E-mail: [email protected] Internet: Severe and complicated malaria Jørgen Kurtzhals Centre for Medical Parasitology Rigshospitalet, Copenhagen,

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Severe and complicated malariaSevere and complicated malaria

Jørgen KurtzhalsCentre for Medical Parasitology

Rigshospitalet, Copenhagen, Denmark


Cerebral malaria kills ½-1 million children every Cerebral malaria kills ½-1 million children every yearyear


Correct treatment: 85% survival Correct treatment: 85% survival – most without sequelae– most without sequelae


15% of cerebral malaria patients die15% of cerebral malaria patients die


The asexual parasite multiplication cycleThe asexual parasite multiplication cycle

Ring-stage trophozoite

Mature trophozoite

Schizont (segmenter)

Free merozoites

Trophozoite maturation

Schizogony

Rupture

Re-invasion


Spleen

Vascular endothelium

Sequestration interferes with splenic removal Sequestration interferes with splenic removal of schizont-infected erythrocytesof schizont-infected erythrocytes


Sequestration of erythrocytes in the brainSequestration of erythrocytes in the brain


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%


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


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


Severe anaemia - pathogenesisSevere anaemia - pathogenesis

• Erythrocyte destruction during schizogony

• Erythrophagocytosis in spleen• Hypersplenism• Immune mediated

• Bone marrow suppression• TNF/IL-10 ratio• Reversible

Spleen


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


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


Other severe complicationsOther severe complications

• Pulmonary oedema

• ARDS

• Renal insufficiency

• Haemolysis

• Thrombocytopaenia, DIC

• Superinfections

• Septicaemia


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)


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


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?



• 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?



• 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


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


Near infrared spectrophotometry (NIRS)Near infrared spectrophotometry (NIRS)


ScOScO22 on admission on admission




• Regional blood flow changes



• Generalised excessive inflammation

• High TNF levels

• Association with TNF promoter polymorphism

• Animal experiments


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




• Regional blood flow changes

• Excessive inflammation

• Regional inflammation


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


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


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

Documents

E-mail: [email protected] Internet: Severe and complicated malaria Jørgen Kurtzhals Centre for Medical Parasitology Rigshospitalet, Copenhagen,