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 Suspect P.f. 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 Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood Sporozoites injected into human host during blood meal Parasites mature in mosquito midgut and migrate to salivary glands Dormant liver stages (hypnozoites) of P. vivax and P. ovale MOSQUITO HUMAN Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts Some merozoites differentiate into male or female gametocyctes Parasite undergoes sexual reproduction in the mosquito

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 Treatment non-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 Treatment non-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 Treatment Plasmodium 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 managing Plasmodium 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 managing Plasmodium 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 Needle exposure 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 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 Cycle Sites of Action for Antimalarial Drugs TISSUE SCHIZONTOCIDES: primaquine pyrimethamine proguanil tetracyclines MOSQUITO HUMAN BLOOD SCHIZONTOCIDES: chloroquine mefloquine quinine/quinidine tetracyclines halofantrine sulfadoxine pyrimethamine artemisinins SPORONTOCIDES: primaquine pyrimethamine proguanil GAMETOCYTOCIDES: primaquine

Malaria Life Cycle Oocyst Sporozoites Mosquito Salivary Gland Zygote Gametocytes Exo- erythrocytic (hepatic) cycle Hypnozoites Erythrocytic Cycle

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