1. Malaria Richard Moriarty, MD University of Massachusetts Medical School

2. Objectives • Scope of the problem • The parasite • The symptoms • The treatment • Preventive measures • Questions

3. Malaria - worldwide • 1.5 billion live in endemic areas • over 500 million infected • 1-2 million deaths per year • Most deaths in children < age 5 years old • Caused by protozoan from Plasmodium genus • Transmitted by female Anopheles mosquito

4. Areas of Malaria Transmission and Antimalarial Drug Resistance

5. Malaria in Liberia • Leading cause of morbidity and mortality • Year-long stable transmission • 40% of outpatient visits • 18% of inpatient deaths • 21,000 deaths in <5 years of age • Only 18% households have bednets • Only 4% of kids get first choice med From President’s Malaria Initiative Liberia’s Malaria Operational Plan FY 2008

6. Life cycle of Plasmodium • Asexual phase http://www.who.int/tdr/diseases/malaria/lifecycle.htm • Blood • Liver • RBC • Sexual phase • Blood • Gut of female mosquito • Saliva gland • http://www.wellcome.ac.uk/stellent/groups/corporatesite/@msh_publishing_group/documents/web_document/wtd039685.swf

8. Life Cycle of Plasmodium falciparum sporozoites Rosenthal P. N Engl J Med 2008;358:1829-1836

9. The Numbers • 70 kg person has @ 5 liters of blood = 5 x 103ml = 5 x 106μL times 5 x 106RBCs per μL of blood = 2.5 x 1013RBCs • 1% parasitemia= 1 in 100 iRBCs= 2.5 x 1011 parasites = 250 billion parasites • P. vivax invades predominately reticulocytes and so has a built-in ceiling, but P. falciparum can invade all ages of RBCs. • Pyrogenic density P. falciparum 10,000/uL nonimmune; 100,000/uL immune; P. vivax100/uL David Sullivan, MD; Johns Hopkins School of Public Health

10. Malaria species • Plasmodium vivax • Plasmodium ovale • Plasmodium malariae • Plasmodium falciparum • www.rph.wa.gov.au/malaria/diagnosis.html

11. Plasmodium vivax • ~43% of cases WW • Paroxysms on a 48 hr cycle • Relapses up to 8 years • merozoites infect only young RBC’s • RBC’s usually enlarged • Schuffner’s dots • common in temperate zones

13. Plasmodium malariae • not found in contiguous distribution • ~7% WW • 72 hour cycle • second exoerythrocytic stage not observed • reactivation can occur up to 53 years post-infection! • merozoites infect only old RBC’s • low parasitemia

14. Plasmodium ovale • rare in humans • found in tropical S. Africa and Western Pacific • <1% WW. • mildest and rarest form of malaria

15. Plasmodium falciparum • most pathogenic and virulent form • common in tropics, formerly in temperate zones • ~50% WW • greatest killer of humans in the tropics • only one exoerythrocytic stage, no relapse • merozoites invade RBC’s of all ages • parasitemia very high • Marginal forms; double chromatin dots

17. Why is P. falciparum so dangerous? • Ability to infect all age of RBCs • Higher multiplication capacity • Sequestration (cytoadherance and rosetting) • Capillary leak syndromes • End organ failure

18. Malaria Symptoms • Early generalized symptoms • Malaise, myagias, headache, low grade fever • Fever is not always present • Repeatedly infected adults may have few symptoms • Paroxysms • Chills, nausea, emesis, intense HA, fever • Severe malaria • Prostration, shock, metabolic acidosis • hypoglycemia • Severe anemia, jaundice • Organ failure (pulmonary edema, hemoglobinuria,etc) • Cerebral malaria

19. Physical Findings • Fever • Tachycardia • Hypotension • Jaundice • Pallor • Splenomegaly • Later, hemoglobinuria, pulmonary edema, bleeding, acute renal failure

20. Cerebral malaria • Agitation • Seizures • Coma • Cytoadherence • CFR 20% • Significant neurological residua

21. Features, Outcome of CNS Malaria in Kenyan Children • 33% of ped admissions malaria 1st dx • 47% of those had neurologic sx • 37% seizures – multiple or prolonged • 20% prostration • 13% impaired consciousness or coma • Neuro involvement associated with met acidosis, hypoglycemia, hyperkalemia • 2.8% mortality (75% of those had CNS) JAMA 2007;297:2232-2240

22. Malaria Diagnosis • Clinical diagnosis is inaccurate • Blood smear • Giemsa • Field’s • Rapid tests • HRP-2: may stay + for >7 days • pLDH: clears quickly • PCR detection of antigen in urine & saliva http://www.wpro.who.int/sites/rdt

23. Malaria in Pregnancy • Increased risk of spontaneous abortion, stillbirth, pre-term birth and low birth weight • Low birth weight is the single greatest risk factor associated with perinatal mortality; up to 200,000 newborn deaths/year occur in Africa due to malaria • Malaria parasites can cross the placenta and cause malaria & anemia in the newborn • HIV-malaria-infected women more likely for anemia, preterm birth, IUGR, infant deaths

24. Increased risk of HIV transmission

25. Differential diagnosis • Dengue • Typhoid • Sepsis/bacteremia • Acute schistosomiasis • Yellow fever • Leptospirosis • African tick fever

26. Treatment • Quinine • IV, oral, rectal • Quinidine • Cinchonism: rashes, deafness, blurred vision, confusion • Chloroquine – resistance common • Sulfadoxine-pyrimethamine – resistance common

27. Treatment • For children < age 5 years in a setting of stable high transmission, consider treating all febrile episodes if no other cause of fever • Liberia’s National Malaria control Program does not support this; NMCP supports confirmatory diagnosis with RDT to encourage HCW’s to see other diagnoses when RDT’s negative

28. Treatment - Artemesinins • Rapid blood schizonticide • Used with other med to prevent recrudescence • Recommended for P. falciparum only • Dose varies with preparation • Possible neurotoxicity • Increasing evidence of safety during pregnancy

29. Artemisinin Preparations • Artesunate • Artemether • Artemotil • Dihydroartemisinin • Rapidly eliminated • Reduces parasite load by 108 • Paired with slowly eliminated drug • Allows effective treatment in 3 days • Very well tolerated; few side effects • Rx failure within 14 days is rare

30. Malaria Treatment • Access to affordable appropriate drugs • Chloroquine $0.20 but widespread resistance • Fansidar widespread resistance • Artemether-lumefantrine (Coartem) $0.90 – 2.40 (private $15) • Artesunate-amodiaquine (ASAQ) $0.50 but limited availability

31. Artemisinin Combination Therapy • Artemether / lumifantrine: Coartem • Artesunate / amodiaquine: ASAQ

32. WHO Malaria Treatment Guidelines 2006

33. Treatment - supportive • Transfusion may be lifesaving to reverse tissue hypoxia and metabolic acidosis • Intermittent preventive treatment during pregnancy • IPTi

34. Preventive Measures • Insecticide-treated bednets • Topical insecticides • Indoor residual spraying • Intermittent Preventive Treatment during pregnancy: sulfadoxine-pyrimethamine • Counterfeit drugs • ? Vaccine

35. Malaria • Low tech solutions: prevention • Insecticide-treated bed nets • In-house spraying • Drainage • Higher tech solutions • Intermittent preventive treatment in pregnancy • Intermittent preventive treatment in infancy • Prompt evaluation of febrile illnesses • Rectal quinine for acute management • High tech solutions • Drugs and vaccine

36. Liberia’s Goals for Malaria • Rapid scale-up of • ACT’s • IPTp • ITN’s • IRS • Expand microscopic diagnosis • Use rapid tests until good microscopy • $12.5 million budget

37. Treatment Miscellany • Antipyretics? • What to do if an infant vomits a dose? • Transfuse at what level? • Steroids? • Anticonvulsants? • Concomitant antibiotics?

38. References • WHO; Guidelines for the Treatment of Malaria; 2006 • WHO; malaria life cycle • CID; 2007;45:1446; intrarectal quinine • PRESIDENT’S MALARIA INITIATIVE; Malaria Operational Plan (MOP) LIBERIA FY 2008