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
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