Malaria Richard Moriarty, MD University of Massachusetts Medical School Objectives • • • • • • Scope of the problem The parasite The symptoms The treatment Preventive measures Questions 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 Areas of Malaria Transmission and Antimalarial Drug Resistance 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 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_publis hing_group/documents/web_document/wtd039685.swf Life Cycle of Plasmodium falciparum sporozoites Rosenthal P. N Engl J Med 2008;358:1829-1836 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 Malaria species • • • • Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium falciparum • www.rph.wa.gov.au/malaria/diagnosis.html 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 Plasmodium malariae • • • • • not found in contiguous distribution ~7% WW 72 hour cycle second exoerythrocytic stage not observed reactivation can occur up to 53 years postinfection! • merozoites infect only old RBC’s • low parasitemia Plasmodium ovale –rare in humans –found in tropical S. Africa and Western Pacific –<1% WW. –mildest and rarest form of malaria 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 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 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 Physical Findings • • • • • • • Fever Tachycardia Hypotension Jaundice Pallor Splenomegaly Later, hemoglobinuria, pulmonary edema, bleeding, acute renal failure Cerebral malaria • • • • • • Agitation Seizures Coma Cytoadherence CFR 20% Significant neurological residua 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 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 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 Increased risk of HIV transmission Differential diagnosis • • • • • • • Dengue Typhoid Sepsis/bacteremia Acute schistosomiasis Yellow fever Leptospirosis African tick fever Treatment • Quinine – IV, oral, rectal • Quinidine – Cinchonism: rashes, deafness, blurred vision, confusion • Chloroquine – resistance common • Sulfadoxine-pyrimethamine – resistance common 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 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 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 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 Artemisinin Combination Therapy • Artemether / lumifantrine: Coartem • Artesunate / amodiaquine: ASAQ WHO Malaria Treatment Guidelines 2006 Treatment - supportive • Transfusion may be lifesaving to reverse tissue hypoxia and metabolic acidosis • Intermittent preventive treatment during pregnancy • IPTi Preventive Measures • • • • Insecticide-treated bednets Topical insecticides Indoor residual spraying Intermittent Preventive Treatment during pregnancy: sulfadoxinepyrimethamine • Counterfeit drugs • ? Vaccine 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 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 Treatment Miscellany • • • • • • Antipyretics? What to do if an infant vomits a dose? Transfuse at what level? Steroids? Anticonvulsants? Concomitant antibiotics? 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