Severe and complicated malaria Jrgen Kurtzhals Centre for

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Severe and complicated malaria Jørgen Kurtzhals Centre for Medical Parasitology Rigshospitalet, Copenhagen, Denmark e-mail:

Severe and complicated malaria Jørgen Kurtzhals Centre for Medical Parasitology Rigshospitalet, Copenhagen, Denmark e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Cerebral malaria kills ½-1 million children every year e-mail: jkcmp@rh. dk Internet: http: //www.

Cerebral malaria kills ½-1 million children every year e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Correct treatment: 85% survival – most without sequelae e-mail: jkcmp@rh. dk Internet: http: //www.

Correct treatment: 85% survival – most without sequelae e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

15% of cerebral malaria patients die e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

15% of cerebral malaria patients die e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

The asexual parasite multiplication cycle Re-invasion Free merozoites Ring-stage trophozoite Rupture Trophozoite maturation Mature

The asexual parasite multiplication cycle Re-invasion Free merozoites Ring-stage trophozoite Rupture Trophozoite maturation Mature trophozoite Schizont (segmenter) Schizogony e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Sequestration interferes with splenic removal of schizont-infected erythrocytes Spleen Vascular endothelium e-mail: jkcmp@rh. dk

Sequestration interferes with splenic removal of schizont-infected erythrocytes Spleen Vascular endothelium e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Sequestration of erythrocytes in the brain e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Sequestration of erythrocytes in the brain e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Cerebral malaria – clinical features • P. falciparum – often (not always) high parasitaemia

Cerebral 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% e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Cerebral malaria - diagnosis • Exclusion diagnosis • Other manifestations of malaria (may co-exist)

Cerebral 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 e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Cerebral malaria – treatment • Effective anti-malarial – i. v. quinine • Alternative: artemisinin,

Cerebral 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 e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Severe anaemia - pathogenesis • Erythrocyte destruction during schizogony • Erythrophagocytosis in spleen •

Severe anaemia - pathogenesis • Erythrocyte destruction during schizogony • Erythrophagocytosis in spleen • Hypersplenism • Immune mediated Spleen • Bone marrow suppression • TNF/IL-10 ratio • Reversible e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Severe anaemia • P. falciparum – often, not always, high parasitaemia • Often prolonged

Severe 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 e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Severe anaemia – treatment • Effective anti-malarial treatment • Parasite clearance restores bone marrow

Severe 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 e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Other severe complications • Pulmonary oedema • ARDS • Renal insufficiency • Haemolysis •

Other severe complications • Pulmonary oedema • ARDS • Renal insufficiency • Haemolysis • Thrombocytopaenia, DIC • Superinfections • Septicaemia e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Recommended laboratory investigations • Blood film (x 3) • Blood culture • Hb, thrombocytes,

Recommended laboratory investigations • Blood film (x 3) • Blood culture • Hb, thrombocytes, WBC and differential count • Na, K, creatinine • Bilirubin, ASAT, factor II-VII-X, LDH • Glucose • (Arterial blood gas, lactate) e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Case 1 • 53 year old male civil engineer, resident in Ghana for 6

Case 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 e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Case 1 (ctd. ) • On arrival pale, acutely ill, tp. 41. 2 o.

Case 1 (ctd. ) • On arrival pale, acutely ill, tp. 41. 2 o. C, slow cerebrated • Blood film: 17% P. falciparum (ring stages) • Hb 8. 2 g/dl, thrombocyte count 46, WBC normal range • Creatinine 320 mmol/l, Na 120 mmol/l, K 4. 0 mmol/l • Glucose 3. 8 mmol/l • Treatment suggestion? e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Case 1 (ctd. ) • Quinine 10 mg/kg infusion in 5% dextrose/saline over 4

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? e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Case 1 (ctd. ) • Hyponatraemia treated with isotonic saline and frusemide • Renal

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 e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Theories about pathogenesis of cerebral malaria • Impaired cerebral blood flow? • Sequestration of

Theories about pathogenesis of cerebral malaria • Impaired cerebral blood flow? • Sequestration of infected RBC in blood vessels • Histological picture • Ophthalmoscopy e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Near infrared spectrophotometry (NIRS) e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Near infrared spectrophotometry (NIRS) e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Sc. O 2 on admission e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Sc. O 2 on admission e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Theories about pathogenesis of cerebral malaria • Impaired cerebral blood flow? • Regional blood

Theories about pathogenesis of cerebral malaria • Impaired cerebral blood flow? • Regional blood flow changes e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Theories about pathogenesis of cerebral malaria • Generalised excessive inflammation • High TNF levels

Theories about pathogenesis of cerebral malaria • Generalised excessive inflammation • High TNF levels • Association with TNF promoter polymorphism • Animal experiments e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Increased levels of inflammation markers in cerebral malaria Clin Exp Immunol 1998; 112: 303

Increased levels of inflammation markers in cerebral malaria Clin Exp Immunol 1998; 112: 303 -307 e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Theories about pathogenesis of cerebral malaria • Impaired cerebral blood flow? • Regional blood

Theories about pathogenesis of cerebral malaria • Impaired cerebral blood flow? • Regional blood flow changes • Excessive inflammation • Regional inflammation e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Theories about pathogenesis of severe malarial anaemia • Destruction of erythrocytes • Schizogony •

Theories about pathogenesis of severe malarial anaemia • Destruction of erythrocytes • Schizogony • Infected cells removed in spleen • Uninfected cells removed in spleen e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Complement binding to erythrocytes - direct Coombs’ test e-mail: jkcmp@rh. dk Internet: http: //www.

Complement binding to erythrocytes - direct Coombs’ test e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk

Pathogenesis of severe malaria • Cerebral malaria – too much • Severe anaemia –

Pathogenesis of severe malaria • Cerebral malaria – too much • Severe anaemia – too little • Excessive inflammation • Insufficient inflammation • Localised in the brain • Long term infection • Local neuronal excitation • Low grade inflammation • Possible focal impairment of micro-circulation • Bone marrow suppression • Redirection of circulation • Erythrocyte destruction e-mail: jkcmp@rh. dk Internet: http: //www. cmp. dk