management of Malaria

malaria treatment regimens

1. Malaria

2. Def: Severe malaria : acute malaria with high levels of parasitemia ( > 5%) and/or major signs of organ dysfunction. Altered consciousness with or without convulsions Deep breathing, respiratory distress Metabolic acidosis Circulatory collapse Pulmonary edema or ARDS Renal failure, hemoglobinuria Clinical jaundice DIC Severe anemia Hypoglycemia

3. Clinical manifestations vary with age and geography In endemic areas: children, pregnant females & travelers are at more risk Older children & adults develop partial immunity to febrile malarial episodes after repeated infections & are low risk for severe malaria Seizures & severe anemia are common in children Hyperparasitemia , acute renal failure, jaundice are common in adults Cerebral malaria, shock, acidosis, respiratory arrest can occur at any age

4. Diagnosis: Available malaria diagnostic tools include: Clinical/presumptive diagnosis Microscopy Rapid diagnostic tests(detecting antigen or antibody) Molecular techniques(detecting parasite genetic material)

5. Clinical / Presumptive diagnosis : Typical clinical features includes fever, malaise, myalgia , arthralgia & headache. Histroy , physical exam, routine lab values are useful in determining whether malaria should be considered in differential diagnosis of pt’s illness. There are no pathognomic clinical features for diagnosing malaria. Accurate diagnosis include detection malaria parasites There are no routine lab test results specific to malaria . Anemia is usually mild to moderate.(severe in P. falciparum )

6. Clinical findings most predictive of malaria include fever without localizing symptoms, enlarged spleen, platelet count < 150* 10(9)/l serum bilirubin >1.3mg/dl Even in endemic areas clinical diagnosis is incorrect If parasite based diagnosis is not available & there is suspicion of P.falciparum infection, it is reasonable to begin antimalarial therapy to prevent progression to severe disease Presumptive diagnosis depends on relevant malaria exposure, clinical manifestations like fever & suggestive lab findings in absence of clear alternative diagnosis.

7. Parasite Based diagnosis: Tools for parasite based diagnosis include: i ) Microscopy: detection of parasite in Giemsa stained blood smear by light microscopy is gold standard It allows identification of Plasmodium sps . & quantification of parasitemia . Also enables detection of hematological abnormalities & other infectious diseases like filariasis , trypanosomiasis etc. Microscopy cannot reliably detect very low parasitemia (< 5-10%) Once diagnosis is established treatment is started & serial smears should be examined to monitor parasitological response & ensure resolution of response

8. Parasite density monitoring: Standard approach to estimating parasite density in thick blood smear involves counting asexual parasite forms & wbc in each microscopy field until 200 wbc’shave been counted. Parasite density = { wbc count(cells/ microL ) / No. of wbc’s counted } * No. of parasites counted. Parasitemia should be monitored during treatment to ensure adequate response CDC recommends daily repeat smears until negative or until treatment day 7.

9. ii) Rapid diagnostic tests: these are becoming increasingly important diagnostic tools due to their accuracy, ease of use & quick results. Provide qualitative results but not quantitative information regarding parasite density Less useful for diagnosing acute infection. a) antigen detection: based on immunochromatographic lateral flow technique. They detect one of the following antigens: histidine -rich protein 2, Plasmodium lactate dehydrogenase & aldolase

10. Molecular tests : Their use has been limited to reference lab & is primarily for research & epidemiological purpose PCR can be used for confirmation of species & identification of drug resistant mutations for malaria cases. Loop mediated isothermal amplification for detection of malarial parasite DNA is being developed to facilitate use of molecular technology in endemic area

11. Treatment: Supportive measures: oxygen, ventilatory support, cardiac monitoring, pulse oximetry Unconscious pts require lumbar puncture to rule out concomitant bacterial meningitis Repeat clinical assessment should be preformed every 2-4 hrs & lab investigations every 6 hrs to detect & treat complications If coma score decreases, investigatons should focus on possibility of seizures, hypoglycemia or worsening anemia Predictors for fatality include acidosis, impaired consciousness, elevated blood urea nitrogen etc

12. Anti malarial therapy Two classes of drugs are available for parenteral therapy: Cinchona alkaloids: Quinine & Quinidine Artemisinin derivatives: Artesunate , Artemether , Artemotil . I.V Artesunate is preferable treatment in adults & childern with severe falciparum malaria. If not available then I.V quinine is the drug of choice

13. Artemisinins These clear parasitemia more rapidly then quinine. They are active against gametocytes Artesunate is preferred for treatment of severe malaria Has lower mortality rate ,better tolerated then quinine & acts rapidly Eligible pts for parenteral artesunate thrapy include those with parasitemia >5%, with signs of severe malaria, or intolerance to oral medications

14. Dosage : Standard dosing regimen for I.V artesunate consists of 5 doses : 2.4mg/kg as 1 st dose followed by 2.4mg/kg at 12 & 24hrs followed by 2.4mg/kg od . Total dose can be administered in three doses as 4mg/kg at 0, 24 & 48hrs Dosing need not be adjusted for hepatic or renal failure Adverse effects: nausea, vomiting, anorexia& dizziness. Delayed onset anemia may occur in pts with severe malaria after completion of artesunate therapy & transfusion may be required

15. Quinine / Quinidine I.V.quinine remains treatment of choice In places where I.V artesunate is not readily available. I.V.quinine dihydrochloride loading dose : 20mg/kg(in 5% dextrose) over 4 hrs followed by 20-30mg/kg in 2-3 equal administrations of 10mg/kg(over 2 hrs at 8 or 12 hrs) I.V.quinine gluconate loading dose 10m/kg in NS over 1 hr followed by 0.02mg/kg /min continuous infusion. I.M injections: 2 injections of 10mg/kg(dilute to 60-100mg/ml)should be administered 4 hrs apart. Anterior thigh is preferred.

16. Quinine & Quinidine acts on pancreatic secretagogues leading to hyperinsulinemic hypoglycemia Other adverse effects include tinnitus, reversible hearing loss, nausea, vomiting, dizziness &visual disturbance. Quinidine causes QT prolongation & should be administered with ECG monitoring. These can be combined with doxycyclin , tetracyclin or clindamycin

17. Pre-referral Treatment: In rural endemic areas, where immediate I.V. therapy is not available, pts should be treated with pre referral dose of I.M quinine or an artesunate or intrarectal administration of artesunate . Single artesunate recal suppository dose for pts > 6yrs- 400mg If referral is impossible, I.M or rectal treatment should be continued until pts can tolerate oral medication

18. Completing therapy: Total duration of therapy for severe malaria: Quinine / Quinidine : 7 days artimisinin -based therapy : 3 days Oral therapy is started after acute stage of therapy is treated with parenteral therapy & when pt can swallow. For uncomplicated malaria, full course of treatment with atovaquone-proguanil or mefloquine may be administered Mefloquine is avoided in pts presenting with altered consciousness

19. Respiratory status : Presence of hypoxia or rales should raise suspicion of concomitant LRTI Pulmonary edema may develop in pts with renal failure ARDS may also complicate severe malaria Management ranges from supplementary oxygen to mechanical ventilation with positive end expiratory pressure Deep breathing-indicates metabolic acidosis & has poor prognosis

20. Neurologic status: Standard clinical case of cerebral malaria includes: Blantyre coma score </= 2 P.falciparum parasitemia No other identifiable cause of coma Histologic hallmark of cerebral malaria is cerebral sequestration of parasitized erythrocytes

21. Malarial retinopathy: Pathognomic of cerebral malaria Features: White centered hemorrhages, vessel changes & whitening in areas of retina. Optic fundi should be evaluated following instillation of mydriatics . Measurement of plasma pHRP2 concentration may be useful marker for presence of retinopathy

22. Lumbar puncture: Pts with altered sensorium should undergo lumbar puncture to exclude concomitant bacterial meningitis In pts with cerebral malaria: pressure is about 16cm of CSF. elevated total protein level & cell count Seizure management: May be generalized or focal with subtle clinical signs. Cause should be evaluated besides cerebral malaria( hypoglycemia, fever).

23. Benzodiazepines- 1 st line agents. Diazepam (0.4mg/kg) I.V/per rectum . Lorazepam (0.1mg/kg) I.V. dose can be repeated once if seizures do not cease within 5 min of initial dose Other options: Phenobarbital (15-20mg/kg slow I.V) or phenytoin (18mg/kg diluted in 100ml NS infused over 20 min) Maintenance doses: phenobarbital (5-15ml/kg/day orally or slow I.V every 12 hrs) or phenytoin (10mg/kg/day I.V every 12 hrs) Pts with severe malaria should not receive routine seizure prophylaxis in absence of clinical seizure activity

24. Anemia : Pts with severe anemia may present with or without altered consciousness Hb conc & hematocrit are routinely measured. Transfusion should be reserved for pts with poor prognosis: altered consciousness, high output cardiac failure, respiratory distress, cool peripheries, high density parasitemia , hb <4-5g/dl. Degree of anemia & level of parasitemia - useful for predicting need for transfusion & volume to be transfused. 10ml/kg of packed cells or 20ml/kg of whole blood are well tolerated as pts are hypovolemic

25. Exchange transfusion: Means to remove infected RBC from circulation & reduce parasite burden. Not regularly used as there is no difference in outcome. Coagulopathy : DIC is rare in severe malaria Thrombocytopenia is common Microcirculation in many organs is occluded by fibrin thrombi

26. Fluids & Nutrition: Hypoglycemia: common complication of malaria& marker of severe disease. Pathogenesis- parasite glucose consumption &/or impaired host gluconeogensis Administration of quinine/ quinidine can cause iatrogenic hypoglycemia Clinical manifestations- seizure& altered consciousness. Blood glucose conc. Should be assessed Administration of initial I.V bolus of dextrose (0.25g/kg). Blood glucose measurement after 15 min with administration of repeat bolus until pt is normoglycemic Maintainance : with 5% or 10% dextrose

27. Volume management: There is thin line b/w under & over hydration Reliable markers for intravascular volume depletion: cool peripheries, delayed capillary refill, low venous pressure & low urine output. Clinical symptoms resolve with transfusion When transfusion is not indicated, repeated bolus of NS or Albumin may de productive In cases with renal failure, renal replacement therapy is beneficial Maintenance fluids:5% dextrose

28. Nutrition: Substitutes like “ eggnog”(eggs, milk, sugar& oil) or high calorie drinks may be used in endemic areas where commercial preparations are not available. NG feeding in comatose pts or who are unable to eat & drink. Most pts eat & drink by 5-7 days. Fever: > 38.5oc is common. Reflect host response to endogenous pyrogens released at time of schizont rupture.

29. Paracetamol (acetaminophen- 15mg/kg every 6hrs orally)reasonable antipyretic agent. If fever persists ibuprofen(10mg/kg every 6 hrs orally) Bacterial infections: Severe anemia- risk factor for nontyphoidal Salmonella septicemia Falciparum infection- major risk factor for bacteremia with multiple organisms. Infection should be suspected in pts with severe anemia& signs of sepsis Broad spectrum antibiotic therapy with activity against gram – ve bacilli should be initiated

30. Pregnancy: Pregnant women are more likely to develop severe P.falciparum malaria particularly in 2 nd & 3 rd trimesters Fetal death & premature labor are common with maternal mortality rate upto 50% Prompt treatment is required. Artesunate or Artemether are preferred over quinines in 2 nd & 3 rd trimesters as quinines are associated with recurrent hypoglycemia In 1 st trimester either Artemisinins or quinines are acceptible . In this period, hypoglycemia with quinines is lower & uncertainities regarding safety of artemisinins is greater.