1. This lecture was conducted during the Nephrology Unit Grand Ground by Medical Students rotated under Nephrology Division under the supervision and administration of Prof. Jamal Al Wakeel, Head of Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al Suwaida, Chairman of Department of Medicine. Nephrology Division is not responsible for the content of the presentation for it is intended for learning and /or education purpose only.

2. Malaria Presented by: Bader Alajlan, Rayan Alalola, Faisal Obeid Medical Students July 2008

3. malaria Introduction Classification Epidemiology Pathogenesis Symptoms and signs Diagnosis Treatment and prevention Complication

4. Introduction Malaria is a tropic life threatening disease. Humans are infected with Plasmodium protozoa when bitten by an infective female Anopheles mosquito vector. Symptoms may appear within weeks to months or even years.

5. Classification There are 4 species:  plasmodium falciparum  plasmodium vivax  plasmodium ovale  plasmodium malariae

6. Diagnosis Timely diagnosis of the correct species is required because the particular species of P falciparum can be fatal and is often resistant to standard chloroquine treatment. Species can usually be distinguished by morphology on a blood smear.

7. Epidemiology

9. Pathogenesis

10. Symptoms and signs Depends on the type of malaria:  P. falciparum: The most dangerous type. Insidious onset. Malaise, headache, vomiting. Fever. Cough, diarrhea. Jaundice. Tender hepatosplenomegaly. Anemia develops rapidly.

11. Symptomology  P.vivax and P.oval: Fever: classically every 48 h. Rigors. Gradual hepatosplenomegaly. Anemia develops slowly. Relapse is common.

12. Symptomology  P.malariea: Fever: every third day. Mild symptoms. Parasitaemia may persist for many years. Causes glomerulonephritis and nephrotic syndrome in children.

13. Diagnosis Malaria should be suspected clinically!! Thick and thin blood films:  Thick film: are 20 times more sensitive than thin smears, but speciation may be more difficult.  Thin films: essential to confirm the diagnosis and to identify the species of the parasite. and In P.falciparum to quantify the parasite load.

14. Blood films P.falciparum P.malariea

15. Diagnosis P.vivax P.ovale

16. Diagnosis Immunochromatographic “dipstick” test for P.falciparum  should be used parallel with blood film examination.

17. Laboratory Investigations Others:  CBC: low Hb, low platelets  Blood cultures  Hypoglycemia – to rule out cerebral malaria  Urea and creatinine.

18. Treatment (based on WHO recommendations 2006) Rx of uncomplicated P.falciparum Rx of sever malaria Rx of P.vivax, P.ovale, P.malariae Prevention

19. Definitions Uncomplicated malaria: symptomatic malaria without signs of vital organ dysfunction.

20. Definitions Complicated malaria:  Clinical features: Prostration. Impaired consciousness. Respiratory distress. Convulsions. Circulatory collapse. Pulmonary edema. Jaundice. Abnormal bleeding.  Laboratory test: Sever anemia. Hypoglycemia. Acidosis. Renal impairment. Hyperlactemia. Hyperparasitemia.

21. Treatment Combination therapy: is the use of 2 or more blood schizontocidal drugs with different modes of action.

22. Rx of uncomplicated P.falciparum Artemisinis combination are the best.  MOA: production of free radicals that kill the parasite. Active against all human malaria parasites. Does not affect the hepatic stage.  Artesunate 100 mg + amodiaquine 270 mg BID for 3 days.  Artemether + lumefantrine (Riamet ® ): 4 tabs/12h for 6 doses.

23. Treatment These combinations are better than the quinine regimens: quinine + doxycycline Which are now considered as second line.

24. Rx of sever malaria Atresunate 2.4 mg/kg IV or IM given on admission then after 12h and 24h, then once daily. Fluid therapy for rehydration. Blood transfusion: usually used in children, because anemia is sever (Hb < 5 g/dl)

25. Rx of sever malaria Exchange blood transfusion:  No solid evidence that showed reduce in mortality.  It could be used to reduce the parasite burden. ?? Steroids: one study showed no significant difference in mortality.  Their recommendation: don’t use steroids.

26. Rx of P.vivax, P.ovale, P.malariae Chloroquine For radical cure of P.vivax and P.ovale:  Primaquine 15 mg daily for 14 days.  It destroys the hypnozoite phase in the liver.  It may cause hemolysis with G6PD deficient patients.

27. Prevention Avoid mosquito bites:  Wearing long sleeves, trousers.  Nets.  Repellent creams or sprays.

28. Prevention Chemoprophylaxis:  Should be given 1 week before traveling, and continued 4 weeks after leaving.  Depends on the area of travel (ie. Chloroquine resistance or not) AreaAntimalarial Chloroquine resistance high Mefloquine (or doxycycline or malarone) Chloroquine resistance moderate Chloroquine + proguanil Chloroquine sensitiveChloroqunie Or proguanil

29. Complication of malaria

30. Malaria is probably the only infection that can be treated in just three days, yet that kills millions every year. Malaria may become a medical emergency by rapidly progressing to complications and death. Early diagnosis & proper management can prevent serious complication. Most complications have similar pathogenesis.

31. Predisposing factors for complications (1.) Extremes of age. (2.) Pregnancy, especially in primigravidae and in 2nd half of pregnancy. (3.) Immunosuppressed - patients on steroids, anti- cancer drugs, immunosuppressant drugs. (4.) Immunocompromised - patients with advanced tuberculosis and cancers. (5.) Splenectomy. (6.) Lack of previous exposure to malaria (non-immune) or lapsed immunity (7.) Pre-existing organ failure.

32. Complications of P. falciparum malaria Complications of P. falciparum malaria  Cerebral malaria ( coma )  Convulsions  Hyperpyrexia  Severe anemia  Metabolic (Lactic) Acidosis  jaundice  renal failure  Pulmonary odema & ARDS  hypoglycemia  Hypotention & shock  Bleeding & clotting disorder  haemoglobinuria  hyperparasitemia  Associated infection Complications of P. vivax / P. malariae Complications of P. vivax / P. malariae  Rupture of spleen  Hepatic dysfunction  Thrombocytopenia  Severe anemia  malarial nephropathy

33. Cerebral Malaria In falciparum malaria, 10% of all admissions and 80% of deaths are due to the C.N.S. involvement Manifestations of cerebral dysfunction include any degree of impaired consciousness, delirium, abnormal neurological signs, and focal and generalized convulsions For a diagnosis of cerebral malaria, the following criteria should be met: (i.) Deep, unarousable coma: Motor response to noxious stimuli is non-localising or absent. (ii.) Exclusion of other encephalopathies. (iii.) Confirmation of P. falciparum infection all patients with P. falciparum malaria with neurological manifestations of any degree should be treated as cases of cerebral malaria.

34. its pathophysiology is not completely understood underlying defect seems to be clogging of the cerebral micocirculation by the parasitized red cells. Obstruction to the cerebral microcirculation results in hypoxia and increased lactate production due to anaerobic glycolysis In patients with cerebral malaria, C.S.F. lactate levels are high and significantly higher in fatal cases complete obstruction to blood flow is unlikely, since the survivors rarely have any permanent neurological deficit. Causes of neurological manifestations in malaria:  High-grade fever  Antimalarial drugs  Hypoglycemia  Hyponatremia  Severe anaemia

35. Management of cerebral malaria : Manage airway Nurse by side Phenobarbitone IM, 10-15 mg/kg body weight should be given y to prevent convulsions Antimalarial treatment: Parenteral Quinine has been traditionally the treatment of choice for cerebral malaria  20mg of salt/kg diluted in 10 ml/kg isotonic fluid, infused over 4 hrs; then 10 mg of salt / kg over 4 hrs, every 8-12 hrs until patient can swallow. Do not administer the following: Corticosteroids; other anti inflammatory drugs; anti oedema drugs like mannitol, urea, invert sugar; low molecular weight dextran; adrenaline; heparin; pentoxifylline; hyperbaric oxygen; ciclosporin etc

36. Metabolic (Lactic) Acidosis Increased production of lactic acid by parasites Decreased clearance by the liver Most importantly the combined effects of several factors that reduce oxygen delivery to tissues  Marked reductions in the deformability of uninfected RBCs may compromise blood flow through tissues  Dehydrated and hypovolemia can exacerbates microvascular obstruction by reducing perfusion pressure  Destruction of RBCs and anemia further compromises oxygen delivery

37. Acute Pulmonary Odema: It is a fatal complication of severe falciparum malaria with more than 50% mortality. In a few patients it could be due to fluid overload increased permeability of pulmonary capillaries. Sequestration of red cells and clogging of pulmonary microcirculation and disseminated intravascular coagulation more common in patients with hyperparasitemia, renal failure and pregnancy. Shock : Hypotension in malaria could be due to many reasons:  Dehydration due to high-grade fever, excessive sweating and inadequate fluid intake.  Dehydration due to vomiting and/or diarrhoea.  Pulmonary oedema.  Metabolic acidosis.  Associated Gram negative septicemia.  Massive gastrointestinal haemorrhage

38. Renal Failure : Renal dysfunction in falciparum malaria can be due to many factors: Renal failure in malaria is caused by renal cortical vasoconstriction and resultant hypoperfusion, sequestration and resultant acute tubular necrosis due to microvascular obstruction and due to massive intravascular hemolysis in blackwater fever. Quartan malarial nephropathy: In areas where P. malariae is prevalent immune-complex mediated glomerulonephritis, leading to nephrotic syndrome Histologically there is progressive focal and segmental glomerulosclerosis with fibrillary splitting or flaking of the capillary basement membrane. Patients usually present by the age of 15 years with typical features of nephrotic syndrome. Treatment with antimalarial drugs, corticosteroids or cytotoxic agents may not be useful.

39. Anemia : In falciparum malaria, anemia can develop rapidly due to profound hemolysis The degree of anemia correlates with parasitemia and schizontemia More serious in children and pregnant. Bleeding disorder : Thrombocytopenia Disseminated intravascular coagulation

40. Hypoglycemia: Hypoglycemia in malaria may be asymptomatic Therefore, hypoglycemia, which is easily treatable, may be missed Causes:  1. Increased consumption of glucose by the host and the growing parasites.  2. Failure of hepatic gluconeogenesis and glycogenolysis as a result of impaired liver function and acidemia and hyperinsulinemia  3. Stimulation of pancreatic insulin secretion by drugs like quinine. More than one of these factors may be at play in a given patient Jaundice : Malaria is the most common cause for jaundice in a malarious area Most often it is caused by hemolysis, rarely due to liver impairment. Hepatic dysfunction more with vivax malaria,  Fever, jaundice, tender hepatomegaly, mild elevation in the levels of hepatic enzymes and bilirubin are observed  Liver function returns to normal shortly after antimalarial treatment

41. Rupture of spleen: It is more common in vivax malaria than falciparum malaria occur in up to 0.7% of the patients Rupture occurs in acute, rapid, hyperplastic enlargement of spleen Patients present with abdominal pain, fever, tachycardia, prostration and rapidly developing anemia and hypotension. Ultra sound evaluation of abdomen and paracentesis of the abdomen can confirm the diagnosis Treatment includes replacement of fluid and blood, laparotomy and splenectomy

42. Complication due to medication Vomiting Dizziness Itching ( chloroquine ) Abdominal pain Convulsion ( chloroquine, quinine, meflequine ) Coma ( chloroquine, quinine) Hypoglycemia ( quinine) Anemia, jaudice,Haemoglobinuria ( primaquine in pt with G6PD deficiency ) fever

43. References emedicine.com/med/TOPIC1385.HTM Guidelines for the treatment of malaria 2006 (WHO) Principles and practice of medicine, Davidson’s (19 th edition) Oxford handbook of clinical medicine (7 th edition) www.malariasite.com