Malaria

1. Malaria Charis Segeritz and Jo-Ann Osei-Twum January 21, 2008

2. Overview 1.) Malaria: Pathology • Transmission • How and through what route? • Main reservoirs? • Prevention? • Life cycle • Tissue schizogony • Erythrocytic schizogony • Sporogony • Clinical manifestation • High risk groups • Diagnosis • Treatment • Use of genetically modified mosquitoes • 2.) Malaria: Discussion • Malaria misdiagnosis • Malaria eradication

3. Transmission • How and through which route does Malaria infect humans? • transmitted by the bite of an infected female Anopheles mosquito most frequently between dusk and dawn • risk of transmission is increased through exposure • between dusk and dawn • in rural areas • at the end of the rainy season • below 2000m • rarely: • transmission by blood transfusion • Transmission by shared needle use • Congenital transmission from mother to fetus

4. Transmission • What are the main reservoirs for the disease? • infection caused by eukaryotic single-celled microorganism of genus Plasmodium • four species infecting humans: • Plasmodiumfalciparum (may be fatal, sub-Saharan Africa, principal cause of malaria deaths in young children in Africa) • Plasmodium vivax (most widespread, but rarely fatal, Indian subcontinent) • Plasmodium ovale (least common, West Africa) • Plasmodium malariae (worldwide, but low frequency) • differences • Morphology • Immunology • Geographical distribution • Relapse pattern • Drug response

5. Transmission • What can be done in order to prevent transmission? • avoid mosquitoes and bites • physical barriers: mosquito nets, clothing • chemical barriers: • repellents: keep mosquitoes from biting • DEET • “natural based” repellents • other synthetic repellents • insecticides: kill mosquitoes • treated mosquito nets • treated clothing • DDT • chemoprophylactic drugs

6. Life cycle • Extremely complex • Involves various proteins that ensure intracellular and extra-cellular survival • Invasion of different cell types • Evasion of the host immune system • Three stages • Tissue Schizogony • Erythrocyte Schizogony • Sporogony

7. Tissue Schizogony [A] • Mosquitoes inject the parasite (sporozoites) into the host bloodstream [1] • Sporozoites travel to the liver and penetrate liver cells (hepatocytes) • Invasion [2] • mediated by thrombospondin domains of the circumsporozoite protein and the thrombospondin-related adhesive protein on sporozoites • bind to heparin sulphate proteoglycans on hepatocytes • Asexual replication [3] • 9-16 days

8. Tissue Schizogony [A] One sporozoite [2] Tens of thousands of merozoites [3] Merozoites released into blood stream [4] One merozoite invades one red blood cell [5]

9. http://www.cdc.gov/malaria/biology/life_cycle.htm

10. Erythrocytic Schizogony [B] • Merozoites invade erythrocytes [5] • Apical reorientation • Junction formation • Signalling • Recognition • Merozoite surface proteins interact with sialic acid residues • Invasion • Erythrocyte binding antigen 175 interacts with glycophorin A on erythrocytes • P. falciparum erythrocytes membrane protein 1 (PfEMP1) • Parasite protein • Expressed at the surface of infected RBC • Bind to various host cell receptors • Endothelium • Placenta

11. Erythrocytic Schizogony [B] • In the RBC, merozoites undergo asexual division • series of developmental stages • Early trophozoite • “ring form” • Trophozoite • Highly metabolic • Glycolysis • Ingestion of host cytoplasm • Proteolysis of hemoglobin • Rounds of nuclear division without cytokinesis forming schizonts • schizonts contain 20 merozoites, these are released once the RBC is lyzed [6] • Cycle of invasion-multiplication-release is repeated • Some merozoites differentiate into male and female gametocytes [7]

12. Sporogony [C] • Gametocytes are ingested into the midgut of feeding mosquitoes [8] • Fertilization • Gametes fuse [9] • Zygote formation • Development of an oocyst [11] • Sporogony in oocyst produces many sporozoites • oocyst raptures releasing sporozoites [12] • sporozoites migrate to salivary glands • cycle begins once a mosquito bites a host [1]

13. Clinical manifestations in humans • develop 6 days - several months after infected mosquito bite • characterized by fever and “flu-like” symptoms: • myalgias • headache • abdominal pain • malaise • often rigors and chills • classically described alternate-day fevers or other periodic fevers are often not present • severe malaria (due to P.falciparum)may cause . . . • seizures • coma • renal and respiratory failure • anemia (= blood loss), even cerebral anemia (= infected erythrocytes obstruct small blood vessels in brain, often fatal, especially in infants) • may lead to death • dormancy • P. ovale and P. vivax: hyponozoites • Dormant liver stages • Remain in organ for weeks/years before onset of new round of pre-erythrocytic schizogony  relapses of malaria infection • P. malariae • May have long-lasting blood-stage infections that persist in human asymptomatically for several decades if left untreated

14. High risk groups • overall case-fatality rate of P. falciparum malaria imported into Canada varies from approximately 1% to 5% and increases to 30% for those > 70 years of age • children • pregnant women Diagnosis • Combination of clinical observations, case history and diagnostic tests (microscopic examination of blood or rapid “dipstick” tests) • the symptoms of malaria are non-specific and diagnosis is not possible without a blood film • the most important factors that determine patient survival are early diagnosis and appropriate therapy • the majority of infections and deaths due to malaria are preventable

15. Treatment • Problems: • widespread resistance of P. falciparum to chloroquine  complicates prevention and treatment of malaria: drug-resistant strains of malaria are now common in much of the world • Insecticide-resistant strains of mosquito • Lack of licensed malaria vaccines of proven efficacy

16. Treatment • Solution: • Combination therapy, e.g. Artemisinin +Fansidar/Mefloquine • Quinine • First widely used antimalarial treatment • From bark of Andean Cinchona tree • Fansidar and Chloroquine • Most commonly used • Most affordable antimalarial drugs • Goals: • Reduce antimalarial resistance • Prolong useful life of current drugs • Three combined strategies to reduce malaria transmission: • Develop clinically approved malaria vaccines • Drug treatment • Vector control

17. Genetically Modified Mosquitoes Germ-line transformations Identification of effector molecules Transgenic mosquitoes Prevent the transmission of the parasite

18. Genetically Modified Mosquitoes • Well studied in the laboratory • Must survive in the wild • Out-compete their wild-type counterparts • Genetic modifications must be permanent

19. Discussion: Malaria misdiagnosis “In a recent study of children reporting to health centres in Uganda, Karin Kallander and colleagues found that 30% had symptoms compatible with both pneumonia and malaria and required dual treatment. This report, and previous studies, have concluded that community treatment of all childhood fevers as malaria is likely to result in malaria over-diagnosis with consequent under-diagnosis of other fever-causing disorders such as pneumonia.” (Amexo et al. 2004. Malaria misdiagnosis: effects on the poor and vulnerable) 1.) Discuss the challenge and problems of this issue. 2.) What do you consider the most ethical and cost-effective policy?

20. Discussion: Malaria misdiagnosis “In a recent study of children reporting to health centres in Uganda, Karin Kallander and colleagues found that 30% had symptoms compatible with both pneumonia and malaria and required dual treatment. This report, and previous studies, have concluded that community treatment of all childhood fevers as malaria is likely to result in malaria over-diagnosis with consequent under-diagnosis of other fever-causing disorders such as pneumonia.” (Amexo et al. 2004. Malaria misdiagnosis: effects on the poor and vulnerable) Discuss the challenge and problems of this issue. • rapid, simple, accurate, inexpensive malaria diagnosis methods are not widely available, particularly in poor communities where they are most needed and individuals are least able to withstand the consequences of the illness • how can one ensure that the more expensive combination therapies reach most of those who truly have malarial illness and not just an elite minority? What do you consider the most ethical and cost-effective policy? • newer drug combinations used only for true cases of malaria • requirement: accurate malaria diagnosis

21. malaria ( = fever symptoms) 70 % 30 % • home treatment: -traditional remedies • drugs from local stores health centres on community level = peripheral health facilities Diagnosis: solely based on clinical features (i.e. fever) bad quality diagnosis pro: can reduce morbidity contra: over-diagnosis/over-treatment of malaria as many infectious diseases mimic malaria pathology • health centres on district level = district hospitals • Diagnosis: • 1) Microscopy • standard for malaria diagnosis (accuracy 70-75%) • challenge: • well-maintained equipment • constant supply of good-quality reagent • trained staff: monitoring, supervising • 2) Rapid Diagnostic Tests • when microscopy unavailable • based on detection of Plasmodium specific proteins • challenge: • cost • not quantitative = inability to provide information about density of infection • Not species specific: can only diagnose P. falciparum specifically Design an educational step-by-step plan for elucidating locals about successful self-treatment.

22. Proposal for educational self-treatment plan • Discuss common errors concerning malaria recognition • i.e. false assumptions such as “malaria can be recognized from its symptoms” • Advise that malaria presents in various ways • i.e. differing malarial symptoms may mimic other diseases • Indicate need to seek professional medical care as soon as possible • i.e. self-treatment is a temporary, life-saving measure while seeking medical attention or if medical care is not available within 24h • Select self-treatment drug with care • i.e. consider drug’s safety, efficacy, individual’s drug tolerance, other medication etc. • Educate about drugs to avoid • i.e. potential severe adverse effects and/or poor efficacy

23. Misdiagnosis of Malaria = contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable • less likely to seek modern medical care for treatment of fevers • wait-and-see approach • unaffordable fees • long waiting lists • unavailability of drugs • poor attitude among staff

24. Misdiagnosis of Malaria = contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable • less likely to seek modern medical care for treatment of fevers • wait-and-see approach • unaffordable fees • long waiting lists • unavailability of drugs • poor attitude among staff inaccurate diagnosis delayed diagnosis & treatment

25. Misdiagnosis of Malaria = contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable • less likely to seek modern medical care for treatment of fevers • wait-and-see approach • unaffordable fees • long waiting lists • unavailability of drugs • poor attitude among staff inaccurate diagnosis delayed diagnosis & treatment more prolonged and severe disease

26. Misdiagnosis of Malaria = contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable • less likely to seek modern medical care for treatment of fevers • wait-and-see approach • unaffordable fees • long waiting lists • unavailability of drugs • poor attitude among staff inaccurate diagnosis delayed diagnosis & treatment more prolonged and severe disease • Misallocation of Resources: • underlying fatal conditions are masked • exposure to unnecessary side-effects • - lost confidence in allopathic health services in favour of traditional healers • lost productive time through illness (no insurance or savings) • impacts on anyone: men, women, children (leave school to look after relatives  reduced • employment prospects

27. Discussion: The long road to malaria eradication • We saw that poverty was a contributing factor to the misdiagnosis of malaria, Peter Russell in 1946 wrote: “but all the evidence we possess would seem to indicate not that poverty is responsible for malaria but that malaria maintains poverty” (Majori. 1999. The long road to malaria eradication) With this in mind consider the following: Three approaches have been identified in the fight against malaria: • drug administration, • vector control (insecticides or insecticide sprayed bed nets) and • vaccine development. Of these three which approach do you think is the most feasible? Which would you allocate funds to?

28. Discussion: The long road to malaria eradication • The Director General of the WHO wrote to the 8th World Health Assembly: “... At present time there are no obvious technical or economic reasons why malaria could not be driven out of the Americas, Europe, Australia and much of Asia within the next quarter of a century. As regards tropical Africa the situation is not quite so promising…one cannot foresee the elimination of malaria from Africa in the near future”. (Majori. 1999. The long road to malaria eradication) Do you agree or disagree with the latter part of this statement? Why do you think the outcomes of malaria eradication differed between countries of tropical Asia and countries of sub-Saharan Africa?

29. Global distribution of malaria Sachs and Malaney, 2002. The economic and social burden of malaria.

30. Global distribution of per capita GDP Sachs and Malaney, 2002. The economic and social burden of malaria.