Malaria
Richard Moriarty, MDUniversity 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_publishing_group/documents/web_document/wtd039685.swf
Life Cycle of Plasmodium falciparum
Rosenthal P. N Engl J Med 2008;358:1829-1836
sporozoites
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 post-
infection!• 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: sulfadoxine-pyrimethamine
• 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