COMPLICATED FALCIPARUM MALARIA

Introduction

• Malaria is the most important parasitic disease of man.

• Approximately 5% of the world’s population is infected, and it causes over 1 million deaths each year.

• The disease is a protozoan infection of red blood cells transmitted by the bite of a blood-feeding female anopheline mosquito.

epidemiology

Mosquito vector

• Malaria is transmitted by some species of anopheline mosquitoes.

• The optimum conditions for transmission are high humidity and an ambient temperature between 20 and 30°C.

LIFE CYCLE

parasite

pathophysiology

• The pathophysiology of malaria results from destruction of erythrocytes,the liberation of parasite and erythrocyte material into the circulation, and the host reaction to these events.

• P. falciparum malaria-infected erythrocytes sequester in the microcirculation of vital organs, interfering with microcirculatory flow and host tissue metabolism.

Toxicity and cytokines

• A glycolipid material with many of the properties of bacterial endotoxin is released on meront rupture.

• The products of malaria parasites, and the crude malaria pigment which is released at schizont rupture, induce activation of the cytokine cascade .

• Initially (TNF), (IL)-1, and (γIFN) are produced and these in turn induce release of ‘pro-infl ammatory’ cytokines including IL-6, IL-8,IL-12, IL-18.

• Cytokines are responsible for many of the symptoms and signs of the infection, fever and malaise.

• Cytokines are involved in placental dysfunction, suppression of erythropoiesis and inhibition of gluconeogenesis.

• TNF played a causal role in coma and cerebral dysfunction.

• Cytokines upregulate the endothelial expression of vascular ligands for P. falciparum-infected erythrocytes, notably ICAM-1, and thus promote cytoadherence.

• They may also be important mediators of parasite killing by activating leukocytes, and , to release toxic oxygen species, nitric oxide, and by generating parasiticidal lipid peroxides, and causing fever.

• Thus, whereas high concentrations of cytokines appear to be harmful, lower levels probably benefit the host.

Sequestration• Erythrocytes containing mature forms of P.

falciparum adhere to microvascular endothelium (‘cytoadherence’) and disappear from the circulation.

• This process is known as sequestration.

• Sequestration is thought to be central to the pathophysiology of falciparum malaria.

• Sequestration occurs predominantly in the venules of vital organs .

• It is not distributed uniformly throughout the body.

• greatest in the brain, particularly the white matter, prominent in the heart, eyes, liver, kidneys, intestines and adipose tissue, and least in the skin.

• Cytoadherence and the related phenomena of rosetting and autoagglutination lead to microcirculatory obstruction in falciparum malaria.

• The consequences of microcirculatory obstruction are

• activation of the vascular endothelium• endothelial dysfunction• reduced oxygen and substrate supply• which leads to anaerobic glycolysis, lactic acidosis

and cellular dysfunction

Rosetting

• Erythrocytes containing mature parasites adhere to uninfected erythrocytes.

• This process leads to the formation of ‘rosettes’

• Rosetting is mediated by attachment of specific domains of PfEMP1 to the complement receptor CR1, heparan sulphate,blood group A antigen.

• Rosetting might encourage cytoadherence by reducing flow (shear rate), which would enhance anaerobic glycolysis,reduce pH and facilitate adherence of infected erythrocytes to venular endothelium.

• Rosetting tends to start in venules, and this could certainly reduce flow.

• .

Clinical features

The classical attack lasts 6-10 hours.• a cold stage (sensation of cold, shivering)• a hot stage (fever, headaches, vomiting; seizures in young children) , fever up to 104 F a sweating stage (sweats, return tonormal temperature, tiredness) Paroxysms coincide synchronus ruptureschizont

• Tertian Malaria , where paroxysms of malaria isrepeated after 48 hrs or fever occurs every thirdday. It is feature of P.falciparum, P.ovale andP.vivax• Quartan Malaria , where paroxysms occurs afterevery 72 hour or fever occurs every fourth day. Itis seen in P.malariae

Renal failure

• The renal injury in severe malaria results from acute tubular necrosis.

• Acute tubular necrosis results from renal microvascular obstruction and cellular injury consequent upon sequestration in the kidney and the filtration of nephrotoxins such as free haemoglobin, myoglobin and other cellular material.

• Massive haemolysis compounds the insult in blackwater fever complicating malaria, and haemoglobinuria may itself lead to renal impairment.

• It always recovers fully in survivors.

• Significant glomerulonephritis is very rare.

Pulmonary edema

• Pulmonary oedema in malaria results from a sudden increase in pulmonary capillary permeability. ( Non cardiogenic pulmonary oedema)

• presence of sequestered PRBC and host leukocytes in pulmonary capillaries may have a role in causing pulmonary capillary endothelial cell dysfunction.

AnaemiaIt results from

• the obligatory destruction of red cells containing parasites at merogony,

• the shortened survival of red cells from which parasites have been extracted by the spleen, and

• the accelerated destruction of non-parasitized red cells that parallels disease severity.

• compounded by bone marrow dyserythropoeisis.

• The cause of the dyserythropoiesis is thought to be related to intramedullary cytokine production.

• Loss of unparasitized erythrocytes accounts for approximately 90% of the acute anaemia resulting from a single uncomplicated infection.

Coagulopathy and thrombocytopenia

In acute malaria, coagulation cascade activity is accelerated with• accelerated fibrinogen turnover,• consumption of antithrombin III,• reduced factor XIII, and• increased concentrations of fibrin

degradation products.

• In severe infections the antithrombin III,protein S and protein C are further reduced and prothrombin and partial thromboplastin times may be prolonged.

• Thrombocytopenia is common to all the four human malarias and is caused by increased splenic clearance

• Plasma concentrations of macrophage colony stimulating factor are high, which stimulate macrophage activity,and may increase platelet destruction

Black water fever

• Blackwater fever is a condition in which there is massive intravascular haemolysis and the passage of ‘Coca-Cola’-coloured urine.

Blackwater (black urine) occurs in three circumstances:

• (1) when patients with G6PD defi ciency take oxidant drugs (e.g. primaquine,sulphones or sulphonamides) irrespective of whether they have malaria or not;

• (2) occasionally when patients with G6PD deficiency have malaria and receive quinine treatment;

• (3) in some patients with severe falciparum malaria who have normal erythrocyte G6PD levels irrespective of the treatment given and

Liver dysfunction

• Jaundice is common in adults with severe malaria.

• Other features are reduced clotting factor synthesis, reduced metabolic clearance of the antimalarial drugs, and a failure of gluconeogenesis which contributes to lactic acidosis and hypoglycaemia.

• Jaundice in malaria appears to have haemolytic,hepatic, and cholestatic components.

• Cholestatic jaundice may persist well into the recovery period.

• There is no residual liver damage following malaria

Acidosis

• Acidosis is a major cause of death in severe falciparum malaria, both in adults and children.

• Mainly a lactic acidosis, although ketoacidosis may predominate in children, and the acidosis of renal failure is common in adults

• Acid-base assessment or venous lactate concentrations on or 4 h after admission to hospital are very good indicators of prognosis in severe malaria.

• Lactic acidosis results from several discrete processes: the tissue anaerobic glycolysis consequent upon microvascular obstruction;

• a failure of hepatic and renal lactate clearance; and the production of lactate by the parasite

HypoglycemiaCauses:

• an increased peripheral requirement for glucose consequent upon anaerobic glycolysis (the Pasteur effect),

• the increased metabolic demands of the febrile illness,and

• the obligatory demands of the parasites, which use glucose as their major fuel ; and

• a failure of hepatic gluconeogenesis and glycogenolysis (reduced supply).

• In patients treated with quinine, this is compounded by quinine-stimulated pancreatic β-cell insulin secretion.

• Hyperinsulinaemia is balanced by a reduced tissue sensitivity to insulin, which returns to normal as the patient improves.

• This probably explains why quinine-induced hypoglycaemia tends to occur after the first24 h of treatment, whereas malaria-related hypoglycaemia is present when the patient with severe malaria first presents.

Placental dysfunction• Pregnancy increases susceptibility to malaria. This is caused

by a suppression of systemic and placental cell-mediated immune responses.

• There is intense sequestration of P. falciparum infected erythrocytes in the placenta, local activation of pro-infl ammatory cytokine production, and maternal anaemia.

• This leads to cellular infiltration and thickening of the syncytiotrophoblast and placental insufficiency with consequent fetal growth retardation.

Bacterial infections

• Patients with severe malaria are vulnerable to bacterial infections , particularly of the lungs and urinary tract (following catheterization).

• Postpartum sepsis is also common.

• Spontaneous bacterial septicaemia may also occur in severe malaria

Relapse

• Both P. vivax and P. ovale have a tendency to relapse after resolution of the primary infection.

• Relapse, which results from maturation of persistent hypnozoites in the liver, must be distinguished from recrudescence of the primary infection because of incomplete treatment.

• P. falciparum is the usual cause of recrudescent infections and these tend to arise 2–4 weeks following treatment.

• Relapses occur weeks or months (or even years) after the primary infection

• The symptoms of a relapse start more abruptly than in the primary infection as the infection is more synchronous.

• They may begin with a sudden chill or rigor.

• Primaquine given for 14 days will eradicate hypnozoites and prevent relapse in over 80% of patients

Malaria in pregnancy

• Anaemia and LBW in primigravida.

• If a pregnant woman does develop severe malaria, fetal loss is common, and the maternal mortality is very high.

• The mortality of cerebral malaria in pregnancy is approximately 50%, compared with 15–20% in non-pregnant adults.

Cerebral malaria

• Unarousable coma (i.e. there is a non-purposeful response or no response to a painful stimulus) in falciparum malaria.

• the onset of coma may be sudden, often following a generalized seizure,

• or gradual, with initial drowsiness, confusion, disorientation, delirium or agitation, followed by unconsciousness.

• Extreme agitation is a poor prognostic sign in falciparum malaria.

• On examination, the patient is febrile and unrousable.

• There may be some passive resistance to neck fl exion.

• Sustained hyperventilation is a poor prognostic sign as it indicates metabolic acidosis if the chest is clear, or pneumonia or pulmonary oedema if it is not.

• On examination of the nervous system, the gaze is usually normal or divergent (but there is no evidence of extraocular muscle paresis).

• Retinal whitening, retinal haemorrhages, focal whitening of vessels, papilloedema and cotton wool spots are seen in fundus.

• Papilloedema is unusual and is a sign of poor prognosis, as is retinal oedema.

• The haemorrhages are often flame or boat shaped, and may have a pale centre resembling Roth spots.

• They rarely affect the macula

• Patients may exhibit phasic increases in tone with extensor posturing of the decorticate (arm flexed, legs extended), or more usually decerebrate (arms and legs extended) types.

• The back may arch as in opisthotonus,with sustained, usually upward and lateral, ocular deviation.

• The posturing is commonly associated with noisy hyperventilation.

TREATMENT

• Artesunate 2.4 mg/kg bw iv or im on admission; then at 12 h and 24 h, then once a day for at least 24 hours, followed by full course of ACT Artesunate plus Sulfadoxine-pyrimethamine

• Artesunate plus Amodiaquine• Artesunate plus clindamycin or doxycycline

• OR Artemether 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day for at least 24 hours, followed by full course of ACT Artemether plus Lumefantrine

Cerebral malaria

• Coma –• Maintain airway, place patient on his or her

side, exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis)

• intubate if necessary

• Hyperpyrexia Administer tepid sponging, fanning, cooling blanket and antipyretic drugs.

• Convulsions Maintain airways; treat promptly with intravenous or rectal diazepam.

• Hypoglycaemia (blood glucose concentration of<2.2 mmol/l; <40 mg/100ml) Check blood glucose, correct hypoglycaemia and maintain with glucose-containing infusion

• Severe anaemia (haemoglobin <5 g/100ml or packed cell volume <15%) Transfuse with screened fresh whole blood

Acute pulmonary oedema

• Over-enthusiastic rehydration should be avoided so as to prevent pulmonary oedema.

• Prop patient up at an angle of 45o, give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure/continuous positive airway pressure in life-threatening hypoxaemia

Acute renal failure

• Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis.

• Spontaneous bleeding and coagulopathy Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets if available); give vitamin K injection

• Metabolic acidosis• Hypovolaemia and septicaemia. • If severe add haemofiltration or haemodialysis

Shock Suspect septicaemia• Take blood for cultures; give parenteral

antimicrobials, correct haemodynamic disturbances.

• Quinine 20 mg salt/kg bw on admission (iv infusion over 4 hrs, then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour; course for 3 days. 7 days for malaria acquired in SE Asia[4] Doxycyclined 100mgs BID for 7 days OR Clindamycin 20mg base/kg/day divided in three doses for 7 days[4] in pregnancy.

• Blood transfusion:

• In high transmission settings, blood transfusion is recommended for

children with a haemoglobin level of <5 g/100 ml (haematocrit

<15%).

• In low-transmission settings, a threshold of 20% (haemoglobin 7

g/100ml) is recommended.

• These general recommendations still need to be tailored to the

individual, as the pathological consequences of rapid development of

anaemia.

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