Malaria Describe Life cycle Enumerate Malarial species Mention the Pathogenesis Discuss the Causes of Anemia Complications Lab. Diagnosis
Malaria “Mal-air” It is a world wide distribution disease acute or chronic characterized by fever ,anemia & spleenomegaly occurs where anopheles mosquito are present & caused by genus plasmodium ,which is host specific In IRAQ it is found significantly in the north part of IRAQAnimal kingdom sub kingdom : protozoa sub phylum : Apicomplexa class : sporozoea genus : plasmodium 41% of the world's population live in areas where malaria istransmitted .
Charles Louis Alphonse Laveran
1907 Nobel Prize for Physiology or Medicine!French army doctor in Algeria observed parasites inside red blood cells of malaria patients and proposed for the first time that a protozoan caused disease
Around 300-500 million clinical cases of malaria are reported every year, of which more than a million die of severe and complicated cases of malaria.
Malaria ranks third among the major infectious diseases in causing deaths after HIV , pneumococcal acute respiratory infections and tuberculosis, then malaria. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to anti malarial drugs.
Malaria
Leading causes of death in Sub-Saharan Africa, South Asia, and Southeast Asia for persons age 0-44 (World Health Organization)As you know in the developing world treatable infectious diseases remain big killers
Species that cause Malaria in man arePlasmodium vivax “bengin tertian malaria” 48hrP falciparum “malignant tertian malaria”P malariae “Qurtan malaria” 72hrP ovale “mild tertian malaria ovale malaria”General characteristics of genus plasmodium:1-All species are parasitic of tissue & blood of their host2-Have very complicated life cycle :alternation of sexual (gametogony & sporogony) & asexual (schizogony)3-No organil of locomotion but at certain stages can move by body flexible or flagella as microgamete
Genus plasmodium requires 2 host to complete their life cycle -Vertebrate hostBird, man where asexual cycle takes place (intermediate host)Asexual =schizogony (Trophozoite → schizont → merozoite)-Vector host Female Anopheline mosquito where sexual cycle takes place (final or difinitine host)Sexual= gametogony microgamete unites macrogamete → zygote Sporogony = zygote → oocyst → sporozoites
“Tertian Malaria” (P.falciparum, P.ovale and P.vivax)fever occurs every third day. “Quartan Malaria” (P. malariae)fever occurs every fourth day.
Each disease has a distinct course
*Malarial parasite in man established their 1st foci in non phagocytic cell of the liver (hepatocyte)=pre erythrocytic cycle before the released into circulating blood to parasitize RBC where erythrocytic cycle established Life cycleMan only reservoir infected stage is the sporozoite
Infection person
Insect female Anopheline mosquitoUn infected person
Malaria
Malaria parasites are transmitted from one person to another by the female anopheline mosquito.
The males do not transmit the disease as they feed only on plant juices. There are about 380 species of anopheline mosquito, but only 60 or so are able to transmit the parasite.
Life cycle
Vertebrate manInvertebrates Female mosquito
Tissue phase“liver” Blood phase
sporogony
gametogony
Erythrocytic cycle (E.C.)
Secondary E.E.C Para-erythocytic cycle
Primary Exo-erythrocytic cycle Primary E.E.C. Pre-erythocytic cycle
Fig 92 : Anopheles Female (Mosquito) The vector of malaria
109110
Anopheles
Transmission
sporozoites injected with saliva enter circulation trapped by liver (receptor-ligand)
Pre.E.E.C. 8 days in P. Vivax ,6 days in P. falciparum Sporozoite inside liver cell trophozoites immature schizont mathure schizont contain 1000 s of merozoites (cryptozoites) In the liver no clinical manifestation produced by the parasite Merozoites
Phagocytized by kupffer cell
Secondary exo-erythro. cycle “para-erythro. cycle Dormant for indifinite time “hypnozoite” in P. vivax & ovale only relapse Blood erythocytic cycle
Hyponozoite Forms
some Merozoites exhibit delayed replication (ie, dormant) merozoites produced months after initial infection only P. vivax and P. ovalerelapse = hypnozoite recrudescence = P.malariae
Exoerythrocytic Schizogony
hepatocyte invasion asexual replication 6-15 days 1000-10,000 merozoites no overt pathologyErythrocytic Cycle (vivax 48 hour) Inside RBCMerozoite enter RBC ,cytoplasm of RBC ingested by the parasite large food vacuole giving the appearance of a ring (nucleus at one end) Ring stage ,As the trophozoite grows ,vacuole becomes less ,but pigmented granules of hemozoin in the vacuole become apparent Hemozoin It is the end product of parasiteґs digestion of the host’s Hb ,the trophozoite incompletely utilize Hb leaving residues of globin & an iron. Prophyrin-hematin which is also called malaria pigment (compound of protein +hematin), it has a toxic effect on the body & macrophage ,depressing their phagocytes activity
HEMOGLOBIN HEME +GLOBIN(PROTEIN PART)
HEMOZOIN
HEMEHEMOZOIN
As the trophozoite grows the ring enlarges with pseudopodia in all direction this stage called Amoeboid stage Here in vivax the infected RBC enlarged ,lose it’s pink color (pale) & develops a peculiar stippling “invaginations in the surface of the infected RBC “ called Schuffner's dots After 24 hour vacuole disappears & nuclear division started (12-24nuclei) this is called Immature schizont Then cytoplasmic division mature schizont with specific number of merozoint in each type “12-24” usually 16
Then RBC rupture & releazing merozoites(parasites)+metabolic wastes inclucing hemozoin which responsible for symptoms of malaria Merozoites enter new RBC & repeat eryth. cycle (every 48hr) After an indeterminate number of asexual cycle (eryth. cycle ) some merozoites when enter RBC become microgametocyte( male) or macrogametocyte (female)
These gametocytes develope in RBC in the capillary of internal organ (spleen + Bone Marrow) & go to peripheral blood only when become mature (96hr) twice the time of E. schizogony The mature gametocyte unless ingested by female anopheline mosq. It will be die & phagocytized Individual who harbor gametocytes in his peripheral blood is called carrier When female anopheline mosq. takes erythrocytes containing gametocytes the sexual cycle begin :
A
B
C
123
Sexual cycle : (gametogony ) + sporogony In the female anoph. mosq. gametocytes develops in to gametes Macro gametocyte one macrogamete Microgametocyte 6-8 microgamete ,by process called exflagellation Exflagellation :the nucleus of microgamete is divided into 6-8 daughter nuclei then axoneme is developed ,then the flagella buds with their associated nuclei to outwards 6-8 microgametes One micro gametes fertilize macrogamete zygote mobile ookinete (in the gut of mosq.)Ookinete penetrates the gut mucosa of female anoph. mosq. To the hemocoel side (outer side ) of the gut → oocyte which contains the sporoblast that divided rapidly to form thousands of sporozoites break out of oocyte hemocoel salivary gland next patient
Sporogony
occurs in mosquito (9-21 d)fusion of micro- and macrogametes zygote ookinete (~24 hr)ookinete transverses gut epithelium ('trans-invasion')Liver stage
SporozoitesMosquito Salivary Gland
Malaria Life Cycle
Gametocytes
Oocyst
Red Blood Cell Cycle
Zygote
Method of transmission *sporozoite induced The infective stage is sporozoite by biting of female anoph. mosq. porter of entry =skin *trophozoite induced Blood transfusion especially P. malaria syringe ,lab. accident & rarely congenital infection
P. Vivax :43% of malaria in the world some merozoites remain in the liver hypenozoite so relapse Merozoite invades only young RBC (reticulocyte) unable to invade fully mature RBC ,black people have got natural resistance to p. vivax infection ,because merozoite enter RBC through receptor which is the duffy blood group protein Ag fy a ,fy b Black people usually with no such Ag fy0 infected RBC in P. vivax enlarge ,pale ,with schuffner’s dots ,(fine dots)Schizont in E. cycle with 12-24 hr usually 16 merozoits E. cycle with 48 hr periodicity = tertian malaria a
a
P. Falciparum = malignant ter. m. 50% of human malaria most virulent ,90% of mortality of malaria greater killer of humanity in tropical zone No relapse (no hypnozoites) Invade RBC at any age even reticulocyte so much higher parasitemia than other types (25% of RBC infected )Soon after invasion of RBC the trophozoite produce protein that are deposite in the eryth. surface membrane in the deformation called knobs, these protein bind to certain glyco-protein on the post capillary venular endothelium this binding cause sequestration of the infected RBCs so stick to venular endothelium , also those RBCs stick to normal RBC thrombosisGametocyte don’t produce these knobs so gametocyte infected RBCs don’t stick
So in the peripheral blood only the early ring stages & gametocyte are seen in P. falciparum Ring stage in P. falciparum are smallest than other species ,multiple infection of the same RBC is common ,rings with bi nucleated (2 chromatin dots) also present may be division of the ring RBC with Maurer's dots larger than the fine schiiffner’s dots of P. vivaxThese dots for transport of nutrient Amoeboid & schizont (8-32merozoites) ,not seen in the peripheral blood but in the capillaries of the internal organ (spleen , B.M.)Gametocytes are crescent in shape
A
B
C
D
E
F
138
A, B, C, D: Gametocytes of P. falciparum in thin blood smears.
AB
C
D
E
( X 1000 )
141
P. Malariae 7%Quatrain malaria (paroxysm every 72hr), amoeboid band form schizont 6-12 (9) merozoites in a rosette shape ,infect only old (aging) RBC so low parasitemia Can live in blood up to 50 years so important in blood transfusion ,transmission & cause recrudescence but no relapse P. Ovale Mild tertian malaria ,oval malaria Rarest type ,RBC oval in shape schuffner’s dots appear earlyer ,larger more numerous than vivax , schizont 6-12 (9)
Pathogenesis of malaria Major clinical manifestation is due to 1- Host inflammatory response which produce chills & fever 2-Anemia due to enormous destruction of RBC *Severity depends on species of malaria ,most serious one is P. falciparum *the fever in malaria is stimulated by the waste products of parasites which are released after lyses of RBSs ,which includs mainly malarial toxins “hemozoin or malarial pigments” into circulation trigger =TNF (tumor necrosis factor) fever
Fever in malaria is intermittent P. vivax : benign tertian malaria 48hr P. faiciparum : malignant tertian malaria P. oval : oval malaria 72hr P. malaria : Quarter malaria
Anemia :- -Malaria causes destruction both infected & non infected RBCs -In ability to recycle iron bounded in hemozoin -Defective bone marrow response -Spleen removes infected & non infected RBCs from blood ,due to TNF toxicity Anemia may cause Juandice
Age
No age limit Pregnant women and children are most likely to get it. People from non-malaria zones are at much higher risk than natives when they are in malaria zones.
Clinical feature of malaria :-Incubation period in P. Vivax = 9-12 days (no symptoms)Then the main clinical manifestation in a typical case of malaria started which include febrile paroxysms followed by anemia & splenomeglay Febrile paroxysms :-each paroxysms shows 3 stages 1-Cold stages (last 20-60 min. usually 1/2hr) Chill , felling of intense cold ,although temp. 40˚C ,shivering2-Hot stages (last 2-4hr)Fever , 40 -41˚C ,headache ,mild delirium 3-sweating stages (last 2- 3 hr)PerspirationThe total duration of febrile cycle ≈ 6-8 hr ,these paroxysms synchronies with the eryth. shizogony
In tertian fever the paroxysms recurs every 48 hr ,while in quarter malaria (P. malaria )recurs every 72hr ,after rupture of RBCsWhen paroxysm is over after 8hr ,patient feels tired & goes to sleep for a while ,& then feels fairly well until next paroxysm Anemia : after few paroxysms anemia occurs microcytic ,hypo chronic type splenomegaly : .one of important physical sign “spleenic index” In P. falciparum there is serious complications due to clotting of capillary of affected organ circulatory stasis & hypoxia-Cerebral malaria :(convolution ,coma ,death)-Pulmonary edema-Algid malaria: rapid development of shock (adrenal involvement) -Septicemia & toxemia
Black water fever :-Only in P. falciparum ,acute Massive lyses of RBCs ,high level of Hb & its products renal insufficiently & renal failureHb & it’s products in urine dark (black) urineUsually occur in patient who is taking inadequate or irregular treatment with quinine drug may produce anti quinine Ab auto immune hemolytic anemia auto Ab to drug or to P. FalciparumAdministration of steroids is often helpful in treatment of this hemolytic crises
Relapse Back into disease months or years after apparent curve occurs only in P.Vivax & oval (activation of hypnozoites in the liver) may be due to:- -Lowered Ab titer -Genetic variation of the parasite Symptoms of relapse usually less severe than the primary attack Recrudescence:- In P. malariae ,renewal of clinical manifestation after month& year , without re-exposure ,because of persistence of the parasite in blood at too low level to be detected & produce symptoms ,such parasitemia persist for years until sudden increase malarial symptoms In P. falciparum ,if the patient survive remission naturally or with treatment the parasite completely disappear from the blood cure
P.ovale and P.vivax can cause chronic malaria, reappearing after months or years due to latent parasites in liver
Each disease has a distinct course
Diagnosis of malaria :- -Depend to some extent on clinical manifestation of the disease -Demonstration of the parasite on stained smears of the peripheral blood Microscopically examination of blood film is the most important diagnostic procedures thin for species identification thick for quick diagnosis Blood film done : Just before or at beginning of paroxysms -Visualizing the parasite after staining by fluorescent dye -PCR -Dip-stick method for detection of material Ag -Serological tests C.F.T. precipitation testImmunity to malaria is specific ,strain & variant specific Genetic resistance to malaria 1-Black people (Duffy blood group) natural resistance to P. vivax 2-Sickle cell anemia fauvism Abnormal Hb Thalassemia Treatment of malaria :- Anti malarial drugs Alkaloid :quinine ,chloroquine ,primequine Chloroquine prevent digestion of Hb so no hemozoin ,it is not effective in exo-eryth. schizgony primequine kill hypnozoint so prevent relapse In resistant malaria :mefloquine , fansidar
Genetic Resistance
Sickle celled anemiaCodominant trait (Allele “A” and “B”)AA have sickle celled anemiaAB have both types of cellsSickle cells don’t support species of Plasmodium well.Resistance to infectionProphylaxis :- Vaccine :difficult (different stages ,changing their Ag ) Travelers to endemic take chloroquine 2 weeks before & contain to 6 weeks after leaving ,followed 2 weeks primequine Control :- Mosquito control (netting ,window screen ,destruction area of mosquito life cycle using predators (fishes) insecticides DDT Drug resistance malaria & mosquito resistance so malaria will be with us as long in there is people