The word malaria comes from 18th century Italian mala meaning "bad" and aria meaning "air". Most likely, the term was first used by Dr.

Transcription

1 The word malaria comes from 18th century Italian mala meaning "bad" and aria meaning "air". Most likely, the term was first used by Dr. Francisco Torti, Italy, when people thought the disease was caused by foul air in marshy areas. Sir Horace Walpole named it malaria.(1740) It was not until 1880 that scientists ((Alphonse Laveran) discovered that malaria was a parasitic disease which is transmitted by the anopheles mosquito ( Ronald Ross, 1897). The mosquito infects the host with a one cell-parasite called Plasmodium.

2 Causative agent of Malaria Four species of plasmodia that causes Malaria P.vivax, P. falciparum P.ovale, P.malariae P.vivax and P. falciparaum 95% of all malaria worlwide.

3 Correlation between human and animal malaria parasites P. knowlesi a monkey parasite found to infect aborigines in the jungles of Malaysia. P.cyanomolgi,P.inui other monkey malaria parasites advanced our understanding on the experimental basis. P.Vivax, P.malariae and P. ovale relates to primate malaria parasite. P.falciparum relates to bird malaria parasites

4 About Malaria The malaria parasite exhibits a complex life cycle involving an insect vector (mosquito) and a vertebrate host (human) The major phases of the life cycle are: aexsual phase in Man, Sexual phase in Mosquito.

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6 Pre- or exo-erythrocytic Stage Infection sporozoites injected by a single bite of mosquito. Infection proper Due to phagocytosis few managed to reach hepatocyte (parenchymal cell) within mins. Growth and reproduction of malaria parasite. Asexual phase i) In the liver spindle shaped sporozoites rounded and enlarged, undergo repeated nuclear division forming several daughter nucli pushing the liver cell nuclei aside. This is the phase of pre-erythrocytic Schizogony or merogony. At the end (5-15 days later) liver cells bursts and thousands of merozoites, the products of merogny comes out to infect the RBC (or erythrocytes). (Some large merzoites re-enter to the hepatocyte). Small number of liver cells involved No clinical illness. 7

7 Schizogony in RBC Asexual phase (erythrocytic schizogony phase ) ii) The merozoites released from liver cells with apical complex attach erythrocytes to the RBC through its glycophorin acting as receptors. It then enters into the RBC which seals them forming parasitophorous vacuole within 30 seconds. Merozoites appears as rounded body and pushed its cytoplasm to the periphery and nucleus situated at one pole thus a ring form develops. Amoeboid form attains after enlargement of the ring form and at certain stage the nucleus starts dividing till then it is known as trophozoite. In the RBC as soon as it starts dividing it is called Schizont or meront ( erythrocytic) and in each one a number of small merozoite are formed by nuclear division and cytoplasm covering up. The merozoite released in the circulation to infect fresh RBC. P. vivax and P.ovale produces two types of sporozoites :1) tachysporozoites 2) bradysprozoites (some of them form hypnozoite) during liver schizogony. Hypnozoites Sporozoites without schizogony remains dormant (P.vivax hibernans)

8 Feature of pre-erythrocytic schizogony P. vivax P.falciparaum P.malariae P.ovale Pre-Eryth Stage (days) Dia. of schizont (µm) No of 10,000 30,000 15,000 15,000 merozoites in schizont 9

9 Erythrocytic stage Prepatent period the interval between the entry of sporozoites and the first appearance of the parasite in the blood is prepatent period. RBC infection pear-shaped merozoite (1.5µm) by its apical complex attaches to erythrocyte receptor (glycophorin), produces a pit and enters into RBC by invagination (30 sec.).

10 Erythrocytic stage contd. Signet ring Merozoite pushing its cytoplasm to the periphery places the nucleus at one pole ( Giemsa staining show a signet ring appearance) Malaria Pigment RBC hemoglobin as parasite food incompletely digested by signet ring form and haematin-globin pigment accumulates. P.vivax Golden brown dust-like particles P.falciparum P.malariae Blocks of black pigment Dark brown particles P. ovale Blackish brown particles 11

11 Erythrocytic phases Trophozoite. Schinzonts Gametocytes Trophozoite the ring form ( early trophozoite) develops amoeboid forms & grow to stag of nuclear division (late trophozoite) Schizonts Variable number of small nucleus produced (early schizoint) within cytoplasm and then each surrounded by cytoplasm ( late schizont). Mature schizont bursts, merozoites released into the circulation 13

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13 P. falciparum Responsible for almost all malaria death. Africa and parts of Asia. Develop resistance to antimalarial quickly. Ring small binucleated, brick red Maurer s dots in normal size RBC. High mol wt strain spec. antigen appears on infected RBC with knob like projection after 24 hrs of trophozoite disappearance. These RBC adheres to the capillary wall*. Gametocytes crescent shaped,60days survival, more in young children. * Cytoadherance of these RBC makes the falciparum malaria highly complicated such as cerebral malaria.

14 Erythrocytic schizogony Parasitism the erythrocytic schizogony repeated progressively to increase the intensity of parasitism Clinical Illness Schizonts release by erythrocyte burst accompanied by the release of pyrogen, RBC cell debris and malaria pigment. Activation of macrophage and polymorphs results febrile paroxyms. Incubation period The time period between the entry of the parasite and manifestation of the clinical illness is called the period of incubation.

15 Variation of Erythrocytic schizogonic period Febrile paroxyms Schizogonic periodicity for P. vivax, P.falciparum,P.ovale, 48 hrs so fever recurs on every third day ( 48hrs. interval) for these parasites. P. malariae with 72 hrs periodicity induces febrile paroxyms on every fourth day. P. vivax, Benign tertian or BT malaria P.falciparum, Malignant tertian malaria P.ovale Ovale tertian malaria P. malariae Quartan malaria

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17 Gametogony Gametogony After few erythrocytic cycles of schizognoy, some merozoites instead of proceeding to form schizont, differentiate sexually into gametocytes with undivided nucleus. It fills the entire RBC (spleen and bone marrow). Gametocytes Appear 4-5 ( P. vivax) & (P.falciparum) days after the asexual form. If not taken by mosquito, then they die, 12 or more /c.mm requires for infectivity. Round in shape but P.falciparum crescent-shaped, micro- and macro-gametocytes; male and female.

18 Sexual Phase Gametocyte maturation and fertilization sporozoites (in female Anopheles mosquito). Sporogony the process of sporozoite formation (invertebrate, exogenous or extrinsic phase) Malaria parasite generation Oscillates between Asexual and Sexual phases alternately ; Mosquito Definite host and Human Intermediate host

19 Mosquito Phase The gametes Male gametocytes within 15 mins.of entry in the mosquito gut goes exflagellation forming 8 nuclei & protruding whip like 8 filament. Female gametocyte matures without division. Exflagellation At 25 0 C P.vivax, P. ovale exflagellate in 15 mins. and P.falciparum in mins and all these changes are. microscopically visible within 10 mins. Fertilization By ½ to 2 hrs after blood meal conjugation occurs between the exflagellated male and mature female gametes to produce zygote. Soon it becomes vermicular motile form, Ookinete within 18-24hrs.

20 Sporogony Oocyst Vermicular Ookinites penerates mosquito stomach wall and becomes rounded forming pigmented Oocyst (500µm) in hundreds. Sporozoites Oocyst matures with increase in size and initiates nuclear division forming sporozite (10-15µm) in thousands. Infective mosquito The sporozoites reaches salivary gland and enter into the salivary ducts of the mosquito so it can infect human during blood meal..

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23 P.vivax P.vivax world wide, accounts 80% of all malaria, less common in Africa Sporozoites Tachysporozoite (active) & bradysporozoite (hypnozoite) Strains variation In temperate zone hypnozoite (P.vivax hibernans), Tropical zone less Hypnozoite Preference young RBC, less than 5% parasitised Ring form Schuffner s dot on the surface. Schizont appearance 36-40hrs, maturation next 6-8 hrs.[12-24merozoite(1.5µm) /schizont] Gametogony 4 days after 1 st appearance of trophozoites.

24 P. malariae, P. ovale Infection similar to P. vivax, except, P.malariae schizogonic periodicity 72 hrs. No hypnozites for P. malariae, but parasitised RBC may exit for 50 years. Band form of trophozite unique to P. malariae. Ziemann s stipplings seen in some cases of P. malariae. For P.ovale James dots present Both show similar schizont but RBC becomes oval for P. ovale. Some time mixed infection (P. vivax and P.falciparum) not uncommon.

25 Pathogenesis & Clinical features Incubation period: days for P.falciparum days P.vivax, P.ovale days P. malariae Clinical manifestation On completion of erythrocytic schizogonic cycle red cell debris, pigments, parasitic debris stimulate the macrophage, polymorphs with cytokines (TNF) lymphokines ( IL-1) release. Febrile paroxysms fever threshold or pyrogenic density to cause fever by parasitisation,15-60 mins., uncontrollable shivering, 2-6 hrs intense hot (41 0 C), headache, nausea etc.

26 Pathogenesis & clinical features Period of latency after primary attack clinical illness subsides due to partial immunity and parasitaemia below the fever threshold. Recrudescence due to waning immunity or building up of the parasitaemia from the parasitised erythrocytes there are several recurrence recrudescence ( till P.falciparum is eliminated) Relapse ( recurrence of fever) Hypnozoites of P. vivax (P.ovale) activate time to time (24 weeks to 5 years) & led recurrence of malaria attack. This is what is known as relapse.

27 Pathogenesis & clinical features Malignant malaria P. falciparum heavily parasitized RBC that become deformed, sticky, adhere on the capillary endothelium in internal organ causing anoxic damage, oedema, and inflammatory reaction. Cerebral malaria Hyperpyrexia, coma and paralysis due to congestion of meninges and brain, occlusion of capillaries in brain having haemrrohages necrotic lesion in mid brain and glial reaction (malarial granuloma) around occluded blood vessel.

28 Malaria Algid malaria Cold clammy skin, peripheral circulatory failure and profound hypotension, vomiting & choleric diarrhoae, bilious vomiting & severe hiccup. Septicaemic malaria High degree of prostration. Acute renal failure, pulmonary oedema. Black fever Malarial haemoglobinuria (P. falciparum) bilious vomiting, prostration and passage of black or dark urine massive haemolysis by antierythrocyte (autoantibody). Anemia Destruction of erythrocyte and lowering of erythropoiesis

29 Malaria Topical splenomegaly syndrome(tss) A chronic benign condition found among adults in endemic area mainly tropical Africa, New Guinea and Vietnam. Abnormal immune response to malaria with enormous spleenomegaly high titer of antimalarial antibody but no parasite in peripheral blood smear. Reduced C3,presence of RF and hyper IgM level. TSS differ from spleenomegaly by way of responsiveness to antimaliral and hsitopathological change. The liver is congested, enlarged and pigmented. Merozoite induced malaria blood transfusion, placental transmission, but self-limiting.

30 In days P.vivax P.falci. P.ova. P. mal. Duration of schizogny Prepatent period Gametocyte after prepatentcy Avrg. duration* of infection (Untreated) * years

31 Immunity. Innate Immunity Lacking Duffy blood group antigen,g6pdh deficiency, sickle cell hemoglobin, and iron deficiency. Acquired Immunity Spc. Immunity cures but not complete elimination of parasites. In endemic area children below 3 months of age protected by passive maternal antibody. Malaria antigen Malaria antigen worked in details and found highly stage and strain specific. Circum sporozoite antigen cloned and produced in vaccinia virus and claimed to check infection. Vaccine spf66 vaccine showed some efficacy in Tanzania and South America but not in Gambia and Thiland.

32 Lab. Diagnosis & Treatment Clinical symptoms requires confirmation by blood test :- Ring form and gametocytes are detected in parasitized RBC. Blood films:- Thick or thin film (gold standard) [Chinese workers prepare serosanguinous fluid and claimed to be more sensitive.] Developing tests. QBC test, Para Sight-F test, RIA, ELISA,IHA; MAT test, PCR-NAA, HRP-2, and LDH (P. falciparum) Drugs;- Chloroquine and primaquine (gametocide). Epidemiology: Hypo-, meso-, hyper- and holoendemic.

33 Historical facts and features of the parasite Roman writers noted the similarities between the enlarged limbs and cracked skin of a W. bancrofti infected individual to that of an elephant. Since this condition has been commonly known as elephantiasis. Timothy Lewis, working in India, first reported the fi nding of microfilariae in human blood in However, this is a misnomer W. bancrofti was named after physician Otto Wucherer and parasitologist Joseph Bancroft, both of whom extensively studied filarial infections.it is speculated that W. bancrofti was brought over to the New World by the slave trade. Phylum:Nematoda Class:SecernenteaOrder:Spirurida Family:Onchocercidae Genus:Wuchereria The male worm is 40 mm long and 100 μm wide, and features a curved tail. In contrast, the female is 6 cm to 10 cm long and 300 μm wide, nearly three times larger in diameter than the male. Females can produce thousands of juveniles known as microfilariae. Microfilariae of W. bancrofti retain the egg membrane as a sheath and are often considered advanced embryos.

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36 Wuchereria bancrofti, Brugia malayi Both the parasite W.bancrofti and B. malayi are infective for human, and it is the definitive host causing Filariasis (Malabar leg or Elephantiasis). They occurs as adults and embryos known as microfilaria (observed in the fluid of a hydrocoele patient in Cuba in 1863 by Demarquay). The presence of microfilaria in blood was first reported in Calcutta by Lewis (1872) W. bancroftii distributed in tropics and subtropics in Asia, Africa, South America; infected 81 million with Wuchereria, over 8 million with Brugia. adults microfilarae vector W. bancrofti lymphatics Blood Culex B. malayi lymphatics Blood Mansonia Endemic area along sea coast and large river bank in India

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38 Initiation of infection Culex, Anopheles, Mansonia, and Aedes. Inside the mosquito vector, also known as the intermediate host, the microfilariae mature into motile larvae called juveniles. When the mosquito vector has its next blood meal, W. bancrofti is egested via the mosquito s proboscis into the blood stream of the new human host. The larvae move through the Lymphatic system to regional lymph nodes, predominantly in the legs and genital area

39 Infection Culex blood meal Microfilaria uptake and egested within 2-6 hrs, penetrate in the stomach wall in 4-17hrs. Then within 2 days it metamorphoses in the first stage larva ( x10-15 μm) changes to second stage ( x15-30 μm ) and then third stage or infective form ( x15-25μm) of the filariform larva. It is passed into human during blood meal of mosquito. Human infection third stage larva penetrate skin passes to the lymphatic duct and settle at the lymphatic inguino-scrotal region and grows. After 5-18 months the parasite sexually mature and give birth to new larva. Prepatent period is 8-12hrs.Carriers may have high microfilarial density in blood (200,000/ml) Early manifestation lymphangitis and lymphadenitis. Typical manifestation blocking lymph nodes or vessels mechanically or by inflammation due to allergic reaction from filarial antigen.

40 Pathogenesis in filariasis. Affected lymphatics infiltrated by lymphocyte macrophage, eosinophils and plasma cell, will get thickened and narrowed with granuloma formation, inflammation leads to permeability change in lymphatics and protein rich lymph leaks to the tissue. This produces typical brawny oedema of filariasis. Fibroblasts invade the oedematous tissue and lays down fibrosis, producing non-pitting gross oedema of elephantiasis. In some person, immune reaction to filarial antigen produce clinical condition that does not relate to lymphatic lesion these are known as occult filariasis.

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43 Clinical manifestation of filariasis The characteristic manifestation of the filariasis are due to obstruction of the lymph vessel and nodes. Some develop fugitive swelling raised, painless,tender,diffuse red areas on the skin. The essential features:- Filarial fever, Lyphadenopathy, Lymphangitis Lymphoangiovarix, Lymphorrhagia, Hydrocoele, Lymphoedema and Elephantiasis Occults filariasis (hypersensitivity) Elephantias

44 Diagnosis The diagnosis of filariasis depends on the clinical feature and history of exposure to endemic area and on the laboratory findings. Demonstration of microfilaria in peripheral blood, chylous urine, hydrocoele fluid. Demonstration of the adult worm in biopsy specimen. Skin test with filarial antigen. Demonstration of anti body to filarial antigen. Demonstration of filarial antigen in blood by serological method. Indirect evidence as eosinophila. The nocturnal periodic or night blood samples (10pm to 4am) are collected and smears (thick and thin) are examined to see the microfilaria specially in the endemic area. B. malayi same as bancrofti but small in size and different in geographical distribution. C. Treatment: Diethyl carbamazine or DEC 6mg /kg body weight daily for 12 days. Allergic reaction may occur due to the release of antigen. D Control : By eradication of vector mosquitoes and treating the carriers.

45 Historical facts and features of the parasite Roman writers noted the similarities between the enlarged limbs and cracked skin of a W. bancrofti infected individual to that of an elephant. Since this condition has been commonly known as elephantiasis. However, this is a misnomer W. bancrofti was named after physician Otto Wucherer and parasitologist Joseph Bancroft, both of whom extensively studied filarial infections. It is speculated that W. bancrofti was brought over to the New World by the slave trade. Kingdom:Animalia Phylum:Nematoda Class:Secernentea Order:Spirurida Suborder:Spirurina Family:Onchocercidae Genus:Wuchereria The male worm is 40 mm long and 100 μm wide, and features a curved tail. In contrast, the female is 6 cm to 10 cm long and 300 μm wide, nearly three times larger in diameter than the male. Females can produce thousands of juveniles known as microfilariae. Microfilariae of W. bancrofti retain the egg membrane as a sheath and are often considered advanced embryos.

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47 Wuchereria bancrofti, Brugia malayi Both the parasite W.bancrofti and B. malayi are infective for human, and it is the definitive host causing Filariasis (Malabar leg or Elephantiasis). They occurs as adults and embryos known as microfilaria (observed in the fluid of a hydrocoele patient in Cuba in 1863 by Demarquay). The presence of microfilaria in blood was first reported in Calcutta by Lewis (1872) W. bancroftii distributed in tropics and subtropics in Asia, Africa, South America; infected 81 million with Wuchereria, over 8 million with Brugia. adults microfilarae vector W. bancrofti lymphatics Blood Culex B. malayi lymphatics Blood Mansonia Endemic area along sea coast and large river bank in India

48 Morphology of Mf. bancrofti A clear space at the head space, cepalic space In the interior half of the microfilaria devoid of grannules called nerve ring Anterior V- spot at the midway of the length of the microfilaria The posterior V- spot represent the cloaca or anal pore. Germinal G- cell at the anterior to the anal pore. The rudimentary alimentary canal from V-spot to the G-spot central body. The tail tip devoid of nuclei in Mf bancrofti, bears two distinct nuclei in Mf. malayi.

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50 Initiation of infection Culex, Anopheles, Mansonia, and Aedes. Inside the mosquito vector, also known as the intermediate host, the microfilariae mature into motile larvae called juveniles. When the mosquito vector has its next blood meal, W. bancrofti is egested via the mosquito s proboscis into the blood stream of the new human host. The larvae move through the Lymphatic system to regional lymph nodes, predominantly in the legs and genital area

51 Infection Culex blood meal Microfilaria uptake and egested within 2-6 hrs, penetrate in the stomach wall in 4-17hrs. Then within 2 days it metamorphoses in the first stage larva ( x10-15 μm) changes to second stage ( x15-30 μm ) and then third stage or infective form ( x15-25μm) of the filariform larva. It is passed into human during blood meal of mosquito. Human infection third stage larva penetrate skin passes to the lymphatic duct and settle at the lymphatic inguino-scrotal region and grows. After 5-18 months the parasite sexually mature and give birth to new larva. Prepatent period is 8-12hrs.Carriers may have high microfilarial density in blood (200,000/ml) Early manifestation lymphangitis and lymphadenitis. Typical manifestation blocking lymph nodes or vessels mechanically or by inflammation due to allergic reaction from filarial antigen.

52 Pathogenesis in filariasis. Affected lymphatics infiltrated by lymphocyte macrophage, eosinophils and plasma cell, will get thickened and narrowed with granuloma formation, inflammation leads to permeability change in lymphatics and protein rich lymph leaks to the tissue. This produces typical brawny oedema of filariasis. Fibroblasts invade the oedematous tissue and lays down fibrosis, producing non-pitting gross oedema of elephantiasis. In some person, immune reaction to filarial antigen produce clinical condition that does not relate to lymphatic lesion these are known as occult filariasis.

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55 Clinical manifestation of filariasis The characteristic manifestation of the filariasis are due to obstruction of the lymph vessel and nodes. Some develop fugitive swelling raised,painless,tender,diffuse red areas on the skin. The essential features:- Filarial fever, Lyphadenopathy, Lymphangitis Lymphoangiovarix, Lymphorrhagia, Hydrocoele, Lymphoedema and Elephantiasis Occults filariasis (hypersensitivity)

56 Diagnosis The diagnosis of filariasis depends on the clinical feature and history of exposure to endemic area and on the laboratory findings. Demonstration of microfilaria in peripheral blood, chylous urine, hydrocoele fluid. Demonstration of the adult worm in biopsy specimen. Skin test with filarial antigen. Demonstration of anti body to filarial antigen. Demonstration of filarial antigen in blood by serological method. Indirect evidence as eosinophila. The nocturnal periodic or night blood samples (10pm to 4am) are collected and smears (thick and thin) are examined to see the microfilaria specially in the endemic area. B. malayi same as bancrofti but small in size and different in geographical distribution. C. Treatment: Diethyl carbamazine or DEC 6mg /kg body weight daily for 12 days. Allergic reaction may occur due to the release of antigen. D Control : By eradication of vector mosquitoes and treating the carriers.

57 Host-parasite interaction Parasite Interaction 1. Ecto parasite HOST 2. Endo parasite 1. Definitive Host 3. Obligatory parasite 2. Intermediate Host 4. Facultative parasite 3. Paratenic Host(Alaria americana) 5. Accidental parasite 4. Natural Host 6. Aberrant parasite 5. Natural Host 6. Reservoir Host Leads to i) Symbiosis9 (mutualism) ii) Commensalism ( no harm or benifit) iii) Parasitism ( disease)

58 Types of host Definitive host ---The host that harbour the parasite when the parasite is sexually reproduced, is definitive host. ( mosquito for malaria) Intermediate Host When the parasite spends some part of its life cycle in this type of host, without sexual reproduction.( the man for the malaria). Reservoir host The host that makes parasite available for the infection of an animal, is reservior host. Paratenic host the host carries the parasite live without any development. Natural host- The hot that is usually infected by the parasite for example Snails for schistosomiasis. Accidental host the host usually not infected but is accidentialy get infected.

59 Types of parasites Ecto parasite-the parasite living on the surface of the body. Endo parasite The parasite which lives in the organ of the body. Obligatory parasite They must live some part of their life time in the host body. Faultative parasite they can live some part of their live in the free living condition. Accidental parasite When the parasite attacks an unusual host. Abberant parasite when the parasite migrate in an unusual site or organ of the hsot body.

60 Cellular body of parasite Plasmodium, Entamoeba, Leishmania These are unicellular ( Protozoa) Wurchereria, Fusiola, Schistosoma These are Study profile: multicellular ( Helminths or worms and flukes). History of discovery, Geographgical distribution, Habitats inside the human body, Morphology and life cycle, Mode of infection. Pathogenic lesion and clinical manifestation, Immunology, Method of diagnosis Approved therapy and

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63 The pathogenic factors of Parasite Agents causing lytic necrosis. (amoebic lytic agent ). Trauma causing factors (irritation, itching, burning pain etc.). Inflammation inducers ( Leishmanial cellular constituents). Toxins (amoebiasis). Allergens ( filarial antigens). The damages that caused by parasites are critically important namely, i) Physical or/and chemical action rupturing the tissue or body components, ii) by immunological mechanism and iii) induction of neoplasia.

64 Damages caused by parasite Physical and chemical damages. a) Rupture of RBC by malaria parasites. b) Immune complex attacking the cell membrane c) Narrowing the vesicular system like pulmonary arterioles. d) Rupture of mucosal surface layer by the worm like fasciola. e) Exerting mechanical pressure by expanding body of the parasite (hydatid mole). f) Intestinal obstruction like the one Ascaris

65 Resistance rendered by the host I) Resistance or defence by the host is mediated by non-specific arm/system of the host. and 2) by the specific system, namely the immunological recognition dependent. Non-specific defence acts instantaneouly by the component of innate immunity. Specific defence is mediated by the acquired/ adoptive immune system.

66 Inflammation the mediator of host defence Obstruction of the Penetration of physical barrier ( skin) leads to inflammation. Phagocytosis leading to granuloma generation and hence inflammation. Complement mediated damage through the development of membrane attacking complex (MAC) with the participation of antigen-antibody interaction. These are the major non-specific mode of resistance by host. Specific resistance rendered by the antigen antibody interaction and creating the parasite survival vulnerable.

67 Clinical manifestation Skin manifestation. (Cutanous Leishmaniasis.) Organ specific manifestation. ( Amoebiasis intestinal/ hepatic). Pulmonary type of manifestation (pneumonia). Cardiac diseases Sleeping sickness (Trypanosoma cruzi). Spleenomegaly ( malaria) Syatemic manifestation. Fever, Immunosupression, alletrgy,