DIAGNOSIS AND MANAGEMENT OF MALARIA

1. DIAGNOSIS AND MANAGEMENT OF MALARIA Dr. Nisheeth M. Patel 3 rd Year Resident M. D. Medicine

2. Introduction: Protozoal disease: Plasmodium species: P. vivax P. falciparum P. ovale P. malariae Transmitted by infected female anopheles mosquito

3. Life cycle:

4. Diagnosis: Demonstration of asexual forms of parasite in stained peripheral blood smear Microscopy: Thick blood smear Thin blood smear RDT (Rapid Diagnostic Test) PfHRP2 dip stick Plasmodia LDH dip stick

5. Thick blood smear Uneven in thickness For plasmodia identification Asexual parasite per 200 WBCs Sensitive, inexpensive Requires experience Underestimate true count Thin blood smear Species identification and quantification RBCs containing asexual parasite per 1000 RBCs Severe Malaria, assess stage of parasite development Count PMNs containing malarial pigment Rapid inexpensive prognostic info Insensitive

6. PfHRP2 dip stick Rapid, relatively inexpensive Sensitive Only for P. Falci Do not quantitate + ve after several weeks of infection Plasmodia LDH dip stick One band in genus specific, other for P. falci Rapid sensitive Miss low level p. vivax , ovale or malariae Do not quantitate

7. A negative blood smear makes the diagnosis of malaria unlikely. if first smear is negative and high suspicion of malaria Repeat PSMP should be performed every 12-24h for 2 days, if malaria is strongly suspected. If all 3 are negative, the diagnosis of malaria has been essentially ruled out.

8. Treatment: The aims of the Malaria case management are: To provide prompt and complete treatment to all suspected/ confirmed cases of malaria To prevent progression of mild cases of malaria in to severe or complicated from of malaria To prevent deaths from severe and complicated malaria To prevent transmission of malaria To minimize risk of spread of drug resistant parasites by use of effective drugs in appropriate dosage by everyone.

9. Uncomplicated P. Vivax malaria Uncomplicated malaria is defined as symptomatic malaria without signs of severity or evidence (clinical/ laboratory)of vital organ dysfunction. Dosage of CQ (CQ sensitive ) 25 mg/kg (base) divided over 3 days. Day 1 -10mg/kg Day 2- 10 mg/kg Day 3- 5 mg/kg Plus Primaquine 0.25 mg/kg for 14 days along with food after negative G6PD testing

10. In mild to moderate G6PD deficiency, primaquine to be given 0.75 mg/kg once a week for 8 weeks In severe deficiency, it should not be given Also contraindicated in pregnancy and children <4 yrs CQ resistant: ACT (except AS+SP) along with primaquine . AS+SP not effective and rapidly develop resistance to P. Vivax species.

11. Treatment of mixed infections ( P.vivax + P.falciparum ) cases: All mixed infections should be treated with full course of ACT and Primaquine 0.25 mg per kg body weight daily for 14 days. Treatment of P. ovale and P. malariae : In India these species are very rarely found in few places. P. ovale should be treated as P. vivax and P. malariae should be treated as P. falciparum . Treatment of mixed infections: All cases of mixed infection are to be treated as Pf plus primaquine for 14 days

12. Uncomplicated P. Falci malaria Dose schedule: Artemisinin based Combination Therapy (ACT-SP) Artesunate 4 mg/kg body weight daily for 3 days Plus Sulfadoxine (25 mg/kg body weight) – Pyrimethamine (1.25 mg/kg body weight) on first day or Artesunate (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days) plus Primaquine : 0.75 mg/kg body weight on day 2.

13. Multidrug-resistant P. falciparum malaria: Artemether-lumefantrine c (1.5/9 mg/kg bid for 3 days with food) or Artesunate c (4 mg/kg qd for 3 days) plus Mefloquine (25 mg of base/kg—either 8 mg/kg qd for 3 days or 15 mg/kg on day 2 and then 10 mg/kg on day 3)

14. Second-line treatment/treatment of imported malaria: Artesunate c (2 mg/kg qd for 7 days) Or Quinine (10 mg of salt/kg tid for 7 days) plus 1 of the following 3: 1. Tetracycline e (4 mg/kg qid for 7 days) 2. Doxycycline e (3 mg/kg qd for 7 days) 3. Clindamycin (10 mg/kg bid for 7 days)

15. Complicated P. Falci malaria presence of one or more of the following clinical or laboratory features classifies the patient as suffering from severe malaria: Clinical features: impaired consciousness or unrousable coma >30 min prostration, i.e. generalized weakness so that the patient is unable walk or sit up without assistance failure to feed multiple convulsions – more than two episodes in 24 h or activity of subtle convulsion

16. Cont…. deep breathing, respiratory distress ( acidotic breathing) circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults and < 50 mm Hg in children clinical jaundice Anuria haemoglobinuria abnormal spontaneous bleeding pulmonary oedema (radiological)

17. Laboratory findings: hypoglycaemia (blood glucose < 2.2 mmol /l or < 40 mg/dl) metabolic acidosis ( pH < 7.25 or plasma bicarbonate < 15 mmol /l) severe normocytic anaemia ( Hb < 5 g/dl, packed cell volume < 15%) haemoglobinuria hyperparasitaemia (> 2%/100 000/ μl in low intensity transmission areas or > 5% or 250 000/ μl in areas of high stable malaria transmission intensity) hyperlactataemia (lactate > 5 mmol /l) renal impairment (serum creatinine > 3 mg/ dL ).

18. Decreased platelet count (<50,000/L) Prolonged prothrombin time (>3 s) Prolonged partial thromboplastin time Decreased fibrinogen (<200 mg/ dL )

19. It’s an emergency…….. An open airway should be secured in unconscious patients and breathing and circulation assessed immediate measurements of blood glucose (stick test), haematocrit / haemoglobin,parasitaemia and, in adults, renal function should be taken. Unconscious patients should have a lumbarpuncture for CSF analysis to exclude bacterial meningitis. After rapid clinical assessment and confirmation of the diagnosis, full doses of parenteral antimalarial treatment should be started without delay with any effective antimalarial first available.

20. Anti malarial treatment: Artesunate (2.4 mg/kg stat IV followed by 2.4 mg/kg at 12 and 24 h and then daily if necessary) g or, if unavailable, one of the following: Artemether c (3.2 mg/kg stat IM followed by 1.6 mg/kg qd ) or Quinine dihydrochloride (20 mg of salt/ kg h infused over 4 h, followed by 10 mg of salt/kg infused over 2–8 h q8h) or Quinidine (10 mg of base/kg infused over 1–2 h, followed by 1.2 mg of base/kg per hour with electrocardiographic monitoring)

21. Give parenteral antimalarials in the treatment of severe malaria for a minimum of 24 h, once started and, thereafter, complete treatment by giving a complete course of: – artemether plus lumefantrine , – artesunate plus amodiaquine , – dihydroartemisinin plus piperaquine , – artesunate plus sulfadoxine-pyrimethamine , – artesunate plus clindamycin or doxycycline , – quinine plus clindamycin or doxycycline .

22. After parenteral artemisinin therapy, patients will receive a full course of Area-specific oral ACT for 3 days. who received parenteral Quinine therapy should receive oral Quinine 10 mg/kg body weight three times a day for 7 days (including the days when parenteral Quinine was administered)plus Doxycycline 3 mg/kg body weight once a day Or Clindamycin 10 mg/kg body weight 12-hourly for 7 days ( Doxycycline is contraindicated in pregnant women and children under 8 years of age)

23. Some don’ts in severe malaria case management Do not use corticosteroids, give intravenous mannitol , use heparin as anticoagulant, administer adrenaline or overhydrate .

24. Adjunctive treatment Coma (cerebral malaria): Maintain airway place patient on his or her side exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis) Avoid harmful treatments Hyperpyrexia: Administer tepid sponging, fanning, a cooling blanket and antipyretic drugs. Paracetamol is preferred over more nephrotoxic drugs

25. Convulsions Maintain airways treat promptly with intravenous or rectal diazepam or intramuscular paraldehyde. Check blood glucose P henobarbitol should never be given without respiratory support Hypoglycaemia Check blood glucose every 4-6 hrly correct hypoglycaemia, glucose level should be >4mmol/L(100mg/ dL ) maintain with glucose containing infusion. Severe anaemia: Hct level should be measured every 6-12h Hct falls <20%, transfuse fresh WB or PCV judiciously

26. Acute pulmonary oedema: Prop patient up at an angle of 45° 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 if in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis.

27. Fluid therapy: degree of fluid depletion varies in each patient Each patient must be individually assessed and fluid resuscitation based on estimated deficit children tolerate rapid fluid resuscitation better than adults In adults, there is a very thin dividing line between over-hydration, which may produce pulmonary oedema, and under-hydration contributing to shock, worsening acidosis and renal impairment. Careful and frequent evaluations of the jugular venous pressure, peripheral perfusion, venous filling, skin turgor and urine output central venous pressure measured directly (target 0–5 cm H2O)

28. Spontaneous bleeding and coagulopathy : Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets, if available) give vitamin K injection Metabolic acidosis: Exclude or treat hypoglycaemia, hypovolaemia and septicaemia. If severe, add haemofiltration or haemodialysis

29. Shock: Suspect septicaemia take blood for cultures give parenteral broad-spectrum antimicrobials correct haemodynamic disturbances Associated bacterial or aspiration pneumonia: third-generation cephalosporin, or the appropriate antibiotic Systemic Salmonella infection and urinary tract infections, especially in catheterized patients. Antibiotic treatments should be based on culture and sensitivity results

30. Management of treatment failures Recurrence of P. falciparum malaria can be the result of a re-infection, or a recrudescence (i.e. failure). In an individual patient, it may not be possible to distinguish recrudescence from re-infection although if fever and parasitaemia fail to resolve or recur within two weeks of treatment then this is considered a failure of treatment. may result from drug resistance, poor adherence or inadequate drug exposure treatment failure must be confirmed parasitologically – preferably by blood slide examination

31. Failure within 14 days Treatment failure within 14 days of receiving an ACT is very unusual, with the majority of treatment failures occurring after two weeks of initial treatment. Treatment failures within 14 days of initial treatment should be treated with a second-line antimalarial Alternative ACT effective in particular region artesunate plus tetracycline or doxycycline or clindamycin (given for a total of 7 days) quinine plus tetracycline or doxycycline or clindamycin (given for a total of 7 days).

32. Failure after 14 days Recurrence of fever and parasitaemia more than two weeks after treatment could result either from recrudescence or new infection and this distinction can only be made through parasite genotyping by PCR considered as new infections, especially in areas of high transmission, and be treated with the first-line ACT If the failure is a recrudescence, then the first-line treatment should still be effective in most cases. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk of neuropsychiatric reactions

33. Treatment in specific populations and situations Treatment of uncomplicated P.falciparum cases in pregnancy: 1st Trimester : Quinine salt 10mg/kg 3 times daily for 7 days. 2nd and 3rd trimester: ACT as per dosage schedule given above. Primaquine is C/I Lactating women recommended antimalarial treatment (including ACT s), except for primaquine and tetracycline.

34. For travellers returning to non-endemic countries with uncomplicated malaria atovaquone plus proguanil (15/6 mg/kg [adult dose – 4 tablets] once a day for 3 days) artemether plus lumefantrine dihydroartemisinin plus piperaquine quinine plus doxycycline or clindamycin For severe malaria: the antimalarial treatment in travellers is the same as Rx of complicated P. Falci travellers with severe malaria should be managed in an intensive care unit

35. Malaria associated with HIV Worsening HIV-related immunosuppressan may lead to more severe manifestations of malaria. In HIV-infected pregnant women, the adverse effects of placental malaria on birth weight are increased. In stable endemic areas, HIV-infected patients with partial immunity to malaria may suffer more frequent and higher density infections; In unstable transmission area, HIV infection is associated with an increased risk of severe malaria and malaria-related deaths

36. Patients with HIV infection who develop malaria should receive prompt, effective antimalarial treatment regimens as recommended Treatment or intermittent preventive treatment with sulfadoxine-pyrimethamine should not be given to HIV-infected patients receiving cotrimoxazole ( trimethoprim plus sulfamethoxazole ) prophylaxis. Treatment in HIV-infected patients on zidovudine or efavirenz should, if possible, avoid amodiaquine -containing ACT regimens.

37. Transfusion Malaria Malaria can be transmitted by blood transfusion, needle-stick injury, sharing of needles by infected injection drug users, or organ transplantation. The incubation period in these settings is often short because there is no pre erythrocytic stage of development. The clinical features and management of these cases are the same as for naturally acquired infections. Radical chemotherapy with primaquine is unnecessary for transfusion-transmitted P. vivax and P. ovale infections.

38. Malnutrition Although there are many reasons why antimalarial pharmacokinetics may be different in malnourished patients as compared with those who are well nourished, there is insufficient evidence to change current mg/kg body weight dosing recommendations.

39. Microscopy results within 24 hrs Suspected malaria case Take slide and send for microscopic examination Positive for mixed inf ACT kit for 3 days + PQ x 14 days Negative No antimalarial treatment Treat as per clinical diagnosis Positive for P. Vivax CQ 3 days + PQ x14 days Acc to weight Positive for P. Falciparum ACT kit for 3 days + PQ single dose on day 2

40. Microscopy not available within 24 hrs and monovalent RDT used Suspected malaria case High transmission area Wait for slide result. Give CQ 25mg/kg over 3 days only if high suspicion of malaria Do RDT for detection of Malaria & Prepare slide Positive for P. Falciparum Treat with: ACT-SP for 3 days + PQ Single dose on second day Positive for P. Vivax CQ if not already given + PQ 0.25 mg/kg single dose for 14 days If confirmed as Pv CQ if not already Given + PQ 0.25 mg/kg/day over 14 days RDT Negative: Wait for slide result. Give CQ 25mg/kg over 3 days, if high suspicion of malaria Positive for P. Falciparum Treat with: ACT-SP for 3 days + PQ Single dose on second day Low trasmission area

41. microscopy result is not available within 24 hours and Bivalent RDT is used Suspected malaria case Do blood test with RDT Positive for mixed inf ACT kit for 3 days + PQ x 14 days Negative No antimalarial treatment Treat as per clinical diagnosis Positive for P. Vivax CQ 3 days + PQ x14 days Acc to weight Positive for P. Falciparum ACT kit for 3 days + PQ single dose on day 2

42. Chemoprophylaxis Chemoprophylaxis should be administered only in selective grips in high P. falciparum endemic areas. Use of personal protection measures including Insecticide Treated bed Nets (ITN) / Long Lasting Insecticidal Nets (LLIN) should be encouraged for pregnant women and other vulnerable population including travellers for longer stay However, for longer stay of Military and Para-Military forces in high Pf endemic areas, the practice of chemoprophylaxis should be followed wherever appropriate.

43. Short term chemoprophylaxis (up to 6 weeks) Doxycycline : 100 mg once daily for adults 1.5 mg/kg once daily for children(contraindicated in children below 8 years) started 2 days before travel and continued for 4 weeks after leaving the malarious area.

44. Chemoprophylaxis for longer stay (more than 6 weeks) Mefloqiune : 250 mg weekly for adults should be administered two weeks before, during and four weeks after exposure. CQ or Mefloquine resist P. falci Atovaquone / proguanil (250/100) ( Malarone ) Begin 1–2 days before travel Take daily at the same time each day while in the malarious areas Continue for 7 days after leaving such areas

45. References: Harrison’s textbook of internal medicine, 18 th / e WHO Guidelines for the treatment of malaria (2010) -- 2nd edition. Diagnosis and treatment of malaria 2013, NVBDCP Website of National Vector Borne Disease Control Programme http://www.nvbdcp.gov.in/malaria-new.html

46. Thank you