1. Principles of malaria clinical management/uncomplicated malaria

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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)

9. 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

10. 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

11. 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

12. 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

13. 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

14. Malaria Treatment Plasmodium falciparum infections
Acquired in CQ-sensitive areas
Chloroquine alone
Acquired in CQ-resistant areas
Quinine + tetracycline
Quinine + sulfadoxine/pyrimethamine

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. Personal Protection Protective clothing Insect repellants
Household insecticide products
Window and door screens
Bed nets

23. 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

24. 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

25. 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

26. 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

27. 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

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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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)

35. 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

36. 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

37. 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