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One day Workshop YUMS |Tissue and Blood Protozoan diseases
Malaria & Leishmaniasis Mohammad Amin Ghatee Ph.D in medical Parasitology
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MALARIA THE KILLER DISEASE
500 million people suffer from malaria Over one million of people die each year. The majority of victims are children and pregnant women. (one African child every 30 seconds) Sub-Saharan Africa bears 90 per cent of the burden. Mal=bad Area=aria= hava Manateghe batlaghi Paludism=malaria Obligatory heteroxenous parasite
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Plasmodium species which infect humans
Plasmodium falciparum (tertian) Plasmodium vivax (tertian) Plasmodium malariae (quartian) Plasmodium ovale (tertian) I am giving the old names for these malarias in parentheses to give some historical perspective in case you see these terms again. I will also explain how these old terms relate to the pathogenesis of these respective diseases and the associated fever patterns. P.ovale is the last descriped plasmodium. Phylum: Apicomplexa Class: Sporozoa (هاگداران) Order: Eucoccidida Suborder: Haemosporina Genera: plasmodium, Leucocytozoon, Haemoproteus, Hepatocystis) Three subgenus: P (plasmodium): schizont with more than 8 merozoites, with stippling, round gametocyte, high mammals as hosts, including 26 species ( 3 species infecting human). P (Laverania): schizont with more than 8 merozoites, with stippling, bean-shaped gametocyte, high mamals as hosts, 2 species including one human pathogen that means P. (Laverania) falciparum. P ( Vinckeia): schizont with less than 8 merozoites, no stippling, round-shaped gametocyte, primary (low level) mamals as hosts, 15 species including P.(vinckeia) bubalis In overall, 100 species but only four species is pathogen for human Strongly host specific but some monkeys were exerimentally infected by human plasmodiums. P. Berghei and P. yoellii: rodents P. gallinarum: birds? P. cathemerium: birds? P. simium: brazillian black monkey P. knowlesi: east monkey P.cynomolgy: baboon P. shortti: Indian and cylanian monkey P. Schwetzi: African chimpanzea P. inui: east monkey P. brasilianum: new world monkey P. eylesi: long hand monkey (in Mali)
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Geographical distribution and incidence of malaria
Figure 23.10
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Plasmodium species Plasmodium falciparum: Tropics. Accounts for 50% of all malaria cases. Most pathogenic. Plasmodium vivax: Tropics, subtropics, and some temperate regions.. About 43% of all malaria cases. Some Africans are refractory to infection because the lack the red cell receptor that the parasite use to enter. Plasmodium malariae: Tropics. About 7% of all malaria cases. Plasmodium ovale: West Africa. Rare. Benign tertian malaria = by Plasmodium vivax Summer-fall malaria, malignant tertian malaria = Plasmodium falciparum Quartiain malaria=P. malarie
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HOSTS DEFINITIVE HOST: Anopheline female Mosquito (sexual reproduction) INTERMEDIATE HOST: Humans (asexual and sexual phases) آنوفل ماده انتقال بیماری احتملا از میمون به انسان در جنوب شرق اسیا و سپس گسترش به افریقا و اروپا و سپس از قرن 16 به آمریکا.
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Malaria Life Cycle پس از ورود گامتوسیت ها به معده پشه در اثر کاهش دما (دمای بدن پشه) به گامت تبدیل می شوند میکروگامتوسیت با انجام میوزیس کاهش کروموزوموزومی می دهند و منجر به تولید 6-8 میکروگامت می شوند. ماکروگامتوسیت نمیدانم چگونه ولی ظاهرا میوز نمی کنند ولی n کروموزوم از طریق یک قطب انگل دفع می شوند کروموزوم دیگر به قطب دیگر به جدار داخلی انگل می چسبد و برامدگی ایجاد می کند. میکروگامتوسیت علاوه بر میوز ایجاد تاژک (exflagellation ) می کند. در زمان لقاح تاژک را از دست می دهد. 20 دقیقه پس از لقاح اووکینت کرمی شکل ایجاد می شود. 24 ساعت درون معده پشه است سپس دیاره معده را سوراخ و مابین دیواره خارجی و داخلی گات قرار می گیرد و ایجاد اووسیست می کند Ookinet is an active zygote Oocyst is 50 µm and ookunet is 20 µm. Ookinet under sporogony converts to oocyst containing many sporozoites. Oocyst open into haemocel (hofreh omomi badan va na mede va govaresh) Sporozoirs go into salivary glands Two salivary gland, each in one side of pharynx. Each salivary gland has three lobes Sporozoites are haploid with prepheral fibrils that may play role in movement. It has mitochondria but no pigment. Female anophele fed blood f host each 48h (gonotrophic cycle or oovolaton period) at early or late night Sporogony (fly cycle) last 7 days for P. vivax, 14d for P. falciparum and d for P. malarie sporozoite injection in each biting
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Types of Infections Recrudescence Relapse
exacerbation of persistent undetectable parasitemia, due to survival of erythrocytic forms, no exo-erythrocytic cycle (P.f., P.m.) Blood origin Can be occurred along the life time Relapse reactivation of hypnozoites forms of parasite in liver, separate from previous infection with same species (P.v. and P.o.) Tissue (liver) origin Up to 3-5 years after primary infection Hypnozoite: Schizozoite (slowly growing merozoite in liver), سلول خفته , no pigmentation in tissue schizont due to lack of hemoglobin.
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Erythrocytic phase stages of parasite in RBC
Young trophozoites or ring form Tropohozoite forms merozoites Schizogeny to forms merozoites releasing merozoites into blood stream. Merozoites invade other RBCs and schizongeny is repeated Parasite density increases until host’s immune response slows it down Merozoites may develop into gametocytes (gametogony), the sexual forms of the parasite Blue-body: parallel to erythrocytic schizogony (segmentation), some round and egg-shaped chromatin granules with blue color. Blue-body may have role in sexall features (stimulate the gametocyte production) Gametocytogenesis starts following 3-4 erythrocytic schizogony. First, immature sexual feature (gamont) is produced that converts to microgametocyt or macrogametocyte in 6 days. Macrogametocyte (female) number is more than microgametocyte to balance the numbers in anopheles
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Development in the mosquito
Upon ingestion with a blood meal, both the micro and macrogametocyte rapidly mature Macrogamete is released from ruptured rbc Microgametocyte rapidly undergoes multiple nuclear divisions to form 8 gametes Exflagellation
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Development in the mosquito: the ookinete
A mature ookinete. A number of organelles are shown. The nucleus can be seen at the lower end of the organism. There are abundant ribosomes in the area above the nucleus and endoplasmic reditulum can also be seen. The zygote is surrounded by a three-layered pellicle. The apical complex at the upper end includes numerous rhoptries and micronemes (dark spots). Image from Sinden RE. "Malaria", Topics in Inernational Health,(1998) The WellcomeTrust, CABI Publishing, CAB International Number of engulfed gametocytes by fly is important in the ability of anophele to infect human. This is 1 gametocyte against 1000 WBC for P. vivax, 2 gametocytes for P. malarie and 5 gametocytes for P. falciparum. Plasmodium fed by pinocytosis and probably by an organel alike the micropore. Glucose phophorylation for enery and globin chain to acquire amino acids. G6PD reduces the glutation. Reduced glutation is needed for hexose monophosphate chant. Plasmodium uses the products of this chant like ribose-phosphate. Host resistance to Plasmodium falciparum : G6PD deficiency, scickle cell anemia (abnormal Hb, it converts to column-shaped Hb when O2 is deficient.
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Development in the mosquito
Encysted ookinete transforms into oocycst 10-14 days of development reductional nuclear division, haploid again multiplication to form 1000’s of sporozoites
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THE OOCYST Plasmodium transmitting Anopheles: In Iran 10 species are vector The most important: An. stephenci The most prevalent: An. Superpictus Southeast, south and central regions: An. dethali and An. Culicifacies The most dangrous anophel: An. Fluviatilis vector of P. falciparum in sistan & Balochestan, Hormozgan and South Kerman An. sacharovi in Ardabil and Azerbayjan An. Maculipenis in Mazandaran and Gillan SEM which shows two oocysts on the outer wall of the midgut of a mosquito. These contain developing P. gallinacium sporozoites. Image from Guggehheim R."Malaria", Topics in Inernational Health,(1998) The WellcomeTrust, CABI Publishing, CAB International) Anopheles gambiae, the deadliest malaria vector (top), and blue-colored Plasmodium oocysts, appearing from the mosquito’s gut. (MOSQUITO ENGINEERING:Building a Disease-Fighting Mosquito. Martin Enserink/Science : (in News Focus)
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Merozoites attach to specific receptors (like some blood groups) by their conoids.
Hb F, thalasemy and duffy-: resistand to P. vivax Applique (Accole): parasite attachment to the RBC, state or cresent-like parasite in periphery of RBC (probably inside RBC?) After accole formation, a vacuele is formed and push parsite nucleus to the one side of RBC. Now it is ring form. Vaivax name is derivate of Vigorous vocabulary with meaning of strong due to amoebic activity and form of throphozoite in RBC Stippling occur in trophozoite form (like schufner ) 36h for P.vivax and falciparum and 50h for P. malariehRing, growing trophozoite, old trophozoite
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Schizogenic periodicity and fever patterns
Schizogenic periodicity is length of asexual erythrocytic phase 48 hours in P.f., P.v., and P.o. (tertian) 72 hours in P.m. (quartian) Initially may not see characteristic fever pattern if schizogony not synchronous. With synchrony, periods of fever or febrile paroxsyms assume a more definite 3 (tertian)- or 4 (quartian)- day pattern. Initially continoius ( fever high in all day (24h) and variation lower than 1.5 F) or remittent ( fever high in all day (24h) and variation higher than 2 F). This adjust cycle of parasites with increasing the speed of convertion of immaature paraites to mature. Then so the fever periodicity synchronised. Prepatent period: the time from entrance parasite to body till parasite appear in blood Incubation period: the time from entrance parasite to body till manifestation of symptoms.
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Clinical presentation
Early symptoms Headache Malaise Fatigue Nausea Muscular pains Slight diarrhea Slight fever Photophobia Anorexia Could mistake for influenza or gastrointestinal infection Malaria 4-1 has longest common period ad malaria caused by P. falciparum has shortest.
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Paroxysm of malaria In cold stage (thrilling for min), the skin became pale like cyanosis Rupture of sRBCs and release of merozoites couses decrease in RBCs and so blood circulation from skin diverted to the viscera to compensate. So patient feel coldness and thrill. In fever stage (2-6h), fard hazyan migoyad, va dard shadid pishani, posht va dast opa shaye ast An acute splenimegally may be observed Schizont rupures, and release of pyogenic endotoxin from schizonts result in production of TNF , IL1 and IL6 from macrophages that affect on the methabolism of archidonic acid that results in production of prostaglandins. Prostaglsndins affect on the hypothalamus (center of temperature adjustment), that finally cause the fever
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Malarial Paroxysm Periodicity
Days 1 and 3 for P.v., P.o., (and P.f.) - tertian Usually persistent fever or daily paroxyms for P.f. Days 1 and 4 for P.m. - quartian
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Malaria Paroxysm Malaria tertiana: 48h between fevers (P. vivax and ovale) Malaria quartana: 72h between fevers (P. malariae) Malaria tropica: irregular high fever (P. falciparum)
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Normochrom normocytic anemia
In black water fever ( vast hemolysis of RBCs) results in hypochrom, microcytic anemia Anemia: 1-periodic schizont and RBC lysis 2-auto-immune mediated haemolysis or through complement mechanism 3-increasing phagocytosis clean and infected RBCs by Spleen 4-cyto adherance and blockage of blood in capillaries that results in hypoxia, tissue damage and distrbance in electrolyte balance between cells and plasma and following entrance of plasma into interstitial space that results in decrease in blood plasma and false (not real) anemia. 5- DIC 6- thrombocytopenia and following bleeding result in anemia 7-black water fever Malaria results in: 1- tropical splenomegaly syndrom (due to hyperproduction of Igm due to disturbance in T-supperssor that can not control B cells) 2-Cerebral malaria: most sever malaria feature, headache, drowsiness, comma, hemiparesis (bihesi yektarafeh) brain ataxia, hipotonia (zafe shadide azolani) Rapid prescribtion of Quinin and qiunidin and blood exchange is essential 3-Reinal failure: Acute renal congestion by P. falciparum: glomeronephritis, oligiria, anuria, edema Chronic renal congestion by P. malarie due to immune complex more in children 4-Pneumonic malaria: pulmonary oedema, 1- alveolar capillary damage 2-secondry odema due to increase in blood plasma volume due to injection of liquids in an oliguric or anuric (renal congested) patient 5-aligid malaria: sever hypotention due to dsterbance in (ghodef foghe koliavi) and following feeling coldness in skin and sever hypothermic state and shock. It may be also due to septesemia by gram negative bacteria, pulmonary oedema, rupture of large spleen, 6-Black water fever: antibody mediated immune respone against knob results in vast heamolysis of RBCs (fever, kidny pain, jundice) Also may be due to treatment with quinine 7-Dysantryic malaria: bleeding from upper GI due to capillary damages. Abdominal pain, nausia, vommiting, bleeding in GI 8- hyperparasitemia: cause cerebral malaria and death. Blood excheng can save patient life 9-hypoglycemia: tretment with quinine and quinidine resukt in hyperinsulinemia and following hypoglycemia that cause abortion or fetus problems in third semester. In children hypoglycemia is not due to drug and hyperinsulenimeia but for disability of liver cells in glyconeogenesis
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Malaria the disease 3 Severe manifestations Cerebral malaria
Severe anemia Renal failure Irritability, loss of reflexes, neurological symptoms similar to menigitis, coma 20% fatality Progressive severe drop of hematocrit, poor oxygen Supply for organs and tissues Dwindling urine, high urea Level in serum
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Knobs and cytoadherence
Cytoadhrence and rosetting correlates with the presence of “knobs” (left column) on the surface of the infected RBC The right column shows a RBC infected with a knob-less strain which does not cause cerebral malaria Knobs are made up of parasite derived proteins knobs knob-less
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Cerebral Malaria Possible metabolic effects, cytokines (eg, TNF-)
Pathophysiology cytoadherence cerebral ischemia hypoxia, metabolic effects, cytokines (eg, TNF-) coma death
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Severe anaemia - pathogenesis
Erythrocyte destruction during schizogony (destruction of both parasitized and nonparasitized erythrocytes) Erythrophagocytosis in spleen Immune mediated response Black water fever Spleen Bone marrow suppression
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Other severe complications
Pulmonary oedema Renal insufficiency (nephrotic syndrome) P. malariae Haemolysis Thrombocytopaenia, DIC Superinfections (secondry infection) Septicaemia
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Immunity and Resistance in malaria
Protective immunity to malaria is primarily a premunition. In highly endemic areas, infants are protected by maternal antibodies, and young children are at greatest risk after weaning.
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Genetically resistance factors
Sickle cell anemia, favism, and thalassemia can cause resistance to infection by P. f -Duffy blood groups and P. v
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Modes of transmission 1. Natural or biological transmission
2. Accidental transmission: blood transfusion sharing of needles by IV drug users 3. Maternal transmission
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Malaria Diagnosis Clinical Diagnosis:
Symptoms: fever, chills, headache, malaise, etc. History of being in endemic area Splenomegaly and anemia as disease progresses
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Malaria Diagnosis Laboratory diagnosis: Microscopic demonstration of parasite in blood smear (distinguish species) thick film: more sensitive thin film: species identification easier Fluorescent microscopy antigen detection ‘dipstick’ Serology Polymerase Chain Reaction Most important form of parasite for diagnosis of falciparum from others is gametocyte. The best time for slide preparation is after paroxysm beccause parasites enter the new RBCs again.
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4. Carry the drop of blood to the first slide and hold at 45degree angle. 1. Touch 3 drops of blood to a clean slide. 2. Spread the drops to make a 1 cm circle. 5. Pull the drop of blood across the first slide in one motion. 3. Touch a fresh drop of blood to the edge of another slide. 6. Wait for both to dry before fixing and staining.
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Malaria Blood Smear Remains the gold standard for diagnosis
Giemsa stain distinguishes between species and life cycle stages parasitemia is quantifiable Requirements: equipment, training, reagents, supervision Simple, inexpensive yet labor-intensive Accuracy depends on laboratorian skill
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Interpreting Thick and Thin Films
THICK FILM lysed RBCs larger volume 0.25 μl blood/100 fields blood elements more concentrated good screening test positive or negative parasite density more difficult to diagnose species THIN FILM fixed RBCs, single layer smaller volume 0.005 μl blood/100 fields good species differentiation requires more time to read low density infections can be missed
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Malaria Parasite Erythrocytic Stages
Ring form Trophozoite Schizont Gametocytes
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Plasmodium falciparum
Infected erythrocytes: normal size, maurers cleft, discrimination of P. falciparum from other species is a important, because P. falciparum in blood of non-immune case is a medical emergency. M I Gametocytes: mature (M)and immature (I) forms Rings: double chromatin dots, multiple infections in same red cell Schizonts: merozoites (rarely seen in peripheral blood) Trophozoites: compact Double infection, triple infection, Also double chromatin Murrers dot: khormaii rang or dark red thousands per cubic milimetter. Falci-parum: means producer of scickle-shaped bodies (gametocytes) Macrogametocyte: taxon-shaped, larger, thinner, more condensed chromatin Microgametocyte: kidney-shaped, banana-shaped, shorter, wider, finer chromattin In thick smear, young tropjozoite is comma or swallow shaped. schizont is not seen in prepheral blood due to sticky property of RBC with schizont:1- knob( vesicles content of glycoprotein and glycolipid obtained from parasite metabolism) in RBC surface 2- change of structure of RBC surface protein 3- change in electrical charge 4- Prasite enzymes coverd the RBC surface
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Plasmodium vivax Infected erythrocytes: enlarged up to 2X; deformed; (Schüffner’s dots)) Rings Trophozoites: ameboid; deforms the erythrocyte Schizonts: merozoites Gametocytes: round-oval In thick smear, P. vovax trophozoites may be a thin cytoplasm near nucleus or thin cytoplasm in both sides of nucleus that are named “Comma” and “Swallow”, respectively. Gametocytes of P. malarie, vivax and ovale are similar (round form) but P. malarie is smaller and darker without schfner dots. So other asexual forms must be evaluated for identification. Male and female gametocytes in all species can be differentiated regarding fine and pale chromatin network of microgametocyte and dense chromatun of macrogametocyte. P. Vivax invade young and so large and pale RBCs. Ddouble-infection can be seen for P. vivax (like falciparum) Schuffner dot is orange. Parasitemia thousands per cubic millimeter of blood P. Vivax previously was named as Haemamobea vivax. Schuffner dots are being from growing (ameboid) trophozoite till latest form meaning gametocyte.
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“malariae - like parasite in vivax - like erythrocyte”
Plasmodium ovale Infected erythrocytes: moderately enlarged (11/4 X); fimbriated; oval; (Schüffner’s dots) “malariae - like parasite in vivax - like erythrocyte” Trophozoites: compact Rings Gametocytes: round-oval Schizonts: 6-12 merozoites;(usually 8) dark pigment Only in West Africa, alternative, substitution for vivax in Wset Africa James dot or Schuffner dot: dark red Oval-shaped parasite, Like vivax
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Plasmodium malariae Infected erythrocytes: size normal to decreased (3/4X), Zeimanns dots Trophozoite: typical band form Trophozoite: compact Schizont: 6-12 merozoites (usually 8); coarse, dark pigment ; (“rosettes”) Gametocyte: round; coarse, dark pigment Old RBC that are smaller RBC is with more color due to increase of pH. 20000 parasites per cubic mililitter Ziemman dot” not seen with romanofsky stains, but yellow with florcent staining Young trophozoite: band form or egg form Rosset form mature schizont: 6-12 merozoites in around RBC and pigments in center of RBC.
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Malaria Serology – antibody detection
Antibodies to asexual parasites appear some days after invasion of RBCs and may persist for months Positive test indicates past infection Not useful for treatment decisions Investigating congenital malaria, esp. if mom’s smear is negative
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Malaria Antigen Detection
Immunologic assays to detect specific antigens Commercial kits now available as immunochromatographic rapid diagnostic tests (RDTs), used with blood P. falciparum histidine-rich protein 2 (PfHRP-2) parasite LDH (pLDH) Monoclonal and polyclonal antibodies used in antigen (Ag) capture test Species- and pan-specific Ab Cross reactivity with rheumatoid factor reportedly corrected Cannot detect mixed infections
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Detection of Plasmodium antigens
A: HRP-2 (histidine-rich protein 2) (ICT) B: pLDH (parasite lactate dehydrogenase)(Flow) C: HRP-2 (histidine-rich protein 2) (PATH)
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Polymerase Chain Reaction (PCR))
Molecular technique to identify parasite genetic material Uses whole blood collected in anticoagulated tube (200 µl) or directly onto filter paper (5 µl) Definitive species-specific diagnosis now possible
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Immunity and Resistance in malaria
Much of the disease results from inflammatory and immune responses of the host Release of proinflammatory cytokines, such as TNF and IFNγ, cause serious metabolic changes.
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Immunity to malaria There is no sterile immunity to malaria
Patients produce strong antibody responses to PfEMP1 which is exposed to the immune system on the surface of the infected RBC. Why is the immunity to malaria relatively weak? PfEMP1 is encoded by a large multigene family (VAR genes) and parasites switch to new variants (antigenic variation again) The parasite genome encodes 60 VAR genes, only one is expressed at a time (allelic exclusion) This phenomenon depends on the VAR promoter
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Immunity to malaria Successful vaccination in humans has been achieved with large doses of irradiated sporozoites, however that is not practical None has yielded a satisfactory and safe human vaccine yet Currently, control depends on drug therapy
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Treatment Chloroquine Primaquine Quinine Artemisinins
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Selected Anti-Malarials
Blood schizonticides: 1-Rapid acting: Chloroquine, Amodiaquine, Quinine, Quinidine, Mefloquine, Atovaquone, Artemisinin 2- Slow acting: Antifolates(Fansidar, proguanil) , Clindamycin, Tetracyclines, Proguanil Tissue schizonticides: Primaquine , Proguanil Gametocidal: Primaquine Anti – relapsing: Primaquine
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Chinchona the source of quinine
Peruvian Indians appear to have been the first to know about the medicinal effects of quinine. They chewed Chinchona bark while working in the mines as forced laborers for the Spanish
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Malaria Drug Therapy in Iran
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Plasmodium falciparum & Plasmodium malariae infections
First day: Chloroquine 600 mg (4 tab), 6 h later: 300 mg Second day: Chloroquine 300 mg Third day: Chloroquine 300 mg & Primaquine 45 mg (3 tab)
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Vaccine Radiated sporozoite Sporozoite recombinant proteins
Spf66: synthethic polypeptides of merozoites RTS,S: recombinant HBV surface protein and parasite proteins
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Plasmodium falciparum (CQ-resistant) infections
First day: Quinine 600 mg (3 tab) q8h & Fansidar 3 tab Second day: Quinine 600 mg (3 tab) q8h Third day: Quinine 600 mg (3 tab) q8h & Primaquine 45 mg
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Plasmodium vivax infections
First day: Chloroquine 600 mg (4 tab), 6 h later: 300 mg Second day: Chloroquine 300 mg Third day: Chloroquine 300 mg & Primaquine 45 mg Weekly × 8 wks or 15 mg daily × 14 d
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Severe anaemia P. falciparum – often, not always, high parasitaemia
Often prolonged duration Hb < 5 g/dl (3 mmol/l) Lactic acidosis – ’respiratory distress’ Haemolysis Hyperbilirubinaemia Haemoglobinuria (Black water fever syndrom)
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P.v P.f P.m P.o
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PARASITE FORMS Merozoite: invades erythrocytes
Sporozoite invades mosquito salivary glands and liver cells Ookinete invades mosquito gut epithelial cells Mosquito forms: gametocytes, Oocyst, ookinete, sporozoite Blood forms: merozoites, rings, trophozoite, schizonts, gametocytes
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The sporozoite 10-15 m long Two sporozoite surface proteins contain hepatocyte adhesive domains (CSP circumsporozoite protein and TRAP thrombospondin related anonymous protein) Both proteins bind to glycosoaminoglycans on the surface of hepatocytes
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Components of the Malaria Life Cycle
Sporogonic cycle Infective Period Mosquito bites uninfected person Mosquito Vector Parasites visible Human Host Mosquito bites gametocytemic person Symptom onset Prepatent Period Recovery Incubation Period Clinical Illness
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Plasmodium blood forms: the ring stage
1st hours spent as ring stage, or young trophozoite little to no Hb degradation only form seen in blood films of P. falciparum
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THE SCHIZONT Schizogony: form of asexual reproduction in which multiple mitoses take place, followed by cytokinesis resulting in multiple daughter cells multiple mitoses produce several nuclei once nuclei & organelles replicated cytokinesis occurs rupture of RBC membrane releases merozoites
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Gamogony Formation of gametocytes
27, 28: Mature macrogametocytes (female); 29, 30: Mature microgametocytes (male). Formation of gametocytes trigger for this is unknown, in in vitro culture it is stress related. 9-10 day development for P. falciparum 36 hours development for P. vivax in P. falciparum have characteristic banana shape
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Malaria Paroxysm paroxysms associated with synchrony of merozoite release 48 or 72 hr cycles release of antigens, etc TNF- temperature is normal and patient feels well between paroxysms falciparum may not exhibit classic paroxysms continuous fever (remittent) paroxysms become less severe and irregular as infection progresses
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Clinical Features manifestations and severity depend on species and host status acquired immunity general health nutritional state genetics
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Common features of P.vivax infections
Paroxysm duration 8-12 hours Relapses 60% untreated or inadequately treated will relapse Time from primary infection to relapse varies by strain Treat blood stages as well as give terminal prophylaxis for hypnozoites
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Common features of P. malariae infections
Clinical picture similar to P.v. Incubation period long – days Anemia less pronounced than P.v. Gross splenomegaly but risk of rupture less common than in P.v. No relapse – no hepatic phase or persisting hepatic cycle Parasitemia rarely > 1%, all asexual stages can be present Can cause nephrotic syndrome, prognosis is poor The danger of transmission of this parasite through blood transfusion is evident.
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15% of cerebral malaria patients die
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The main causes of the anemia are:
destruction of both parasitized and nonparasitized erythrocytes inability of the body to recycle the iron bound in hemozoin inadequate erythropoietic response of the bone marrow
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Species Differentiation on Thin Films
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Drugs Used to Treat Malaria
1- Tissue schizonticides 2- Blood schizonticides (drugs used to clinical cure) 3- Gametocides - Drugs used to radical cure
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Chloroquine 4-amino quinoline acts on asexual intraerythrocytic forms
useful for treatment or prophylaxis safe for children and in pregnancy side effects: GI, headache, blurred vision, pruritis limited efficacy against P. falciparum resistant strains of P. vivax emerging
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Primaquine 8-aminoquinoline
acts on gametocytes, hypnozoites; weak against asexual blood stage parasites primarily used as post-exposure prophylaxis and radical cure for P. vivax and P. ovale contraindicated in G6PD deficiency and pregnancy decreased activity against some P. vivax
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Primaquine (PQ) use in P. vivax and P. ovale infections
Use to achieve radical cure and prevent relapses Check glucose-6-phosphate dehydrogenase (G6PD) level first PQ can cause hemolysis in G6PD-deficient patients If mildly deficient, consider weekly PQ dosing instead of daily Contraindicated in pregnancy Pregnant women and newborns use prophylactic CQ weekly until delivery or until end of breast-feeding Then use primaquine
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Quinine first isolated from cinchona bark in 1820
dextroisomer: QUINIDINE acts against asexual erythrocytic stages used for treatment of all 4 species safe in pregnancy and for children side effects: nausea, blurred vision, tinnitus diminished activity against some P. falciparum from SE Asia
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Other Medications--Artemisinins
novel class of antimalarial drugs derived from Chinese herb: qinghaosu act on earlier parasite developmental stages than CQ or Quinine rapid parasite clearance no resistance to date, but high rates of recrudescence if used alone effective in combination with MQ neurological lesions in animal studies
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Chloroquine the wonder drug
Chloroquine an artificial quinine analog developed by German and American chemists during WWII was a very potent drug that was cheap to make, stable and had no serious side effects Chloroquine was a major part of the 60/70s malaria eradication campaign None of the drugs developed since come close to chloroquine
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Chloroquine accumulates in the food vacuole
The food vacuole is the home of hemoglobin digestion Heme is toxic to the parasite (inducing of ROS production) and has to be polymerized into malaria pigment Chloroquine is thought to interfere with this detoxification of heme
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Resistance to chloroquine
1965 1960 1978 1989
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Features of P.falciparum cases
Common features of P. falciparum infections Fever constant or remittent Hypotension, jaundice, tender hepatosplenomegaly Can progress to severe malaria rapidly in non-immune patients Cerebral malaria can occur with P.f.
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Cerebral malaria Cerebral malaria is characterized by multiple hemorrhages Excessive serum and tissue levels of TNFa and INFg are associated with severe malaria Some researchers believe this inflammation is the main cause for pathology
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The life cycle of Plasmodium
Figure 23.11
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