11 year old male with 11 year old male with fever and malaisefever and malaise

Chairman’s RoundsChairman’s RoundsSeptember 24, 2010September 24, 2010

David H. Rubin, MDDavid H. Rubin, MDDepartment of Pediatrics Department of Pediatrics St. Barnabas HospitalSt. Barnabas HospitalProfessor of Clinical PediatricsProfessor of Clinical PediatricsAlbert Einstein College of MedicineAlbert Einstein College of Medicine

PATIENT PROFILEPATIENT PROFILE

11 year old male with spiking 11 year old male with spiking temperatures to 103temperatures to 103F for 3 days, F for 3 days, vomiting, diarrhea, abdominal painvomiting, diarrhea, abdominal pain

Recent 1.5 month visit to Togo Recent 1.5 month visit to Togo (West Africa)(West Africa)

Labs Labs blood smear plasmodium blood smear plasmodium species 10.8%species 10.8%

Treatment: quinidineTreatment: quinidine

MALARIAMALARIA

Derived from Italian….”mal’aria” Derived from Italian….”mal’aria” meaning “bad air” – association with meaning “bad air” – association with marshy areasmarshy areas

End of 19End of 19thth century, Charles Laveran, century, Charles Laveran, French Army Surgeon: parasites in blood French Army Surgeon: parasites in blood of patient dying from malariaof patient dying from malaria

Dr. Ronald Ross; British Army in India: Dr. Ronald Ross; British Army in India: mosquitoes transmitted malariamosquitoes transmitted malaria

Professor Giovanni Grassi: human Professor Giovanni Grassi: human malaria only transmitted by malaria only transmitted by Anopheles Anopheles mosquitoesmosquitoes

MALARIAMALARIA

An ancient human diseaseAn ancient human disease Mentioned as early as 2700 BC in Mentioned as early as 2700 BC in

European and Chinese writingsEuropean and Chinese writings European colonists imported European colonists imported

malaria to America malaria to America (p vivax and (p vivax and p. malariae);p. malariae); p. falciparump. falciparum coincided with African slave tradecoincided with African slave trade

Prevention difficult, no drug Prevention difficult, no drug universally effectiveuniversally effective

MALARIAMALARIA

2004: 350-400 million cases worldwide2004: 350-400 million cases worldwide Over 2 billion people (40% of world’s Over 2 billion people (40% of world’s

population) at risk of contracting population) at risk of contracting diseasedisease

Malaria deaths (1999-2004, WHO data) Malaria deaths (1999-2004, WHO data) estimated at 1.1-1.3 millionestimated at 1.1-1.3 million

Cost (in Africa): $12 billion; 25% of all Cost (in Africa): $12 billion; 25% of all deaths of children < 5 years of agedeaths of children < 5 years of age

USA and Europe: health measures, USA and Europe: health measures, economic development have achieved economic development have achieved near elimination of diseasenear elimination of disease

MALARIAMALARIA

Transmitted through bite of Transmitted through bite of Anopheles Anopheles mosquito (400 mosquito (400 species-60 malaria vectors)species-60 malaria vectors)

Malaria parasites are single celled Malaria parasites are single celled organisms of genus organisms of genus PlasmodiumPlasmodium • Only 4 species can infect humansOnly 4 species can infect humans• P. Falciparum, P. vivax, P. ovale, P. P. Falciparum, P. vivax, P. ovale, P.

malariaemalariae

GLOBAL BURDEN OF GLOBAL BURDEN OF MALARIA MALARIA

(Milner 2008)(Milner 2008)

1.1-1.3 million deaths worldwide; 1.1-1.3 million deaths worldwide; primarily young children with severe primarily young children with severe malaria presenting as coma, severe malaria presenting as coma, severe anemia, or respiratory distressanemia, or respiratory distress

Current responseCurrent response: drugs, : drugs, impregnated bed nets, indoor impregnated bed nets, indoor spraying, DEET, long sleeves, pants, spraying, DEET, long sleeves, pants, and footwareand footware

Future goalsFuture goals: vaccine, improved : vaccine, improved treatment of severe diseasetreatment of severe disease

MALARIAMALARIA

P. falciparumP. falciparum – severe potentially fatal – severe potentially fatal malaria; primary cause of malaria deaths malaria; primary cause of malaria deaths of young children in Africaof young children in Africa• Infected erythrocytes can obstruct Infected erythrocytes can obstruct

small vessels causing cerebral malariasmall vessels causing cerebral malaria P. vivax – P. vivax – most commonly causes anemiamost commonly causes anemia P. ovale – P. ovale – least common; primarily in least common; primarily in

West AfricaWest Africa

COMPLICATIONS FROM COMPLICATIONS FROM P. falciparumP. falciparum

Massive hemolysis (Blackwater fever)Massive hemolysis (Blackwater fever) Renal failureRenal failure Pulmonary edemaPulmonary edema Cerebral dysfunctionCerebral dysfunction

level of consciousnesslevel of consciousness• Behavioral changesBehavioral changes• HallucinationsHallucinations• SeizuresSeizures• LP is usually NORMALLP is usually NORMAL

Local Mosquito-Borne Transmission - United States, 1957-2005

SYMPTOMS OF SYMPTOMS OF MALARIAL INFECTIONMALARIAL INFECTION

Accumulation and sequestration of Accumulation and sequestration of parasitic infected RBC’s in brain, heart, parasitic infected RBC’s in brain, heart, kidney, lung, is commonkidney, lung, is common

SymptomsSymptoms: as early as 6-8 days after bite : as early as 6-8 days after bite or several months lateror several months later

Typical attackTypical attack: chills and tachycardia, : chills and tachycardia, high temperature followed by a profuse high temperature followed by a profuse diaphoresisdiaphoresis

Also may have: cough, respiratory distress, Also may have: cough, respiratory distress, joint pain, headache, watery diarrhea, joint pain, headache, watery diarrhea, vomiting, seizuresvomiting, seizures

Severe malariaSevere malaria: jaundice, kidney failure, : jaundice, kidney failure, severe anemiasevere anemia

DIAGNOSIS OF DIAGNOSIS OF MALARIAMALARIA

Clinical observations, case history, and Clinical observations, case history, and diagnostic testingdiagnostic testing

Collect blood when temperature rising Collect blood when temperature rising (best yield)(best yield)

Examine thick/thin smears; Examine thick/thin smears; 1 parasite/200ųL blood can be 1 parasite/200ųL blood can be detected – detected – CAUTION: these may be CAUTION: these may be negative early in illness; negative early in illness; interpretation variableinterpretation variable

Rapid diagnostic dip tests – expensive Rapid diagnostic dip tests – expensive and only falciparum can be diagnosedand only falciparum can be diagnosed

TRANSMISSION (CDC)TRANSMISSION (CDC)

In rare cases malaria parasites can be In rare cases malaria parasites can be transmitted from one person to another transmitted from one person to another without requiring passage through a mosquito without requiring passage through a mosquito (from mother to child in "congenital malaria", (from mother to child in "congenital malaria", or through transfusion, organ transplantation or through transfusion, organ transplantation or shared needles)or shared needles)

Some species of monkeys and apes can be Some species of monkeys and apes can be experimentally infected with some of the four experimentally infected with some of the four "human" malaria parasite species, and in "human" malaria parasite species, and in nature some apes are infected with parasites nature some apes are infected with parasites similar to those infecting humans. But for all similar to those infecting humans. But for all practical purposes the role of an animal practical purposes the role of an animal reservoir is negligible.reservoir is negligible.

MANAGEMENTMANAGEMENT

Suspect in any febrile child from Suspect in any febrile child from endemic areaendemic area

CBC, platelets may show anemia CBC, platelets may show anemia and thrombocytopeniaand thrombocytopenia

See CDC “Guidelines for See CDC “Guidelines for Treatment” Treatment” (www.cdc.gov/malaria/pdf/treatm(www.cdc.gov/malaria/pdf/treatmenttable.prf)enttable.prf)

LIFE CYCLELIFE CYCLE

LIFE CYCLELIFE CYCLE

Sporozoite entry into blood stream Sporozoite entry into blood stream (mosquito takes a blood meal)(mosquito takes a blood meal)• Infective sporozoites from salivary gland Infective sporozoites from salivary gland

of of AnophelesAnopheles mosquito injected into mosquito injected into human host (with anticoagulant saliva)human host (with anticoagulant saliva)

• Once in bloodstream, Once in bloodstream, P. falciparumP. falciparum sporozoites reach the liver, remain for 9-sporozoites reach the liver, remain for 9-16 days and undergo asexual replication 16 days and undergo asexual replication ((exo-erythrocytic schizogonyexo-erythrocytic schizogony))

LIFE CYCLELIFE CYCLE

Each sporozoite gives rise to Each sporozoite gives rise to thousands of merozoites, thousands of merozoites, which invade RBC’s when which invade RBC’s when released from the liverreleased from the liver

This process takes 8-25 daysThis process takes 8-25 days Ensures protection of parasite Ensures protection of parasite

from host immune systemfrom host immune system

ERYTHROCYTIC ERYTHROCYTIC SCHIZOGONYSCHIZOGONY

Trophozoite developmentTrophozoite development• ““Ring” formRing” form• Multiple rounds of nuclear divisionMultiple rounds of nuclear division• Formation of schizonts, which contains 20 Formation of schizonts, which contains 20

merozoites; released after RBC lysis to merozoites; released after RBC lysis to further invade infected RBC’sfurther invade infected RBC’s

• Coincides with increase in temperatureCoincides with increase in temperature• Usually occurs at same time of the dayUsually occurs at same time of the day

• Infected RBC’s (after lysis) stimulates TNF Infected RBC’s (after lysis) stimulates TNF and other cytokines producing clinical and other cytokines producing clinical presentationpresentation

GAMETOCYTE GAMETOCYTE FORMATIONFORMATION

Small number of merozoites in Small number of merozoites in RBC’s differentiate to form micro- RBC’s differentiate to form micro- and macro-gametocytes and macro-gametocytes (male/female) and have no other (male/female) and have no other activityactivity

These gametocytes transmit the These gametocytes transmit the infection to new hosts through infection to new hosts through female female AnophelesAnopheles

MALARIA AND RED BLOOD CELLS

MALARIA AND THE RED MALARIA AND THE RED BLOOD CELLBLOOD CELL

Malaria defenses inherent in Malaria defenses inherent in RBC’s – constant creation and RBC’s – constant creation and destructiondestruction

RBC defenses have arisen by RBC defenses have arisen by natural selectionnatural selection

Mechanisms not well Mechanisms not well understoodunderstood

Cell Cell ComponentComponent

AlterationAlteration Global Global DistributionDistribution

MembraneMembrane Duffy antigen Duffy antigen wallwall

AfricaAfrica

Melanesian Melanesian elliptocytosiselliptocytosis

Africa, Middle Africa, Middle East, IndiaEast, India

HemoglobinHemoglobin Hb SHb S AfricaAfrica

Hb CHb C AfricaAfrica

Hb EHb E SE AsiaSE Asia

ThalassemiaThalassemia Africa, Medit., Africa, Medit., India, SE AsiaIndia, SE Asia

ThalassemiaThalassemia Africa, IndiaAfrica, India

RBC EnzymesRBC Enzymes G6PDG6PD Africa, Medit., Africa, Medit., India, SE AsiaIndia, SE Asia

MALARIA AND THE RED MALARIA AND THE RED BLOOD CELLBLOOD CELL

Sickle Cell TraitSickle Cell Trait• Sickle cell trait offspring may Sickle cell trait offspring may

have 1 gene for normal Hg and 1 have 1 gene for normal Hg and 1 for sickle Hg transmitted to next for sickle Hg transmitted to next generation generation

• Impairs malaria growth and Impairs malaria growth and developmentdevelopment

• Sickle cell trait is the genetic Sickle cell trait is the genetic condition selected for in regions condition selected for in regions of endemic malariaof endemic malaria

SPECIAL POPULATIONSSPECIAL POPULATIONS

Malaria especially dangerous toMalaria especially dangerous to• Pregnant womenPregnant women

• Parasitic infiltration of placentaParasitic infiltration of placenta• Associated with premature Associated with premature

delivery, low birthweight, delivery, low birthweight, increased mortality in newbornincreased mortality in newborn

• After repeated exposure to After repeated exposure to malaria, pregnant women develop malaria, pregnant women develop immunityimmunity

• Young childrenYoung children

MALARIA AND MALARIA AND PREGNANCYPREGNANCY

Susceptibility to malaria greatest Susceptibility to malaria greatest in 1in 1stst and 2 and 2ndnd pregnancy pregnancy

Ability of infected erythrocytes to Ability of infected erythrocytes to accumulate in the maternal accumulate in the maternal vascular area of the placenta; vascular area of the placenta; other stages are sequestered in other stages are sequestered in the placentathe placenta

Clinical trials now occurringClinical trials now occurring

CONGENITAL MALARIACONGENITAL MALARIA

5 cases reported since 2000 (75 5 cases reported since 2000 (75 since 1950)since 1950)

Diagnosis when parasites are Diagnosis when parasites are seen on peripheral smear during seen on peripheral smear during 11stst week of life week of life

In the USA, presentation usually In the USA, presentation usually with fever, splenomegaly, with fever, splenomegaly, hepatomegaly, irritability, icterus, hepatomegaly, irritability, icterus, feverfever

TREATMENT

ANTIMALARIAL ANTIMALARIAL MEDICATIONSMEDICATIONS

Chloroquine, mefloquine, Chloroquine, mefloquine, doxycycline do not prevent initial doxycycline do not prevent initial malarial infections in humans; they malarial infections in humans; they act on parasites that infect act on parasites that infect erythrocytes once released from erythrocytes once released from maturational phase in the livermaturational phase in the liver

Currently high worldwide resistance Currently high worldwide resistance of of p. falciparump. falciparum to chloroquine to chloroquine

Copyright restrictions may apply.Griffith, K. S. et al. JAMA 2007;297:2264-2277.

MALARIA TREATMENT ALGORITHM

?SAFETY OF ?SAFETY OF ANTIMALARIAL DRUGSANTIMALARIAL DRUGS

ChloroquineChloroquine• Headaches, nausea, vomiting, blurred Headaches, nausea, vomiting, blurred

vision, pruritis, itchingvision, pruritis, itching• Long term use: neuropathy (rare)Long term use: neuropathy (rare)• Safe in pregnancy; but low safety Safe in pregnancy; but low safety

marginmargin• Cardiotoxicity in overdoses a major Cardiotoxicity in overdoses a major

problemproblem• Contraindicated if H/O seizures, renal Contraindicated if H/O seizures, renal

disease, hepatic diseasedisease, hepatic disease

?SAFETY OF ?SAFETY OF ANTIMALARIAL DRUGSANTIMALARIAL DRUGS

QuinineQuinine• Oral prep may cause “cinchonism” Oral prep may cause “cinchonism”

– nausea, vomiting, vertigo, – nausea, vomiting, vertigo, tinnitus, headache, blurred vision; tinnitus, headache, blurred vision; these are reversible symptomsthese are reversible symptoms

• Increased insulin secretion; causes Increased insulin secretion; causes severe hypoglycemia in pregnancy severe hypoglycemia in pregnancy in 50% of patients in 50% of patients

• May damage auditory nerveMay damage auditory nerve

MALARIA VACCINESMALARIA VACCINES

Clinical trials now underway using Clinical trials now underway using target antigens at each parasite target antigens at each parasite stagestage

Vaccine and field trials extremely Vaccine and field trials extremely expensiveexpensive

Sterile immunity NOT observed in a Sterile immunity NOT observed in a large proportion of subjectslarge proportion of subjects• Are children in endemic areas ready for Are children in endemic areas ready for

multiple doses?multiple doses?

ETIOLOGY OF TRAVEL ETIOLOGY OF TRAVEL RELATED FEVERRELATED FEVER

(Wilson, 2007)(Wilson, 2007)

Geosentinel Surveillance Network – Geosentinel Surveillance Network – worldwide multicenter databaseworldwide multicenter database

From 3/97-3/06, N=24,920 travelersFrom 3/97-3/06, N=24,920 travelers• 28% had fever28% had fever

• 26% hospitalized26% hospitalized

• Malaria: 21%Malaria: 21%• 33% of all deaths (N=12)33% of all deaths (N=12)

• Others: Dengue fever, enteric fever, Others: Dengue fever, enteric fever, rickettsiosesrickettsioses

SUMMARYSUMMARY

Malaria is caused by mosquito Malaria is caused by mosquito transmitted parasite transmitted parasite P. falciparumP. falciparum and is and is responsible for deaths in responsible for deaths in tropical/subtropical regionstropical/subtropical regions

Genome of Genome of p. falciparum p. falciparum clone 3D7 clone 3D7 already sequenced – will be able to already sequenced – will be able to reveal drug targetsreveal drug targets

Race is on to develop vaccines/drugs to Race is on to develop vaccines/drugs to interrupt life cycle of parasiteinterrupt life cycle of parasite

Think of diagnosis with FUO and travel Think of diagnosis with FUO and travel history – watch for neurologic signs and history – watch for neurologic signs and symptomssymptoms

REFERENCESREFERENCES

Tuteja R. Malaria – an overview. Tuteja R. Malaria – an overview. FEBS Journal. 2007;274:4670-4679.FEBS Journal. 2007;274:4670-4679.

Wilson ME, Freedman DO. Etiology Wilson ME, Freedman DO. Etiology of travel related fever. Curr Opin of travel related fever. Curr Opin Infect Dis 2007;20:449-453.Infect Dis 2007;20:449-453.

Hagmann et al. Congenital malaria. Hagmann et al. Congenital malaria. Ped Emerg Care 2007:23(5):326-Ped Emerg Care 2007:23(5):326-329.329.

WWW.CDC.GOVWWW.CDC.GOV

REFERENCESREFERENCES

Freedman D. Malaria prevention in short Freedman D. Malaria prevention in short term travelers. N Engl J Med term travelers. N Engl J Med 2008;359:603-12.2008;359:603-12.

Sharma S and Pathak S. Malaria vaccine: Sharma S and Pathak S. Malaria vaccine: a current perspective. J Vector Borne Dis a current perspective. J Vector Borne Dis 2008;45:1-20.2008;45:1-20.

Milner DA et al. Severe malaria in children Milner DA et al. Severe malaria in children and pregnancy: an update and and pregnancy: an update and perspective. Trends in parasitology perspective. Trends in parasitology 2008;24:12:590-595.2008;24:12:590-595.