Principles of malaria clinical management/uncomplicated

malaria

Uncomplicated Malaria

• Symptoms: fever, chills, headache, body pains, diarrhea, vomiting, cough

• Signs: anemia, thrombocytopenia

• Symptoms may be very nonspecific

• Synchronous infections with predictable cycles of symptoms are rare

Features of severe malaria

• Decrease in conscious level, neurological signs or fits• Severe anemia – Hematocrit < 15%• Hyperpyrexia• Hyperparasitemia > 5%• Hypoglycemia (glucose < 2.2 mmol/L)• Renal impairment or oliguria• Pulmonary edema, hypoxia, acidosis• Circulatory collapse or shock• Hemostasis abnormalities – hemolysis, DIC

Principles of management of uncomplicated malaria

• Prompt and accurate diagnosis• Assess for signs of complicated/severe malaria

– Can occur with low parasitemias– Can develop after parasites clear peripherally

• Prompt use of appropriate antimalarial drugs• Monitor clinical and parasitological improvement• Cure – parasitic and/or clinical• Ancillary treatment• Instructions for future prevention of malaria

Information requested when evaluating a potential case of

malaria– Age

– Sex and pregnancy status

– Travel history, travel outside major or urban areas

– Visitors from endemic areas

– Exposure to mosquitoes

– Malaria prophylaxis used

– Receipt of blood transfusions or transplant

– Past history of malaria– Drug allergies– Clinical status of the

patient, esp. neurological

– Lab results

Diagnosis

• Thick and thin blood smears are gold standard– Identify species and quantify density

– If can not identify species, treat for P.f.• Re-examine smears or use alternative diagnostic tool

• Suspect P.f.– If critically ill, suspect P.f.

– If returned from Sub-Saharan Africa, > 95 % chance of P.f. pure or mixed infection

– Parasitemia > 1%

– Doubly infected cells

Malaria Transmission Cycle

Parasite undergoes sexual reproduction in the mosquito

Some merozoites differentiate into male or female gametocyctes

Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts

Dormant liver stages (hypnozoites) of P. vivax and P. ovale

Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood

MOSQUITO HUMAN

Sporozoites injected into human host during blood meal

Parasites mature in mosquito midgut and migrate to salivary glands

Drugs Used to Treat Malaria

• Chloroquine (Aralen, Dawaquine)

• Amodiaquine (Camoquine)

• Quinine and Quinidine

• Sulfa combination drugs (Fansidar, Metakelfin)

• Mefloquine (Lariam)

• Halofantrine (Halfan)

• Atovaquone-proguanil (Malarone)

• Atemisinin derivatives (Paluther)

Malaria Treatmentnon-falciparum infections

Chloroquine (CQ) is the drug of choice Some CQ-resistant P. vivax has been reported

from Oceania and South America Mefloquine or quinine for proven resistant cases Primaquine to eradicate liver phase in P. vivax

and P. ovale infections

Chloroquine

4-amino quinoline acts on asexual intraerythrocytic forms useful for treatment or prophylaxis safe for children and in pregnancy side effects: GI, headache, blurred vision,

pruritis limited efficacy against P. falciparum resistant strains of P. vivax emerging

Malaria Treatmentnon-falciparum infections

If symptoms or parasites persist at end of treatment

Additional infection Rarely, CQ- resistant strain Repeat blood smears

Pruritis is major side effect of CQ More common in dark-skinned people Can offer antihistamines, continue use

CQ-resistant P. vivax

• Emerged in Southeast Asia• Indonesia, Papua New Guinea, Birma

• Also documented in Latin America• Guyana

• Also documented in South Asia• India

• CQ therapy still recommended• Quinine after documented treatment failure

Primaquine (PQ) use in P. vivax and P. ovale infections

Use to achieve radical cure and prevent relapses Check glucose-6-phosphate dehydrogenase (G6PD) level first

PQ can cause hemolysis in G6PD-deficient patients If mildly deficient, consider weekly PQ dosing instead of daily

Partial resistance in Oceania and Southeast Asia Double usual dose if exposed in these areas

Contraindicated in pregnancy Pregnant women and newborns use prophylactic CQ weekly until

delivery or until end of breast-feeding Then use primaquine

Malaria TreatmentPlasmodium falciparum infections

Acquired in CQ-sensitive areas Chloroquine alone

Acquired in CQ-resistant areas Quinine + tetracycline Quinine + sulfadoxine/pyrimethamine

CQ-resistant P. falciparum

• Emerged in Southeast Asia• Near global distribution

• Few areas of susceptibility remain– Middle East– Central America/Caribbean

• CQ is still the first-line drug in most African countries

• Non-immune migrant populations may be at higher risk

Multidrug-resistant P. falciparum

• Focus in Southeast Asia• Border areas, forest transmission• Recommendations

• Prophylaxis: Doxycycline• Treatment:

– Quinine combinations, longer duration of therapy– High-dose MQ,artemisinin combinations

• Identifying and documenting treatment failure is critical

Considerations when managingPlasmodium falciparum infections

Can underestimate severity Significant damage occurs at certain times during repeated

cycles of development and reproduction Patient can deteriorate quickly Low parasite density does not mean infection is trivial Complications can arise after parasites clear peripheral

blood, parasites can sequester in tissues Monitor for neurological changes and hypoglycemia

Severe malaria and antimalarials can cause hypoglycemia Pregnant women are at particular risk

Considerations when managingPlasmodium falciparum infections

Potentially complicated case, with no other risk factors

Pregnancy Hyperpyrexia ( > 39o)

Parasite count > 2% Mature parasites ( schizonts or late trophozoites) on

blood film

Management of induced or congenital cases

• No sporozoites are injected into the human by mosquito

• Therefore no exo-erythrocytic (hepatic) cycle

• No need for primaquine

Adjunct treatment of uncomplicated malaria

• Fever– Acetominophen, paracetamol

• Avoid aspirin in kids due to risk of Reyes Syndrome

– Sponge baths

• Anemia– Transfusion of RBCs may be needed– Iron, folic acid

• Rehydration– Solutions with extra glucose

Antimalarial Chemoprophylaxis• Prevents disease, not infection• Appropriate for non-immune travelers• Practical only for some populations in

endemic areas• Consider:

• immune status• intensity/duration of exposure• parasite drug resistance• resources for diagnosis and treatment

Personal Protection

• Protective clothing

• Insect repellants

• Household insecticide products

• Window and door screens

• Bed nets

Evaluation of febrile illnesses

– Age

– Sex and pregnancy status

– Travel history, travel outside major or urban areas

– Visitors from endemic areas

– Exposure to mosquitoes

– Malaria prophylaxis used

– Receipt of blood transfusions or transplant

– Past history of malaria– Drug allergies– Clinical status of the

patient, esp. neurological

– Labs

Don’t forget to ask

– Occupational history• Healthcare workers

• Exposure to mosquitoes

– Needle exposure• IV drug abuse

• Needlestick injuries

• Tattoos

• Acupuncture

– Other meds used with potential antimalarial effect

• Sulfa – Bactrim ®

• Tetra – or doxycycline

• Quinine

• Hydroxychloroquine – Plaquenil®

• Atovaquone

• Clindamycin

– Meds received abroad• Artesunates

• Halofantrine

All “malaria” is not malaria

• Incubation periods unlikely• Parasite density very high for nonfalciparum• Species not likely given travel history• Drug resistance?• Misdiagnosis – species or parasite or negative• Miscalculation of density• Previously undetected mixed infection

Antimalarial drug actions

• Actions– Causal (true) – drug acts on early stages in liver, before release

of merozoites into blood

– Blood schizontocidal drugs (suppressive or clinical)– attack parasite in RBC, preventing or ending clinical attack

– Gametocytocidal – destroy sexual forms in human, decreases transmission

– Hypnozoitocidal – kill dormant hypnozoites in liver, antirelapse drugs

– Sporontocidal – inhibit development of oocysts in mosquito, decreases transmission

The Malaria Transmission CycleSites of Action for Antimalarial Drugs

SPORONTOCIDES:primaquine pyrimethamineproguanil

MOSQUITO HUMAN

GAMETOCYTOCIDES:primaquine

TISSUE SCHIZONTOCIDES:primaquinepyrimethamineproguaniltetracyclines

BLOOD SCHIZONTOCIDES:chloroquinemefloquinequinine/quinidinetetracyclineshalofantrinesulfadoxinepyrimethamineartemisinins

Exo-erythrocytic (hepatic) cycle

Hypnozoites

Sporozoites

Mosquito Salivary Gland

Malaria Life Cycle

Gametocytes

Oocyst

Erythrocytic Cycle

Zygote

Primaquine

8-aminoquinoline acts on gametocytes, hypnozoites; weak against

asexual blood stage parasites primarily used as post-exposure prophylaxis and

radical cure for P. vivax and P. ovale contraindicated in G6PD deficiency and

pregnancy decreased activity against some P. vivax

Doxycycline tetracycline antibiotic sites of action unknown daily dose is effective prophylaxis against CRPF

and MRPF (in SE Asia) contraindicated in pregnancy and in children side effects: GI problems, photosensitivity,

yeast infections no identified resistance compliance can limit its effectiveness

Quinine

• first isolated from cinchona bark in 1820• dextroisomer: QUINIDINE• acts against asexual erythrocytic stages• used for treatment of all 4 species• safe in pregnancy and for children• side effects: nausea, blurred vision, tinnitus• duration shortened by adding SP or TCN• diminished activity against some P. falciparum

from SE Asia

Fansidar antifol combination drug (sulfadoxine-

pyrimethamine) acts on asexual intracellular stages no longer recommended for CRPF used for treatment of CRPF, alone and in

combination with quinine benefits outweigh risks in pregnancy side effects: sulfa allergy, severe cutaneous resistance developed rapidly in SE Asia

Mefloquine 4-quinolinemethanol acts on asexual intraerythrocytic forms effective prophylaxis against CRPF treatment doses less well tolerated not licensed for use in pregnancy or infants < 5

kg side effects: neuropsychiatric reactions, cardiac

dysrhythmias, vomiting in children resistance is limited to SE Asia

Other Medications--Clindamycin

common antibiotic weak antimalarial activity alone may be used for treatment in combination with

quinine, especially for pregnant women and young children

still need to give full course of quinine

more effective drugs can be used in these groups (MQ, SP)

Other Medications--Halofantrine

licensed and marketed in the United States widely used in Africa, South Asia GI absorption is highly variable cardiac conduction abnormalities are a concern increased risk after MQ prophylaxis or treatment repeat dosing one week after initial treatment

Other Medications--Malarone

fixed combination of atovaquone and proguanil

effective against asexual intraerythrocytic stages

intrinsically expensive to produce approval for treatment in UK large donation planned in Africa

Other Medications--Artemisinins novel class of antimalarial drugs derived from Chinese herb: qinghaosu act on earlier parasite developmental stages

than CQ or Quinine rapid parasite clearance no resistance to date, but high rates of

recrudescence if used alone effective in combination with MQ neurological lesions in animal studies