emerging trends in malaria by professor dr intekhab alam department of medicine postgraduate medical...
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Emerging TrendsEmerging Trends in in
MalariaMalariaByBy
Professor Dr Intekhab AlamProfessor Dr Intekhab AlamDepartment of medicineDepartment of medicine
Postgraduate medical institutePostgraduate medical institute
Lady Reading Hospital PeshawarLady Reading Hospital Peshawar
Disease Incidence & TrendsDisease Incidence & Trends
Malaria occurs in about 100 countries worldwideMalaria occurs in about 100 countries worldwide 40% of the global population is at risk of malaria40% of the global population is at risk of malaria Over 300 million acute cases annuallyOver 300 million acute cases annually At least one million deaths annuallyAt least one million deaths annually Malaria kills an African child every 30 secondsMalaria kills an African child every 30 seconds In AfricaIn Africa P. falciparum P. falciparum infection during pregnancy infection during pregnancy
is estimated to cause as many as 10,000 is estimated to cause as many as 10,000 maternal deaths each yearmaternal deaths each year
Ref: World malaria situation; rbm.who.int/cmc/015/372/RBMinfosheet Ref: World malaria situation; rbm.who.int/cmc/015/372/RBMinfosheet
Prevalence-EMROPrevalence-EMRO
Countries with moderate Countries with moderate endemicity (Pakistan, Iraq, endemicity (Pakistan, Iraq, Iran and Saudi Arabia)Iran and Saudi Arabia)
Countries with severe Countries with severe malaria problem malaria problem (Afghanistan, Djibouti, (Afghanistan, Djibouti, Somalia, Sudan, and Somalia, Sudan, and Yemen)Yemen)
Situation in PakistanSituation in Pakistan
EpidemiologyEpidemiology Malaria belongs to the Oriental eco-epidemiological Malaria belongs to the Oriental eco-epidemiological
typetype P. falciparum P. falciparum and and P. Vivax are P. Vivax are major speciesmajor species In the 1990s, the annual number of cases In the 1990s, the annual number of cases
oscillated between 74-112,000 of which about 40% oscillated between 74-112,000 of which about 40% were due to were due to P. FalciparumP. Falciparum
Due to poor reporting system less than 20% of the Due to poor reporting system less than 20% of the actual number of cases are recordedactual number of cases are recorded
ConstraintConstraint Massive importation from AfghanistanMassive importation from Afghanistan Resistance of Resistance of P. falciparum to P. falciparum to choloroquine and choloroquine and
vector resistance to insecticidesvector resistance to insecticides
Clinical FeaturesClinical Features Indefinite malaise, anemia, splenomegaly and Indefinite malaise, anemia, splenomegaly and
slowly rising fever of several days durationslowly rising fever of several days duration
Followed by shaking chills and rapidly rising Followed by shaking chills and rapidly rising temperature, that ends with profuse sweatingtemperature, that ends with profuse sweating
Falciparum malaria (malignant tertian) may Falciparum malaria (malignant tertian) may present a varied clinical picture with an atypical present a varied clinical picture with an atypical onset including diarrhoea onset including diarrhoea
The above features may progress to jaundice, The above features may progress to jaundice, coagulation defects, shock, renal and hepatic coagulation defects, shock, renal and hepatic failure, acute encephalopathy, pulmonary and failure, acute encephalopathy, pulmonary and cerebral oedema, coma and death cerebral oedema, coma and death
Complicated malariaComplicated malaria
Cerebral malariaCerebral malaria Renal FailureRenal Failure Gastrointestinal Gastrointestinal
typetype Shock type(Algid Shock type(Algid
malaria.malaria. Severe liver Severe liver
damagedamage Severe anemia Severe anemia
(PCV < 15%)(PCV < 15%) Hemolytic anemia Hemolytic anemia
(Black water fever).(Black water fever).
Acidosis.Acidosis. ARDSARDS HypoglycemiaHypoglycemia 22ndnd or 3 or 3rdrd trimester trimester
of pregnancyof pregnancy DICDIC Hyperparasitaemia Hyperparasitaemia
(>5% nonimmune (>5% nonimmune >20% in >20% in any)any)
Poor prognostic factorsPoor prognostic factors
Clinical:Clinical:Agitation,hyperventilation, Agitation,hyperventilation, hypothermia,bleeding,deep coma,cunvulsions, hypothermia,bleeding,deep coma,cunvulsions, anuria and shock.anuria and shock.
Laboratory:Laboratory:Hypoglycemia(<40mg%), Hypoglycemia(<40mg%), Acidosis(pH <7.3 or HCOAcidosis(pH <7.3 or HCO3 3 <15mmol/l), S. Creat <15mmol/l), S. Creat >3 mg%, SBR > 3mg%, ALT>3XULN, TLC >3 mg%, SBR > 3mg%, ALT>3XULN, TLC >12000/cmm, PCV <15%, PLT < 50,000/cmm, PT >12000/cmm, PCV <15%, PLT < 50,000/cmm, PT >3sec.>3sec.
Parasitology:Parasitology:Inceased mortality at Inceased mortality at >100,000/µl(approx: 2%), High mortality at >100,000/µl(approx: 2%), High mortality at >500,000/µl, >5% of Neutrophils with pigment.>500,000/µl, >5% of Neutrophils with pigment.
DiagnosisDiagnosis
Clinical (presumptive) diagnosisClinical (presumptive) diagnosis Microscopy: Microscopy: Thick filmThick film (sensitivity 0.0001%.)(sensitivity 0.0001%.)
Thin film Thin film (sensitivity 0.05%)(sensitivity 0.05%)
Antigen detection tests: Antigen detection tests: rapid and rapid and sensitive sensitive (0.0001%.). (0.0001%.). PfHRP2 dipstick or PfHRP2 dipstick or Plasmodium LDH dipstick tests.Plasmodium LDH dipstick tests.
Molecular tests: Molecular tests: e.g. PCRe.g. PCR
Morphological characteristics of the four species
Simple light microscopic examination Simple light microscopic examination of Giemsa stained blood films is the of Giemsa stained blood films is the most widely practiced and useful most widely practiced and useful method for definitive malaria method for definitive malaria diagnosisdiagnosis
Diagnostic pointsDiagnostic points Rings appear fine and Red
Cells are not enlarged. delicate and there may be
several in one cell. Some rings may have two
chromatin dots. Presence of marginal forms. It is unusual to see
developing forms in peripheral blood films.
Gametocytes have a characteristic crescent shape appearance. However, they do not usually appear in the blood for the first four weeks of infection.
Maurer's dots may be present.
Diagnostic pointsDiagnostic points
• Red cells containing parasites are usually enlarged.
• Schuffner's dots are frequently present in the red cells as shown above.
• The mature ring forms tend to be large and coarse.
• Developing forms are frequently present.
Diagnostic pointsDiagnostic points
• Ring forms may have a squarish appearance.
• Band forms are a characteristic of this species.
• Mature schizonts may have a typical daisy head appearance with up to ten merozoites.
• Red cells are not enlarged.
• Chromatin dot may be on the inner surface of the ring.
Diagnostic pointsDiagnostic points
•Red cells enlarged. •Comet forms common (top right)
•Rings large and coarse.
•Schuffner's dots, when present, may be prominent.
•Mature schizonts similar to those of P.malariae but larger and more coarse.
Current status of drug-resistant malaria Current status of drug-resistant malaria
Resistance to antimalarial drugs has Resistance to antimalarial drugs has been described for two of the four been described for two of the four species of malaria parasite that species of malaria parasite that naturally infect humans, naturally infect humans, P. P. falciparum falciparum and and P. vivaxP. vivax
Resistance in vivo has been reported Resistance in vivo has been reported to all antimalarial drugs except to all antimalarial drugs except artemisnin and its derivatives artemisnin and its derivatives
Mechanism of ResistanceMechanism of Resistance Physiological adaptations due to non genetic Physiological adaptations due to non genetic
changeschanges
Selection of previously existing drug Selection of previously existing drug resistant cells from a mixed population resistant cells from a mixed population under drug pressureunder drug pressure
Spontaneous mutationSpontaneous mutation
Mutation of extra-nuclear genes, orMutation of extra-nuclear genes, or
The existence of plasmid-like factorsThe existence of plasmid-like factors
EstablishedEstablished ResistanceResistance
Chloroquine Chloroquine
(amodiaquine, mefloquine, halofantrine, and (amodiaquine, mefloquine, halofantrine, and quinine) quinine)
Antifolate combination drugsAntifolate combination drugs
(Sulphadoxine + Pyrimethamine)(Sulphadoxine + Pyrimethamine)
AtovaquoneAtovaquone
Drug ResistanceDrug Resistance
Declining trend in cure rates Declining trend in cure rates of previously effective of previously effective antimalarial drugs reported antimalarial drugs reported over last 3 decades reflects over last 3 decades reflects development of resistant development of resistant strains of Plasmodiumstrains of Plasmodium
Drugs Available for TreatmentDrugs Available for Treatment Chlorquin phosphate.Chlorquin phosphate. ArtemisininArtemisinin and its derivatives and its derivatives Quinine hydrochloride.Quinine hydrochloride. Antibiotics Antibiotics (Doxycycline and Clindamycine).(Doxycycline and Clindamycine). Mefloquin hydrochloride.Mefloquin hydrochloride. Malarone Malarone (Atovaquone+Proguanil).(Atovaquone+Proguanil). Halofantrine.Halofantrine. Pyrimethamine+Sulfadoxine.Pyrimethamine+Sulfadoxine. Pimaquine.Pimaquine. Proguanil.Proguanil.
Artemisinin compoundsArtemisinin compounds
DihydroartemisininDihydroartemisinin
ArteetherArteether
ArtesunateArtesunate
ArtemetherArtemether
DihydroartemisininDihydroartemisinin Most rapidly acting antimaMost rapidly acting antimalalarial drugrial drug Only artemisinin derivative available in active Only artemisinin derivative available in active
metabolite formmetabolite form Fastest fever clearance timeFastest fever clearance time Fastest parasite clearance timeFastest parasite clearance time Schizontocidal and Gametocidal effectsSchizontocidal and Gametocidal effects
Fast relief of symptoms and reduces transmissionFast relief of symptoms and reduces transmission
No resistance reported to dateNo resistance reported to date
Does not exhibit mutagenic or teratogenic effectsDoes not exhibit mutagenic or teratogenic effects
Well tolerated even at 987.5mg/kg doseWell tolerated even at 987.5mg/kg dose
Easy dosage regime i.e. once dailyEasy dosage regime i.e. once daily
Word of caution!!!!Word of caution!!!!
Safety in pregnancy Safety in pregnancy (Embryotoxic in (Embryotoxic in animal studies).animal studies).
High recrudescence ratesHigh recrudescence rates (approx: 50%) (approx: 50%)
Preventionof future resistance to Preventionof future resistance to Artimisinin and its derivatives. Artimisinin and its derivatives. (role of ACTs)(role of ACTs)
Miscellaneous compounds Miscellaneous compounds Halofantrine Halofantrine produce potentially produce potentially
fatal cardiac conduction fatal cardiac conduction abnormalities (specifically, abnormalities (specifically, prolongation of the PR and QT prolongation of the PR and QT interval), limiting its usefulness interval), limiting its usefulness
LumefantrineLumefantrine, a fluoro-methanol , a fluoro-methanol compound, is being produced as a compound, is being produced as a fixed combination tablet with fixed combination tablet with artemetherartemether
Artemisinin compounds Artemisinin compounds
Sesquiterpine lactone compounds Sesquiterpine lactone compounds
Synthesized from the plant Synthesized from the plant Artemisia Artemisia annua annua
Used for treatment of severe malaria Used for treatment of severe malaria
Shown very rapid parasite clearance times Shown very rapid parasite clearance times and faster fever resolution than with and faster fever resolution than with quinine quinine
Quinine and related compoundsQuinine and related compounds Quinine, along with its dextroisomer Quinine, along with its dextroisomer
quinidine, has been the drug of last resort quinidine, has been the drug of last resort for the treatment of malaria, especially for the treatment of malaria, especially severe disease severe disease
Amodiaquine is a relatively widely Amodiaquine is a relatively widely available compound closely related to available compound closely related to chloroquine chloroquine
Other quinine-related compounds in Other quinine-related compounds in common use include primaquine common use include primaquine (specifically used for eliminating the (specifically used for eliminating the exoerythrocytic forms of exoerythrocytic forms of P. vivax P. vivax and and P. P. ovale ovale that cause relapses), and mefloquine that cause relapses), and mefloquine (a quinoline-methanol derivative of (a quinoline-methanol derivative of quinine) quinine)
Antifolate combination drugsAntifolate combination drugs
These drugs are various combinations of These drugs are various combinations of dihydrofolate-reductase inhibitors dihydrofolate-reductase inhibitors (proguanil, chlorproguanil, pyrimethamine, (proguanil, chlorproguanil, pyrimethamine, and trimethoprim) and sulfa drugs and trimethoprim) and sulfa drugs (dapsone, sulfalene, sulfamethoxazole, (dapsone, sulfalene, sulfamethoxazole, sulfadoxine, and others)sulfadoxine, and others)
A new combination of chlorproguanil and A new combination of chlorproguanil and dapsone, also known as Lap-Dap, has a dapsone, also known as Lap-Dap, has a much more potent synergistic effect on much more potent synergistic effect on malaria than existing drugs such as SP malaria than existing drugs such as SP
Antibiotics Antibiotics Tetracycline and derivatives such as Tetracycline and derivatives such as
doxycycline are very potent antimalarials doxycycline are very potent antimalarials and are used for both treatment and and are used for both treatment and prophylaxis prophylaxis
Clindamycin has been used but offers only Clindamycin has been used but offers only limited advantage when compared to other limited advantage when compared to other available anti-malarial drugs available anti-malarial drugs
Parasitological response is slow to Parasitological response is slow to clindamycin and recrudescence rates are clindamycin and recrudescence rates are high high
Chloroquine resistanceChloroquine resistance As the malaria parasite digests haemoglobin, large As the malaria parasite digests haemoglobin, large
amounts of a toxic by-product are formed amounts of a toxic by-product are formed The parasite polymerizes this by-product in its food The parasite polymerizes this by-product in its food
vacuole, producing non-toxic haemozoin (malaria vacuole, producing non-toxic haemozoin (malaria pigment)pigment)
It is believed that resistance of It is believed that resistance of P. falciparum P. falciparum to to chloroquine is related to an increased capacity for chloroquine is related to an increased capacity for the parasite to expel chloroquine at a rate that does the parasite to expel chloroquine at a rate that does not allow chloroquine to reach levels required for not allow chloroquine to reach levels required for inhibition of haem polymerizationinhibition of haem polymerization
Chloroquine resistance can be reversed by drugs Chloroquine resistance can be reversed by drugs which interfere with this efflux system which interfere with this efflux system
It is unclear whether parasite resistance to other It is unclear whether parasite resistance to other quino-line antimalarials occurs via similar quino-line antimalarials occurs via similar mechanisms mechanisms