Malaria Richard Moriarty, MD University of Massachusetts Medical School.

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