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