Malaria

Richard Moriarty, MD University of Massachusetts Medical School

Objectives

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Scope of the problem The parasite The symptoms The treatment Preventive measures Questions

Malaria - worldwide

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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

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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

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Asexual phase http://www.who.int/tdr/diseases/malaria/lifecycle.htm

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Blood Liver RBC Sexual phase

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Blood Gut of female mosquito Saliva gland http://www.wellcome.ac.uk/stellent/groups/corporatesite/@msh_publis hing_group/documents/web_document/wtd039685.swf

sporozoites

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

The Numbers

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70 kg person has @ 5 liters of blood = 5 x 10 3 ml = 5 x 10 6 μL times 5 x 10 6 RBCs per μL of blood = 2.5 x 10 13 RBCs 1% parasitemia= 1 in 100 iRBCs= 2.5 x 10 11 = 250 billion parasites 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

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Plasmodium vivax Plasmodium ovale

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Plasmodium malariae

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Plasmodium falciparum

• www.rph.wa.gov.au/malaria/diagnosis.html

Plasmodium vivax

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~43% of cases WW

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Paroxysms on a 48 hr cycle

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Relapses up to 8 years

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merozoites infect only young RBC’s

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RBC’s usually enlarged

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Schuffner’s dots

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common in temperate zones

Plasmodium malariae

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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

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rare in humans

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found in tropical S. Africa and Western Pacific

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<1% WW.

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mildest and rarest form of malaria

Plasmodium falciparum

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most pathogenic and virulent form

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common in tropics, formerly in temperate zones

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~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?

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Ability to infect all age of RBCs Higher multiplication capacity Sequestration (cytoadherance and rosetting)

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Capillary leak syndromes End organ failure

Malaria Symptoms

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Early generalized symptoms

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Malaise, myagias, headache, low grade fever Fever is not always present Repeatedly infected adults may have few symptoms Paroxysms

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Chills, nausea, emesis, intense HA, fever Severe malaria

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Prostration, shock, metabolic acidosis hypoglycemia Severe anemia, jaundice Organ failure (pulmonary edema, hemoglobinuria,etc) Cerebral malaria

Physical Findings

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Fever Tachycardia Hypotension Jaundice Pallor Splenomegaly Later, hemoglobinuria, pulmonary edema, bleeding, acute renal failure

Cerebral malaria

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Agitation Seizures Coma Cytoadherence CFR 20% Significant neurological residua

Features, Outcome of CNS Malaria in Kenyan Children

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33% of ped admissions malaria 1 st dx 47% of those had neurologic sx

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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

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Clinical diagnosis is inaccurate Blood smear

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Giemsa

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Field’s Rapid tests

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HRP-2: may stay + for >7 days

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pLDH: clears quickly PCR detection of antigen in urine & saliva http://www.wpro.who.int/sites/rdt

Malaria in Pregnancy

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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

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Dengue Typhoid Sepsis/bacteremia Acute schistosomiasis Yellow fever Leptospirosis African tick fever

Treatment

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Quinine

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IV, oral, rectal Quinidine

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Cinchonism: rashes, deafness, blurred vision, confusion Chloroquine – resistance common Sulfadoxine-pyrimethamine – resistance common

Treatment

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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

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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

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Artesunate Artemether Artemotil Dihydroartemisinin Rapidly eliminated Reduces parasite load by 10 8 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

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Access to affordable appropriate drugs

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Chloroquine $0.20 but widespread resistance

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Fansidar widespread resistance

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Artemether-lumefantrine (Coartem) $0.90 – 2.40 (private $15)

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Artesunate-amodiaquine (ASAQ) $0.50 but limited availability

Artemisinin Combination Therapy

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Artemether / lumifantrine: Coartem Artesunate / amodiaquine: ASAQ

WHO Malaria Treatment Guidelines 2006

Treatment - supportive

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Transfusion may be lifesaving to reverse tissue hypoxia and metabolic acidosis

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Intermittent preventive treatment during pregnancy

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IPTi

Preventive Measures

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Insecticide-treated bednets Topical insecticides Indoor residual spraying Intermittent Preventive Treatment during pregnancy: sulfadoxine pyrimethamine

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Counterfeit drugs ? Vaccine

Malaria

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Low tech solutions: prevention

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Insecticide-treated bed nets

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In-house spraying Drainage Higher tech solutions

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Intermittent preventive treatment in pregnancy

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Intermittent preventive treatment in infancy Prompt evaluation of febrile illnesses Rectal quinine for acute management High tech solutions

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Drugs and vaccine

Liberia’s Goals for Malaria

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Rapid scale-up of

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ACT’s

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IPTp

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ITN’s

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IRS Expand microscopic diagnosis Use rapid tests until good microscopy $12.5 million budget

Treatment Miscellany

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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