INTRODUCTION Definition: Malaria is an acute and chronic illness characterized by paroxysms of fever ,chills ,sweats , fatigue , anaemia and splenomegaly . Causative agent: intracellular plasmodium protozoa. Species :P.falciparum , P.malariae , P.ovale , P.vivax. (P.knowlesi -documented in malaysia , , indonesia,singapur,phillippines)o Transmission: Female anopheles mosquitoes. ( Also transmitted through blood transfusion ,use of contaminated needles, from pregnant women to fetal)
DIAGNOSIS Clinical diagnosis-WHO recommendation1.Low risk area-based on possibility of exposure to malaria and h/o fever in previous 3 days with no features of other disease.2.High risk area-h/o fever in previous 24 hr &/or anaemia ,for which pallor is +ent to be more reliable. Parasitological diagnosis- 1.light microscopy – by it we able to detect asexual parasites at densities of fewer than 10/µl Typical field condition the limit of sensitivity is app 100/µl. Stain used-giemsa staining and oil immersion microscopy.
2.Rapid diagnostic test Immunochromatographic test that detect parasite specific antigen in finger prick blood sample. WHO recommends - RDT should have a sensitivity of >95% in detecting plasmodium at densities of more than 100 parasites /µl. .Based on-detection of histidine rich protein (HRP2)which are specific for p.falciparum, panspecific or species specific plasmodium lactate dehydrogenase or panspecific aldolase.SENSITIVITY->90 %at 100-500 parasites/µl of blood.(for p.falciparum)Causes of poor sensitivity-poor test manufacture, damage due to exposure to high temp and humidity , variation in target antigen.
Advantage-1.rapid result 2.fewer requierment for training and skilled personnel.Disadvantage-1.the likelihood of misinterpreting a positive result as indicating malaria in patients with parasitaemia incidental to another illness,when host immunity is high. 2.the inability, in the case of some RDT to distinguish new infections from a recently and effectively treated infection. its due to persistence of certain target antigens(HRP2) in the blood for 1-3 weeks after effective treatment. Immunodiagnosis and PCR based molecular detection method-1.Detection of antibodies to parsites.2.Detect parasite DNA based on PCR
OTHER LAB INVESTIGAION-Complete blood count.Blood urea .sugar, creatinineABGCSF
WHO Guidelines for malariaTreatment of uncomplicated P.falciparum malaria. 1.Artemisinin based combination therapies (ACTs)are recommended. Choice of ACTs based of level of resistance of the partner medicine in combination. Artemisinin derivative should not be used as monotherapy. Recommended ACTs –1.Artemether +lumefantrine 2.artesunate+mefloquine 3.Aretesunate +sulfadoxine –pyrimethamineDOSING-Lumifantrin - 120 mg artemether -20 mgdose -10 -16 mg /kg/dose dose -1.4 to 4 mg/kg/day 5 -14 kg 1 tab 15 -24 kg 2 tab BD for 3 days 25 -34 kg 3 tab >34 kg 4 tab
Artesunate +amodiaquineartesunate - 2 to 10 mg/kg/dayamodiaquine – 7.5 – 15 mg /kg/day(availablity – 25/67.5mg 50/135 mg 100/270mg)Artesunate+mefloquine target dose 4 mg/kg/day OD for 3 days artesunate &25 mg/kg/day meflaquine either split in 2 doses 15 & 10 or 3 doses 8.3 mg/kg/day OD(Availabilty-50/250 mg base)Artesunate+sulfadoxine-pyrimethamineTarget dose 4 mg/kg/day OD for 3 days –artesunate25/1.25 mg/kg sulfadoxine pyrimethamine on day 1.(availabilty-50mgartesunate 500 mg sulfadoxine 25mg pyrimethamine)
2.Second line antimalarial treatment alternative ACT known to be effective in the region. Artesunate +tetracycline or doxycycline or clindamycine any of these combination to be given for 7 days. Quinine +tetracycline or doxycyline or clindamycine any of these should be given for 7 days. Addition of a single dose primaquine (0.75 mg/kg)to ACT treatment for uncomplicated falciparum malaria as an antigametocytes medicine 3.Travellers returning to nonendemic countries.. Atovaquine +proguanil Artemeter +lumefantrine Quinine +doxycycline or clindamycine. Dihydroartemisinin +piperaquine is an option for the first line treatment of uncomplicated malaria worldwide
Artesunate +tetracycline or doxycycline or clindamycineArtesunate 2mg /kg OD + tetracycline 4 mg /kg qid or doxycycline 3.5 mg /kg OD a day. Or clindamycine 10 mg/kg BD a day. Used for 7days.Treatment of uncomplicated P.vivax malaria Chloroquine 25 mg base /kg body weight divided over 3 day,combined withprimaquine 0.25 mg base /kg bw,taken with food once daily for 14 days is thetreatment of choice for chloroquine sensitive infection. ACTs combined with primaquine for chloroquine resistant vivax malaria. In mild to moderate G6PD deficiency,primaquine 0.75mg/kg/BW –once a weekfor 8 weeks. In severe G6PD deficiency- primaquine is contraindicated
Complicated p.falciparum malariaPresence of one or more of the following clinical features-Severe complicated P.FALCI1.impaired conciousness2.Prostrarion3.Convulsion >2 episode in 24 hrs4.Acidotic breathing5.Shock –SBP<50mm Hg6.Hemglobinuria7.Pulmonary edema8.Abnormal spontaneous bleeding
TREATMENT OF COMPLICATED P.FALCIPARUMMALARIA Its a medical emergency. Artesunate-2.4 mg/kg BW IV/IM time=o than 12 hr and 24 hr.than once a day.. OR Artemether-3.4 mg/kg BW im given on admission then 1.6 mg/kg BW . ORquinine 20 mg salt/kg BW on admission than 10 mg mg/kg BW every 8 hr.infusion rate should not be >5mg salt/kg bw/hr.Thereafter course should be completed by-Artemether +lumifantrine artesunate +amodiaquineDihydroartemisinin +piperaquine artesunate+sulfadoxine- pyrimethamineQuinine+clindamycine or doxycycline
Supportive treatment1.antipyretic- paracetamol 15 mg /kg/dose q 4 -6 hr.2.t/t of hypoglycemia.3.Anticonvulsant drug4.Blood transfusion5.ARF-maintanace dose of quinine should be reduced to ½ to 1/3. peritonial dialysis-persistent oliguria and rising creatinine6.antibiotics-indication-a)fever persists 48 hr after starting antimalarial t/tb).Presence of shock and respiratory distressc)Age <1yrd)Presence of severe anaemia
EXCHANGE OF BLOOD TRANSFUSIONRational for EBTRemoving rapidly RBC from the circulation and therefore lowering the parasite.Removing rapidly both the antigen load and burden of parasite derived toxin, metabolite and toxic mediators produced by host.Removing the rigid unparasitized red cells by more deformable cells therefore alleviating microcirculatory obstruction.Used in case of –parasitemia >10 % and evidence of complication in case of p. Falciparum.
Treatment failure &ResistanceTreatment failure- its a faliure to clear malarial parasitaemia &/or resolve clinical symptoms within 2 weeks of treatment . Treatment failure in presence of parasites,despite the blood conc.>10 ng/ml is the good marker of resistance of p.vivax to chloroquine.Causes-1.resistance 2.recrudescence 3.inadequete dosing and inappropriate use of drug 4.new infectionAll treatment filure cases should be confirmed by parasitologicly and should asked about prevous drug history and course of thearpy.
Treatment faliure Within 14 days after 14 days(pcr) Initial therapy should be2nd line therapy7 days course recrudescence new infection 1st line treatment 1st line treatmentReuse of meflaquine should be avoided.
RESISTANCE OF ANTIMALARIAL DRUGS Definition-Ability of a parasite strain to survive &/or multiply despite the proper administration and absorption of antimalarial drug in the dose normally recommended. Only patients who meet the following criteria are classified as RESISTANCE CASE: persistence of parasites 7 days after treatment or recrudescence within 28 days after the start of treatment adequate plasma concentration of DRUG prolonged time to parasite clearance
F actors that influence the development ofantimalarial drug resistance • the intrinsic frequency with which the genetic changes occur; • the degree of resistance conferred by the genetic change; • the proportion of all transmissible infectious agents exposed to the drug (selection pressure); • the number of parasites exposed to the drug; • the concentrations of drug to which the parasites are exposed; • the pharmacokinetics and pharmacodynamics of the antimalarial medicine; • individual (dosing, duration, adherence) and community (quality, availability, distribution) patterns of drug use; • the immunity profile of the community and the individual; • the simultaneous presence of other antimalarial drugs or substances
Molecular basis of resistance- chloroquine-resistant parasites, there is a decrease in the accumulation of drug within the food vacuole. Genetic crosses have identified the role of the Plasmodium falciparum chloroquine resistance transporter (Pf CRT, Pf MDR) When present in a mutated form, it is associated with decreased chloroquine accumulation. Pf MDR N86, the chloroquine susceptible allele has been proposed as a molecular marker for lumefantrine resistance. PfATP6, is an ortholog of the mammalian sarcoendoplasmic reticulum Ca2+ ATPase (SERCA)-mutation shows artimissinin compounds resistance. Resistance to antifolate drugs is the result of the accumulation of mutations in DHFR and DHPS.
Pharmacological contributing to drugresistance When used as monotherapy, artemisinins are associated with recurrent parasitemia unless the medication is administered for 5–7 days.. Artemether acts rapidly, with a half-life of 1 to 3 hours, while lumefantrine, with a half-life of three to six days, is responsible for preventing the recurrent parasitemia associated with short course artemisinin therapy. As a result, the artemisinins are administered with longer acting partner drugs in a fixed-dose combination treatment regimen that is used to protect against recrudescent infections
Immunity profile determining resistance All infected individuals develop symptomatic infection, and theinfections always prompt treatment with an antimalarial drug. It ispossible that the difference in the extent of drug pressure on the parasitepopulation drives the spread of drug resistance. HIV infection leads to an increase in the parasite biomass by 18% . Increased biomass raises the possibility that mutations associated with drug resistance may emerge more frequently than in the absence of co-infection. There is evidence that antimalarials in patients with hemoglobinopathies have different pharmacokinetic properties , and that standard doses of antimalarials may be less efficacious .
How to overcome resistanceI. use combination therapyII. Drug therapy monitoringIII. Notified treatment failureIV. 2nd line drug if treatment failure proportion is more than 10 %.
key messages SP should be avoided 1st week of life. Primaquine should be avoided in 1st month in severe G6PDdeficiency . Tetracycline avoided throughout infancy and in children <8yr. Parentral treatment should be continued until the parasitemia is < 1 % which usual occurs within 48 hrs.and pt can tolerate oral medication.
REFRENCE:1.PARK –prevention and social medicine2.NELSON –textbook of pediatrics3.GUIDLINES FOR THE TREATMENT OF MALARIA :WHO4.MEHERBAN SINGH –emergency medicine
Memorable points Chloroquine - interferes with parasite haem detoxification. resistance is related to genetic changes in transporters (PfCRT ,PfMDR) which reduce the conc.of drug at its site of action. Toxicity-1.headache ,skin eruption, GI disturbance,convulsion and mental change. 2.chronic use-keratopathy and retinopathy 3.myopathy,reduced hearing ,photosensitivity,loss of hair,aplastic anaemia. Acute overdose- drowsy with headache and GI upset ,visual loss, convulsion,hypokalamia,hypotension,cardiac arrhythmias. t/t-diazpam and epinephrine (no any specific treatment)Cloroquine+halofantrine-cardiac toxicityCloroquine+meflaquine-convulsion.
There are a number of human genetic polymorphisms that offer protection against malaria, including enzyme deficiencies such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency and hemoglobin variants such as thalassemia and hemoglobin S . Little is known about how effectively patients with these polymorphisms respond to antimalarial drugs. In human populations with high prevalence of these hemoglobinopathies, drug efficacy may seem impaired, even in the absence of intrinsic resistance or may be threatened by even minimal increases in IC50s.
Emergence and spread of antimalarial resistance Malaria continues to cause hundreds of millions of infections per year Resistance to chloroquine and sulfadoxine- pyrimethamine has fueled the on-going burden of Plasmodium falciparum malaria. In response, the World Health Organization (WHO) has recommended the use of combination treatments that include artemisinin derivatives as first-line therapy
Human host The host immune response to malaria infection likely influences the speed of spread of drug resistance and also the extent to which drug resistance translates into clinical drug. . In high transmission settings, children are susceptible to symptomatic and severe malaria infection, while adults are considered semi-immune because they can acquire infection, but are not at risk for severe disease and often experience asymptomatic infection. Malaria parasites in these semi-immune adults are not under drug pressure because infection is not usually recognized or treated. In contrast, individuals in low and sporadic transmission settings, such as Southeast Asia, are not exposed to malaria with enough frequency to develop immunity . As a result .
Denova folate synthesis is essential for parasite survivel. The antifolate medications interrupt this process by targeting two enzymes: pyrimethamine and proguanil target dihydrofolate reductase (DHFR), and sulfa drugs such as sulfadoxine target dihydropteroate synthase (DHPS). multidrug resistance in cancer cells glycoproteins found in mammals that mediate The gene encoding the PfMDR is an ortholog of P- resistance gene Plasmodium falciparum multidrug