Malaria ReviewMalaria Review

ObjectivesObjectives

Recognize parasite on thin filmUnderstand patterns of illness by speciesBe able to treat a caseBe able to prevent a caseUnderstand the global epidemiology of this

disease

Past ExperiencePast Experience

One of worst ID pathogens in world, clearly expanding range and increasing prevalence

Objective of WHO eradication campaign in 1950’s-60’s, and became one of most impressive public health defeats ever

Target of current “Roll Back Malaria” initiative, in face of resurgence

Recent Issues in MalariaRecent Issues in Malaria

“Monkey malaria”Rise of vivaxChloroquine – an antiviral agent?PF4 – the cause of cerebral malaria?

Baird, J. K. N Engl J Med 2005;352:1565-1577

Risk of Plasmodium falciparum Malaria Worldwide

Malaria EpidemiologyMalaria Epidemiology

2.4 billion people live in malaria endemic countries

Annual incidence of 100 to 300 million cases

About 1.5 to 2.7 million deaths per year from malaria

Malaria EpidemiologyMalaria Epidemiology

Endemicity measured by percentage of 2 to 9 y.o. with splenomegaly or parasitemia– Hypoendemic - 0-10%– Mesoendemic - 10-50%– Hyperendemic - 50-75%– Holoendemic - over 75%

Prevalence/Disease PatternsPrevalence/Disease Patterns

P. falciparumP. falciparum Epidemiology Epidemiology

Only malaria parasite routinely causing death

1.5-2.7 million deaths/yearMost in sub-Saharan AfricaMostly among infants

EpidemiologyEpidemiology

More than 90% of all malaria cases are in sub-Saharan Africa. Two-thirds of the remainder are concentrated in six countries -- India, Brazil, Sri Lanka, Vietnam, Colombia and Solomon Islands, in decreasing order of prevalence.

Malaria Life CycleMalaria Life Cycle

Baird, J. K. N Engl J Med 2005;352:1565-1577

Plasmodium sppPlasmodium spp..

172 Plasmodium species of birds, mammals, reptiles

4 routinely infect humans, 1 every so often– vivax, ovale, falciparum and malariae– knowlesi occasional human pathogen

P vivax and P falciparum are the most important, causing the vast majority of disease

Details of Details of Plasmodium sppPlasmodium spp.. P falciparum P vivax P ovale P malariae

Hepatic phase

5.5 8 9 15

RBC cycle 2 2 2 3

RBC preference

All reticulocyte reticulocyte Old RBC

Hypnozoites No Yes Yes No

Schizont/ merozoites

30,000 10,000 15,000 2,000

Max duration

2 years 4 years 4 years 40+ yrs.

P. knowlesiP. knowlesi

The fifth human malariaMost cases from Malaysia, recognized to

naturally infect humans in 1965May cause fatal disease due to 24 hour

replication cycleDx – difficult to differentiate from Pm; PCRChloroquine is effective rx (for both of the

above)

Incubation PeriodIncubation Period

Case Report 1Case Report 1

7 y.o. African boy with fever, seizures and DIC

Subject well until arrival from Sierra Leone, c/o fever, malaise

2 days after arrival new onset generalized seizure, taken immediately to hospital. Treated for meningitis with ceftriaxone.

Case Report 1Case Report 1

Seizures and fever continue over next 2 days, despite antiseizure medication

On 4th hospital day, lab tech notes malaria parasites on CBC

Patient transferred to tertiary care facility

Case Report 1Case Report 1

On arrival, patient comatose, frank DIC and P.falciparum parasitemia of 20%

Intravenous quinidine/doxy plus exchange transfusion in the intensive care unit (ICU)

Day 1 ICU, subject develops renal and hepatic insufficiency, requires endotracheal intubation for respiratory failure.

Focal neuro exam ICU day 2 – CT head shows small CVA

Fully recovers, walks out of hospital day 10

Pathogenesis ModelsPathogenesis Models

Sequestration ModelCytokine Model

Fever CurveFever Curve

Clinical PresentationClinical Presentation

The classic flu-like illness Commonly mistaken for influenza, other URI,

travelers' diarrhea, viral hepatitis, or encephalitis Fever, headache, muscle and joint aches,

abdominal pain, diarrhea, etc. Anyone coming from endemic area must be

considered to have malaria until proven otherwise Main reason it’s missed – no travel history taken

SymptomsSymptoms

Symptom Frequency Symptom Frequency

Fever 97% Abd pain 21%

Chills 88% Diarrhea 18%

Malaise 82% Cough 18%

Nausea 36% Vomiting 31% Pharyngitis 25%

SignsSigns

Sign Frequency Temperature > 39C 30% Splenomegaly 26% Hepatomegaly 11% Icterus 7% Rash 4% CNS changes 2%

Laboratory ValuesLaboratory Values

Lab value Frequency Lab value Frequency

LDH >200 78% BUN > 18 20%

Plt < 150K 58% Alk phos > 115

19%

WBC < 5K 37% Creat > 1.2 14%

Proteinuria 33% WBC > 10K 8%

Hb < 12 28%

AST > 40 25%

Differential DiagnosisDifferential Diagnosis

Typhoid feverDengueInfluenzaMeningococcemiaLeptospirosisBacterial gastroenteritisViral encephalitis

DiagnosisDiagnosis

Thick/Thin Blood film– Gold Standard– quantify by parasites/200 WBC, then convert to

parasites/L for thick film– % RBC parasitized in 1000 cells for thin film– films must be repeated every 6-8 hours for 2

days to confirm negative

Newer Diagnostic MethodsNewer Diagnostic Methods

Rapid testing (multiple)Antibody testing (ELISA)PCR testing

– P. malariae

Case Report 2Case Report 2

17 y.o. resident of Ghana visiting as tourist seen for fever, HA, myalgias

Diagnosed with P. falciparum malaria, 2% RBC infected, treated with oral quinine and Fansidar

2 days into therapy develops cough and SOB

Case Report 2Case Report 2

Cough and SOB worsen over next 2 daysSeen at hospital, exam with bibasilar

crackles, CXR with alveolar infiltrate, possible pulmonary edema. Smear neg

Pt decompensates, requires ETTAfter 2 days, extubatedFull recovery in next 2 days

Case number 3Case number 3

25 yo Guyanese gold miner admitted with h/o fever, MS changes.

On admission pt is comatose, Hct=8.0 and glucose=45.

Pt has parasitemia of 25%Given IV Quinidine and doxyStill comatose 24 hours post-Rx

Case number 3Case number 3

Multiple amps D50 given, still intermittently hypoglycemic day 2

QT interval prolongation necessitates reduction of quinidine drip rate

Dramatic recovery after 48 hours of therapy, recovers full neuro function

The AntimalarialsThe Antimalarials

Quinolines– 4-aminoquinolines chloroquine, amodiaquine, pyronaridine– Aryl-amino alcohols quinine and quinidine, mefloquine,

halofantrine, lumefantrine (benflumetol) Artemisinins: dihydroartemisinin, artesunate,

artemether, arteether Antifolates

– sulphonamides and sulphones– pyrimethamine, biguanides and triazine metabolites,

quinazolines 8-aminoquinolines (primaquine)

Treatment – Uncomplicated Not PFTreatment – Uncomplicated Not PF

P. vivax, ovale, malariae, known sensitive Pf

Chloroquine 10 mg base/kg followed by 5 mg/kg at 12, 24 and 36 h (or amodiaquine, see below)

Chloroquine-R but SP-S

SP 3 tablets x 1

Amodiaquine (not Asia) 10 mg/kg qd for 3 days

Treatment-Uncomplicated PFTreatment-Uncomplicated PF

Malarone 4 tabs po qd for 3 daysMefloquine 25 mg/kg (5 tab) for non-

immune; 15 mg/kg semi-immuneQuinine 10 mg/kg 3x/day + doxy 2.5

mg/kg/day x 7 days (or SP, or Clinda)Coartem (not in US) 1.5/9 mg/kg 2x/day for

3 days with foodLapdap (not in US) 1 po qd for 3 days

WHO CRITERIA FOR SEVERE WHO CRITERIA FOR SEVERE MALARIAMALARIA

Cerebral malaria with unrousable coma

Severe normocytic anemia

Renal failure Pulmonary edema Hypoglycemia

Shock (DIC)/spontaneous

bleeding Repeated generalized

convulsions Acidemia/acidosis Malarial

hemoglobinuria

Severe MalariaSevere Malaria

Cerebral Malaria– unrousable coma

Severe Anemia– Hct 15% in 10K para

Renal failure– 400 cc/24 hrs

Pulmonary Edema Hypoglycemia

– <40mg/dl

Shock– sys BP <70 mm Hg

DIC Generalized Seizures

– >2 in 24 hrs Acidemia

– pH<7.25 or HCO3<15 Macrohemoglobinuria Postmortem dx

Severe Malaria: Adult vs. Severe Malaria: Adult vs. ChildChild

Sign/symptom Adult Child

Cough Uncommon early Common early

Duration sx b severe 2-3 days 1-2 days

Duration coma p rx 2-4 days 1-2 days

Jaundice Common Uncommon

Hypoglycemia Uncommon pre-rx Common pre-rx

Renal failure Common Rare

Post-neuro seq Uncommon Common (10%)

Treatment - Severe MalariaTreatment - Severe Malaria

– For chloroquine sensitive P.f.Chloroquine 10 mg base/kg IV over 8 h f/b

15 mg/kg over 24 h OR 3.5 mg/kg q6h OR oral regimen by NG tube– For chloroquine resistant P.f.

Quinine or Quinidine IV + doxy/clinda/SPArtemether IM/artensunate IV or IM,

artemisinin PR

Management of Severe Management of Severe MalariaMalaria

A Few PointsA Few Points Exchange transfusion - controversial Fluid balance

– avoid pulm edema or azotemia (dialysis in severe overload, acidosis, electrolyte changes)

Watch for Gram - sepsis and pneumonia Monitor serum glucose Aggressive antiseizure therapy Intubation may be necessary

Other Aspects of Severe Other Aspects of Severe MalariaMalaria

Other Manifestations– Impaired consciousness but rousable– Prostration, extreme weakness– Hyperparasitemia (>5%)– Jaundice (3 mg/dL)– Hyperpyrexia (>40C rectal)– Secondary infections

Goal of Exchange TransfusionGoal of Exchange Transfusion

Parasitemia >10%Exchange transfusion until

Parasitemia 1-5%

Parasitemia <5%Altered mental status

or

Parasitemia 5-10%

plus

IV Quinidine

until

Parasitemia <1% ANDNormal mental status

Malaria in PregnancyMalaria in Pregnancy

Consider “complicated”Severe malaria a risk in pregnant women

from areas of unstable or mesoendemic disease

Women in holoendemic areas: infant with low birth weight

Personal Protective MeasuresPersonal Protective Measures

Protective clothing (covers arms, legs)Skin repellent (DEET)Insecticide-impregnated bednetPermethrin on clothesAvoid outdoor exposure during prime

mosquito biting times (dusk to dawn)Insect repellent/spray in room at night

Why We Give ProphylaxisWhy We Give Prophylaxis

Prophylaxis - Chloroquine RProphylaxis - Chloroquine R

Personal Protective Measures Mefloquine (250 mg weekly 2 weeks b to 4 weeks a) Doxycycline (100 mg qd 1 day b to 4 weeks a) Malarone (250/100 mg qd 1 day b to 1 week a) Primaquine – terminal prophylaxis for some and… New Agents - Not yet licensed

– Azithromycin, Tafenoquine

SBT – Malarone (unless taking)

Chemoprophylaxis to avoidChemoprophylaxis to avoid

Fansidar– Fatal Stevens-Johnson syndrome, other

Halofantrine– EKG abnormalities, early studies stopped

Maloprim– Fatal agranulocytosis, dapsone T1/2=28 hours

Amodiaquine– Agranulocytosis, hematologic problems

Babesia InfectionsBabesia Infections

Mostly US illness, transmitted by deer ticks NE US (Martha’s Vinyard), WI, CA, WA Incubation 1-4 weeks Illness of fever, myalgias, anemia, hematuria,

jaundice – many with minimal or no sx Worse in splenectomized/compromised patients Diagnose with blood smear or PCR; Ab levels

may dx, but usually low during acute infection (variants like WA-1 will not react with CDC test)

Babesia microtiBabesia microti

Babesia TherapyBabesia Therapy

Clindamycin 300-600 mg IV q6 plus quinine 650 mg po q8

For less severe infection, may give clinda 600 mg po q8 + quinine

Atovaquone + azithromycin may be effective

Most antimalarials may no effect