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e-mail: [email protected]: http://www.cmp.dk
Severe and complicated malariaSevere and complicated malaria
Jørgen KurtzhalsCentre for Medical Parasitology
Rigshospitalet, Copenhagen, Denmark
e-mail: [email protected]: http://www.cmp.dk
Cerebral malaria kills ½-1 million children every Cerebral malaria kills ½-1 million children every yearyear
e-mail: [email protected]: http://www.cmp.dk
Correct treatment: 85% survival Correct treatment: 85% survival – most without sequelae– most without sequelae
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15% of cerebral malaria patients die15% of cerebral malaria patients die
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The asexual parasite multiplication cycleThe asexual parasite multiplication cycle
Ring-stage trophozoite
Mature trophozoite
Schizont (segmenter)
Free merozoites
Trophozoite maturation
Schizogony
Rupture
Re-invasion
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Spleen
Vascular endothelium
Sequestration interferes with splenic removal Sequestration interferes with splenic removal of schizont-infected erythrocytesof schizont-infected erythrocytes
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Sequestration of erythrocytes in the brainSequestration of erythrocytes in the brain
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Cerebral malaria – clinical featuresCerebral malaria – clinical features
• P. falciparum – often (not always) high parasitaemia
• High temperature – (or hypothermia)
• Impaired consciousness
• From prostration and convulsions -> deep coma
• Convulsions
• Partial motor seizures
• Convulsions is a bad sign
• Classical definition of cerebral malaria
• Unrousable coma
• Mortality 5-15%
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Cerebral malaria - diagnosisCerebral malaria - diagnosis
• Exclusion diagnosis
• Other manifestations of malaria (may co-exist)• Hypoglycaemia• Hyponatriaemia• Multi-organ failure• Prolonged post-ictal state
• Other infections (may co-exist!)• Meningitis• Sepsis
• Metabolic diseases (e.g. DM)
• Neurologic diseases
• Head trauma
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Cerebral malaria – treatmentCerebral malaria – treatment
• Effective anti-malarial – i.v. quinine
• Alternative: artemisinin, artesunate… i.v. or rectal
• Anti-convulsive therapy
• Only when clinically indicated (respiration depression)
• Avoid hypoglycaemia
• Ensure vital functions
• Correct electrolyte derangement
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Severe anaemia - pathogenesisSevere anaemia - pathogenesis
• Erythrocyte destruction during schizogony
• Erythrophagocytosis in spleen• Hypersplenism• Immune mediated
• Bone marrow suppression• TNF/IL-10 ratio• Reversible
Spleen
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Severe anaemiaSevere anaemia
• P. falciparum – often, not always, high parasitaemia
• Often prolonged duration
• Hb < 5 g/dl (3 mmol/l)
• Lactic acidosis – ’respiratory distress’
• Hypovolaemia
• Haemolysis
• Hyperbilirubinaemia
• Haemoglobinuria
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Severe anaemia – treatmentSevere anaemia – treatment
• Effective anti-malarial treatment
• Parasite clearance restores bone marrow function
• Blood transfusion
• At >20% parasitaemia ~ exchange transfusion
• Optimise circulation and oxygenation
• Keep high urinary output
• Caveat: do not precipitate pulmonary oedema
• General supportive treatment
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Other severe complicationsOther severe complications
• Pulmonary oedema
• ARDS
• Renal insufficiency
• Haemolysis
• Thrombocytopaenia, DIC
• Superinfections
• Septicaemia
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Recommended laboratory investigationsRecommended laboratory investigations
• Blood film (x3)
• Blood culture
• Hb, thrombocytes, WBC and differential count
• Na, K, creatinine
• Bilirubin, ASAT, factor II-VII-X, LDH
• Glucose
• (Arterial blood gas, lactate)
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Case 1Case 1
• 53 year old male civil engineer, resident in Ghana for 6 years.
• No malaria prophylaxis due to fear of side effects (and general opposition toward doctors)
• During field work feeling feverish, treated with aspirin
• Returned after 5 days. Wife finds the patient extremely ill looking and rushes him to hospital
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Case 1 (ctd.)Case 1 (ctd.)
• On arrival pale, acutely ill, tp. 41.2oC, slow cerebrated
• Blood film: 17% P. falciparum (ring stages)
• Hb 8.2 g/dl, thrombocyte count 46, WBC normal range
• Creatinine 320 mol/l, Na 120 mmol/l, K 4.0 mmol/l
• Glucose 3.8 mmol/l
• Treatment suggestion?
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Case 1 (ctd.)Case 1 (ctd.)
• Quinine 10 mg/kg infusion in 5% dextrose/saline over 4 h stat.
• Quinine 10 mg/kg infusion tds
• After parasite clearance (marked reduction) continue oral quinine at same dosage for 7 days
• Alternatively doxycycline 100 mg/day for 7 days
• CAVE! Never use mefloquine after quinine
• Other necessary measures?
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Case 1 (ctd.)Case 1 (ctd.)
• Hyponatraemia treated with isotonic saline and frusemide
• Renal function did not deteriorate but was normalised after rehydration
• Follow blood glucose carefully
• Thrombocytes normalised after parasite clearance
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Theories about pathogenesis of cerebral malariaTheories about pathogenesis of cerebral malaria
• Impaired cerebral blood flow?
• Sequestration of infected RBC in blood vessels
• Histological picture
• Ophthalmoscopy
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Near infrared spectrophotometry (NIRS)Near infrared spectrophotometry (NIRS)
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ScOScO22 on admission on admission
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Theories about pathogenesis of cerebral malariaTheories about pathogenesis of cerebral malaria
• Impaired cerebral blood flow?
• Regional blood flow changes
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Theories about pathogenesis of cerebral malariaTheories about pathogenesis of cerebral malaria
• Generalised excessive inflammation
• High TNF levels
• Association with TNF promoter polymorphism
• Animal experiments
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Clin Exp Immunol 1998; 112: 303-307
CM SA UM
Eosinophil cationic protein (ng/ml)
2
3
4
5
6789
1
10 Day 0Day 30
***
Increased levels of inflammation markers in Increased levels of inflammation markers in cerebral malariacerebral malaria
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Theories about pathogenesis of cerebral malariaTheories about pathogenesis of cerebral malaria
• Impaired cerebral blood flow?
• Regional blood flow changes
• Excessive inflammation
• Regional inflammation
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Theories about pathogenesis of severe malarial Theories about pathogenesis of severe malarial anaemiaanaemia
• Destruction of erythrocytes
• Schizogony
• Infected cells removed in spleen
• Uninfected cells removed in spleen
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Complement binding to erythrocytesComplement binding to erythrocytes- direct Coombs’ test- direct Coombs’ test
Direct agglutination test (C3d binding)
Negative Positive
Hae
mog
lobi
n (g
/L)
30
40
50
60
70
80
***
*** P<0.001
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Pathogenesis of severe malariaPathogenesis of severe malaria
• Cerebral malaria – too much
• Excessive inflammation
• Localised in the brain
• Local neuronal excitation
• Possible focal impairment of micro-circulation
• Redirection of circulation
• Severe anaemia – too little
• Insufficient inflammation
• Long term infection
• Low grade inflammation
• Bone marrow suppression
• Erythrocyte destruction