistance

NR

Included: prostration, age, hyperpyrexia, convulsions, leukocytosis, coma Excluded: delays, jaundice, anemia, hepatomegaly, splenomegaly, hypoglycemia, hemoglobinuria, fever, vomiting

Bronzan 2007 [35]

Retro

Malawi; pediatric research ward,

≥6 months

1388

16.0%

Presenting one of three severe malaria syndromes: CM, SMA, or CM with SMA and confirmed by P. falciparum blood film test

Other identifiable causes of coma (such as hypoglycemia, postictal state, and meningitis)

Included: severe anemia, cerebral malaria (BCS ≤2 persisting for >2 hours after other identifiable causes of coma have been excluded), HIV infection

Issifou 2007 [36]

Prosp

Gabon; medical research unit; IPD

1–120 months

2235

3.0%

Age 1–120 months, “non per os” falciparum malaria (patients hospitalized for malaria and treated with intravenous quinine in a 10% glucose infusion)

NR

Included: coma (BCS ≤2), hypoglycemia, severe anemia, respiratory distress

Oduro 2007 [37]

Prosp

Ghana; IPD

6–59 months

868

3.5%

1990 and 2000 WHO severe malaria criteria

NR

Included: coma (BCS <3), severe anemia, respiratory distress, hyperlactatemia, hypoglycemia

Orimadegun 2007 [38]

Retro

Nigeria; tertiary hospital

6 months to 15 years

1806

6.9%

2000 WHO severe malaria criteria

NR

Included: severe anemia, coma (BCS <3), sex Excluded: hypoglycemia, respiratory distress

Bassat 2008 [39]

Retro

Mozambique; district hospital

<15 years

1100

4.4%

Malaria case with at least one of the following criteria: PCV <15%, deep coma (BCS ≤2), prostration, hypoglycemia, convulsions, respiratory distress

Children with malaria parasitaemia for whom the cause of death was not malaria were not considered severe malaria cases

Included: severe anemia, coma, convulsions, hypoglycemia, prostration, respiratory distress, impaired consciousness, jaundice, dehydration

Ranque 2008 [40]

Prosp

Mali; pediatric ward

<15 years

455

16.0%

Fever >38 °C and P. falciparum trophozoites, and no suggestion of other diagnosis; all children diagnosed with CM and/or SMA

NR

Included: fever >4 days, personal history of CM, CM history in siblings, coma score, severe anemia, hypoglycemia, dehydration, spleen enlargement, liver enlargement, prior antimalarial treatment, respiratory distress, age group, sex

Ogetii 2010 [41]

Retro

Kenya; pediatric high-dependency unit

0–12 years

1236

10.5%

P. falciparum parasitemia plus impaired consciousness and/or respiratory distress

Children admitted to the general ward with malaria parasitaemia who deteriorated after admission fulfilling the definition of severe malaria

Included: hypoglycemia

Camara 2011 [42]

Prosp

Senegal; pediatric ward

0–15 years

162

11.1%

Aged 0–15 years, P. falciparum-positive thick drop examination and at least one of the WHO 2000 malaria severity criteria

All children with anti-malarial treatment started less than 72 hours prior to hospitalization

Included: sex, age, impaired consciousness, prostration, respiratory distress, coma, shock, convulsions, jaundice, hypoglycemia, thrombocytopenia, severe anemia, hemoglobinuria

Hendrikson 2012 [15]^a

RCT

Mozambique; tertiary referral hospital

<15 years

655

10.9%

Children (<15 years) with suspected severe malaria according to modified WHO clinical criteria, positive pLDH-based RDT

If treated parenterally for >24 hours before admission

Included: HIV infection

Hendriksen 2012 [14]^a

RCT

Mozambique, Gambia, Kenya, Tanzania, Uganda, Rwanda, DRC; pediatric wards

1 month to 15 years

3826

9.9%

Positive P. falciparum histidine-rich protein two-based rapid test (Optimal), and at least one of coma, prostration, convulsions, compensated shock, decompensated shock, severe respiratory distress, hypoglycemia, severe symptomatic anemia, blackwater fever, clinical jaundice, hyperparasitemia

If treated parenterally for >24 hours before admission

Included: acidosis, severe anemia, hypoglycemia, hyperparasitemia Excluded: respiratory distress, coma, convulsions, jaundice, shock, black water fever

Jallow 2012 [18]

Prosp obser

Gambia; pediatric ward

4 months to 14 years

2901

13.0%

Asexual P. falciparum parasitemia, and one or more of the following WHO criteria for severe malaria: severe anemia, respiratory distress, hypoglycemia, decompensated shock, repeated convulsion, acidosis, hyperlactatemia

NR

Included: acidosis, coma score, convulsions, severe anemia, hyperalactatemia, hyperparsitemia, hyperpyrexia, hypoglycemia, impaired consciousness, deep breathing, jaundice, liver enlargement, prostration, renal failure, respiratory distress, shock, spleen enlargement

von Seidlein 2012 [13]^a

RCT

Gambia, Mozambique, Nigeria, Rwanda, Kenya, DRC, Tanzania, Ghana, Uganda; pediatric wards

<15 years

5426

9.7%

Positive P. falciparum histidine-rich protein two-based rapid test (Optimal), and at least one of coma, prostration, convulsions, compensated shock, decompensated shock, severe respiratory distress, hypoglycemia, severe symptomatic anemia, blackwater fever, clinical jaundice, hyperparasitemia

If treated parenterally for >24 hours before admission

Included: convulsions, prostration, coma shock, respiratory distress, deep breathing, jaundice, chronic disease, sex, black water fever Excluded: blood urea nitrogen, base excess, pH, respiratory rate, parasite density, hemoglobin, glucose level, temperature, age, heart rate

Kendjo 2013 [19]^b

Prosp, cx

Sub-Saharan Africa; hospital research centres

<15 years

26 296

4.3%

Severe P. falciparum malaria

NR

Included: seizures prior to admission, vomiting prior to admission, deep breathing, indrawing, irregular breathing, prostration, coma, hyperparasitemia, severe anemia, hypoglycemia Excluded: hyperlactatemia

Orimadegun 2014 [43]

Prosp, cx

Nigeria; tertiary hospital

<5 years

369

8.1%

P. falciparum malaria parasitaemia confirmed with blood film microscopy and the presence of any of the defined life-threatening features for malaria according to WHO (2000)

Children who had clinical signs suggestive of cardiac defect and those whose parents refused consent

Included: severe anemia, hyperparasitemia, acidosis, hemoglobinuria, hypoglycemia, coma score, renal impairment, hypoxia Excluded: hypokalemia, hyponatremia, pneumonia, azotemia, wasting