malaria-mission impossible

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Malaria is the third leading cause of death due to infectious disease. It affects 300- 500 million people annually worldwide and accounts for over 100 million deaths, mainly in African children under the age of 5 years. A child in Africa dies every 30 seconds of malaria. Years of research and Millions of Dollars have been spend in the quest to eradicate this deadly infectious disease. The War is still on but is the mission impossible. This presentation was made during a graduate class to review the victories and the challenges so far in the treatment and vaccination against this disease. More still need to be done but their seems to be light at the end of the tunnel. Malaria is not inevitable, it can be eradicated, the mission is possible if only we devote ourselves to quality research and we never give-up. (Oseni Saheed Oluwasina (2013))

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2. DEFINITION AETIOLOGY & TAXONOMY EPIDEMIOLOGY LIFE CYCLE MORPHOLOGY CLINICAL SIGNS PATHOGENESIS AND IMMUNOLOGY DIAGNOSIS CONTROL ( VACCINE DEVELOPMENT) TREATMENT 3 3. DEFINITION A protozoan disease caused by Plasmodium species of the phylum Apicomplexa. Transmitted by the bite of infected female anopheline mosquitoes. It is characterized by periodic paroxysm with shaking chills, high fever, heavy sweating. Anemia and splenomegaly may also occur in cases. 4 4. AETIOLOGY Four species of Plasmodium cause malaria in human. P. vi vax (benign t ert ian malaria) P. oval e (benign t ert ian malaria) P. mal ari ae (quart an malaria) P. f al ci parum(malignant t ert ian malaria) Each species has its own morphologic, biologic, pathogenic, and clinical characteristics. 5 5. TAXONOMY Kingdom: Prot ist a Sub-Kingdom: Prot ozoa Phylum: Apicomplexa Class: Sporozoasida Order: Eucoccidiorida Family: Plasmodiidae Genus: Plasmodium Specie: P. falciparum 6 6. EPIDEMIOLOGY 7 7. EPIDEMIOLOGY Malaria is t he t hird leading cause of deat h due t o inf ect ious disease. I t af f ect s 300- 500 million people annually worldwide and account s f or over 100million deat hs, mainly in Af rican children under t he age of 5yrs. A child in Af rica dies every 30 seconds of malaria. Endemic around t he t ropics and sub-t ropics alt hough it is world wide in dist ribut ion. 8 8. FEMALE ANOPELES MOSQUI TO 9 TRANSMI SSI ON 9. DISTRIBUTION OF PLASMODIUM FALCIPARUM 10 10. DISTRIBUTION OF PLASMODIUM VIVAX 11 11. WATERSHEDS OF THE AFRI CAN CONTI NENT 12 Mosquitoes are aquatic insects Population density 12. LI FE CYCLE 13 13. 14 14. LIFE CYCLE CONTD 15 15. 16 16. PLASMODI UM MORPHOLOGY 17 17. PLASMODIUM ANATOMY 18 18. 19 19. 20 20. EX-FLAGELLATI ON OF THE MI CROGAMETOCYTE OF A MALARI A PARASI TE I N MOSQUI TO STOMACH 21 21. PORTI ON OF AN I NFECTED MOSQUI TO STOMACH. NOTE NUMEROUS OOCYSTS ON OUTER WALL. 22 22. SPOROZOI TES OF MALARI A I N I NFECTED MOSQUI TO STOMACH PREPARATI ON 23 Light Micrograph SEM 23. ERYTHROCYTIC STAGES OF MALARIA: ALL INFECTIONS BEGIN WITH THE RING STAGE REGARDLESS OF THE SPECIES 24 Ring stage 24. 25 25. CLINICAL SIGNS & SYMPTOMSCLINICAL SIGNS & SYMPTOMS 26 Cold stage 26. MALARIAL PAROXYSM Cold stage f eeling of int ense cold vigorous shivering last s 15-60 minut es Hot stage int ense heat dry burning skin t hrobbing headache last s 2-6 hours Sweating stage prof use sweat ing declining t emperat ure exhaust ed and weak sleep last s 2-4 hours 27 27. UNCOMPLICATED MALARIA Uncomplicat ed malaria is def ined as: Sympt omat ic inf ect ion wit h malaria parasit aemia wit hout signs of severit y and/ or evidence of vit al organ dysf unct ion. 28 28. SEVERE MALARIA Severe malaria is defined as symptomatic malaria in a patient with P. f al ci parumasexual parasitaemia with one or more of the following complications: Cerebral malaria (unrousablecomanotattributabletoothercauses). Generalised convulsions (> 2episodeswithin24hours) Severe normocyt ic anaemia (Ht< 15%orHb< 5g/dl) Hypoglycaemia (gloodglucose< 2.2mmol/lor40mg/dl) Met abolic acidosis wit h respirat ory dist ress (arterialpH< 7.35orbicarbonate< 15mmol/l)* Fluid and elect rolyt e dist urbances Acut e renal f ailure (urine< 400ml/24hinadults; 12ml/kg/24hinchildren) Acut e pulmonary oedema and adult respirat ory dist ress syndrome* Abnormal bleeding J aundice Haemoglobinuria Circulat ory collapse, shock, sept icaema (algid malaria) Hyperparasit aemia (> 10%innon-immune; > 20%insemi-immune) 29 29. RELAPSE A specif ic at t ack t hat it is up t o mont hs or even years af t er t he primary at t acks. Tachysporozoit e grow in t he hepat ic cell and mult iply t o f orm exoeryt hrocyt ic schizont s and t hen invade RBCs t o clinic malaria. Bradysporozoit es in t he liver spend a rest and sleeping t imes of mont hs or even years , t hen t hey st art develop in exoeryt hrocyt ic st age and eryt hrocyt ic st age. at t his t ime, t he pat ient occurs paroxysm , showing as periodic f ever like t he primary at t acks, it is called Relapse. NB: Relapse only occurs in P.vi vax. 30 30. Paroxysms (acute febrile episodes) associated with synchrony coincide with the Merozoite release. Temperature is normal and patient feels well. P. falciparum may not exhibit classic paroxysms (continuous fever) 31 Plasmodium falciparumPlasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium vivax Plasmodium ovale Plasmodium malariaePlasmodium malariae 31. 32 Chronic Asymptomatic Infection Placental Malaria Anemia Infection During Pregnancy Developmental Disorders; Transfusions; Death Low Birth weight Increased Infant Mortality Non-severe Acute Febrile disease Cerebral Malaria Death CLINICAL PICTURECLINICAL PICTURE 32. COMPLICATIONS OF MALARIA : CEREBRAL MALARIA 33 33. COMPLICATIONS OF MALARIA : 34 Child with severe malaria anaemia in conjunction with acidosis and respiratory distress Pulmonary Edema 34. 35 Hepato-splenomegalyHepato-splenomegaly survivors part ially immuned of t en wit h splenomegaly 35. MALARIAL HAEMOGLOBINURIA 36 Clinical Picture : Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop intravascular haemolysis and haemoglobinuria precipitated by Primaquine and other oxidant drugs, even in the absence of malaria. Haemoglobinuria associated with malaria (blackwater fever) is uncommon and malarial haemoglobinuria usually presents in adults as severe disease with anaemia and renal failure. 36. PATHOGENESIS & IMMUNOLOGY 37 37. SUSCEPTI BI LI TY TO MALARI A, ANTI BODY PRODUCTI ON, AND LETHALI TY 38 38. PATHOGENESIS 39 39. The f unct ions of most of t he met abolic product s of P. falciparumare not known. I t is known t hat t hey are resist ant t o t reat ment wit h prot eases. P. falciparumuses hemoglobin as a source of energy and produces hemozin t o digest hemoglobin, t his t oxin is st ored in t he pigment of P. falciparum. This pigment has been linked t o over product ion of t umor necrosis f act or alpha, t he gamma int erf eron and int erleukin-1. These are import ant and nat ural part s of human immune syst ems, but over product ion can lead t o f ever and t he dest ruct ion of healt hy host cells. Information for the following slides adapted from: Chen, Q., M. Schlichtherle, and M. Wahlgren. 2000. Molecular aspects of severe malaria. Clin. Microbiol. Rev. 13:439-450 40 40. TOXI CI TY AND PATHOGENI CI TY I nf ect ion by P. falciparumalso radically changes t he cell membrane of red blood cells. The membrane of inf ect ed cells becomes rigid and t he parasit e creat es channels t hrough t he membrane in order t o t ransport nut r ient s int o t he cell. Prot ein component s of t he cell membrane are digest ed by t he parasit e and are replaced by t he knobs (elect ron rich prot rusions of ~100 micromet ers). The knobs are used t o bind t o uninf ect ed RBCs and t o t he walls of veins and art eries. This is known as roset t ing and can lead t o some of t he most severe complicat ions of malaria, including cerebral malaria, wher e such roset t es occur in t he brain. 41 41. 42 42. There are f ive recept ors on RBC which are t hought t o be involved wit h t he f ormat ion of roset t es. They include blood group ant igens A and B, CD-36, compliment recept or 1 and HS-like GAGs (heparin sulf at e glycosaminoglycans). Roset t es f ormed in blood t ypes A and B are larger, t ight er and st ronger t han t hose f ormed in persons wit h O t ype blood. Blood t ype A is most of t en af f ect ed by severe malaria. P. Falciparum also binds using knobs t o bot h I gG and I gM. The reason f or having accumulat ions of I gM is not precisely known, but it is t heorized t hat such accumulat ions hinder t he access of ant ibodies specif ic t o inf ect ed cells and t hus help malaria t o evade t he 43 43. ANTIGENIC VARIATION Malaria has many t ools t o evade t he immune syst em. P. falciparumhas a very high degree of ant igenic variat ion, making it dif f icult f or t he immune syst em t o recognize malaria. P. falciparumhas t wo dif f erent ways in which t o vary which ant igens it expresses. The f irst way in which t his might occur is during t he sexually reproducing st age in t he lif ecycle when P. Falciparumrecombines genet ic mat erial. This has unlimit ed pot ent ial t o change t he genome of P. Falciparum. The second way in which ant igenic variat ion can occur is t hr ough variable genes and point mut at ions during asexually repr oducing st ages of t he lif ecycle. P. Falciparum o has several f amilies of variable ant igenic genes. These are varf amily, t he roset t in/ rif f amily, and t he p60 f amily. Wit h such a large amount of variabilit y available t o malaria it is no wonder t hat it can successf ully evade t he immune syst em and cause many recurring inf ect ions if not properly t reat ed. 44 44. VAR FAMILY There are ~40-50 genes in t he var f amily wit h a f ew except ion t hey are ext remely variable. The var genes are scat t ered t hroughout t he chromosomes, but concent rat ed on t he 4, 7, and 12 chromosomes. Using t he high variabilit y in t hese regions at least 2% of individuals vary t heir ant igenic expression each generat ion. These genes are t hought t o be involved wit h resist ance t o chloroquine and t o help P. falciparumevade t he host s immune syst em. Mut at ions at t his sight are f ound in 100% of all resist ant st r ains of P. falciparum. The ef f icacy of t he resist ance is gr eat er when a mut at ion also occurs at a sight known as pf mdr1 (P. falciparummult idrug resist ance gene). I nf or mat ion f or t he f ollowing slides adapt ed f r om: Chen, Q., M. Schlicht her le, and M. Wahlgren. 2000. Molecular aspect s of sever e malar ia. Cli