10Section1IntroductionTable 1.4: Hypersensitivity reactions seen in parasitic diseasesHypersensitive reactionsParasiticdiseasesCercarialdermatitis(Swimmer'sItch)inTypeIhypersensitivityreactionsschistosomiasisTheseareallergicoranaphylacticreactions,occurringLoeffler's syndrome in ascariasiswithinminutesofexposuretoparasiticantigensdueGrounditch (Hookworminfection)to IgEmediated degranulation ofmast cellsAnaphylaxis due to leakage of hydatid fluid(Echinococcusgranulosus)Casoni's test (done in the diagnosis of hydatid disease):Tropical pulmonaryeosinophilia (occultfilariasis)Anemia in malariaType llhypersensitivity reactionsBlack waterfever inmalariafollowing quinine therapyThese are mediated by IgG or rarely IgM antibodies.Myocarditis inChagasdiseaseproduced against the antigens on surfaces of the·Killingof thehelminthsbyNK cellsparasitic cells causingantibodymediated destructionofthecellsbyi)thecomplementactivationorii)bytheNKcellactivation (ADCC-antibodydependentcellmediatedcytotoxicity)NephroticsyndromeinPlasmodiummalariaeType lllhypersensitivity reactionsKatayamafeverinschistosomiasisImmunecomplexesareformedbythecombinationofAfricantrypanosomiasisparasiticantigenswiththecirculatingantibodies(lgG)Onchocerciasiswhichgetdeposited invarioustissuesElephantiasis(infilariasis)TypeIVhypersensitivityreactionsGranulomatous diseasein schistosomiasis and otherThis is T-cell mediated delayed type of hypersensitivityhelminthic infectionsreaction.PreviouslysensitizedThelpercellssecreteaLeishmaniasisvariety of cytokines,on subsequent exposure to theparasitic antigens.Usually, the pathogen is clearedrapidlywithlittletissuedamage.However,insomecases, it maybe destructiveto the host resulting ingranulomatousreactionAbbreviations:IlgE,immunoglobulin E;IgG,immunoglobulin G;IgM,immunoglobulin M;NKs,naturalkillercellsthe specific diagnosis of various parasiticTREATMENTOFPARASITICinfections.Following techniques are used inDISEASESdiagnosis of parasitic infections (has beenTreatment of parasitic disease is primarilydiscussed indetail inChapter15):basedon chemotherapy and in somecases.Parasiticdiagnosis-eithermicroscopicallyby surgery.ormacroscopically.CulturemethodsAntiparasiticDrugs.Immunodiagnosticmethods (antigenandVariouschemotherapeutic agents are usedantibody detection)forthetreatmentandprophylaxis of parasitic·Intradermal skintestsinfections (Table 1.6)..MolecularmethodsSurgical Management·Xenodiagnostictechniques.AnimalinoculationFormanagement of parasitic diseases like.Imagingtechniquescystic echinococcosis and neurocysticercosissurgery is indicated
10 Section 1 Introduction Hypersensitive reactions Parasitic diseases Type I hypersensitivity reactions These are allergic or anaphylactic reactions, occurring within minutes of exposure to parasitic antigens due to IgE mediated degranulation of mast cells • Cercarial dermatitis (Swimmer’s Itch) in schistosomiasis • Loeffl er’s syndrome in ascariasis • Ground itch (Hookworm infection) • Anaphylaxis due to leakage of hydatid fl uid (Echinococcus granulosus) • Casoni’s test (done in the diagnosis of hydatid disease). • Tropical pulmonary eosinophilia (occult fi lariasis) Type II hypersensitivity reactions These are mediated by IgG or rarely IgM antibodies produced against the antigens on surfaces of the parasitic cells causing antibody mediated destruction of the cells by i) the complement activation or ii) by the NK cell activation (ADCC -antibody dependent cell mediated cytotoxicity) • Anemia in malaria • Black water fever in malaria following quinine therapy • Myocarditis in Chagas’ disease • Killing of the helminths by NK cells Type III hypersensitivity reactions Immune complexes are formed by the combination of parasitic antigens with the circulating antibodies (IgG) which get deposited in various tissues • Nephrotic syndrome in Plasmodium malariae • Katayama fever in schistosomiasis • African trypanosomiasis • Onchocerciasis Type IV hypersensitivity reactions This is T-cell mediated delayed type of hypersensitivity reaction. Previously sensitized T helper cells secrete a variety of cytokines, on subsequent exposure to the parasitic antigens. Usually, the pathogen is cleared rapidly with little tissue damage. However, in some cases, it may be destructive to the host resulting in granulomatous reaction • Elephantiasis (in fi lariasis) • Granulomatous disease in schistosomiasis and other helminthic infections • Leishmaniasis Table 1.4: Hypersensitivity reactions seen in parasitic diseases Abbreviations: IgE, immunoglobulin E; IgG, immunoglobulin G; IgM, immunoglobulin M; NKs, natural killer cells. the specifi c diagnosis of various parasitic infections. Following techniques are used in diagnosis of parasitic infections (has been discussed in detail in Chapter 15): z Parasitic diagnosis—either microscopically or macroscopically z Culture methods z Immunodiagnostic methods (antigen and antibody detection) z Intradermal skin tests z Molecular methods z Xenodiagnostic techniques z Animal inoculation z Imaging techniques. TREATMENT OF PARASITIC DISEASES Treatment of parasitic disease is primarily based on chemotherapy and in some cases by surgery. Antiparasitic Drugs Various chemotherapeutic agents are used for the treatment and prophylaxis of parasitic infections (Table 1.6). Surgical Management For management of parasitic diseases like cystic echinococcosis and neurocysticercosis surgery is indicated. Chapter-01.indd 10 5/17/2014 5:48:06 PM
11Chapter1General Introduction:ParasitologyTable 1.5: Immune evasion mechanisms of the parasitesImmuneevasionmechanismsParasites involvedBy intracellular locationPlasmodiumspp,Babesiaspp,Trypanosomaspp.,Toxoplasmaspp.,Leishmaniaspp.andMicrosporidiaEnters an immunologicallyprotected sitesoon after infectionPlasmodium spp.entering intohepatocytesLeave the site where the immune response is already establishedAscaris undergoes intestinal phaseandmigratorylungphaseduring itslifecycleSurvivesinmacrophagesbypreventingphago-lysosomefusionLeishmania,TrypanosomaandToxoplasmaAntigenicshedding(capping):SurfacemembraneantigensoftheEntamoebahistolytica,Trypanosomabruceiparasites bound to the antibodies undergo redistribution so thatandAcylostomacaninumtheparasiteis covered byafoldedmembranethatlaterextrudeasacapcontainingmostoftheantibodiesthatwereoriginallyboundtothemembraneP.falciparum(pf-EMPprotein),GiardiaandAntigenicvariation:Bychangeofantigeniccomposition,theparasites canbeprotected from the antibodies whichareformedTrypanosomabruceiagainsttheoriginal antigensAntigenicmimicry:TheadultflukesofSchistosomagetcoatedwithSchistosoma spp.thehostredcellantigensandhistocompatibilityantigens,sothattheyarenotrecognizedasforeignand livefreefromhostattackInhibit antibody bindingSchistosoma mansoniSchistosoma mansoniLymphocytesuppressionPolyclonal stimulationof lymphocytesP.falciparum,Trypanosomabrucei,Babesia,Trichinella and Ehistolytica.SuppressionofimmunesystemTrypanosoma,PlasmodiumandLesimaniaTable1.6:Common antiparasitic drugs,their mechanism ofaction andclinical indicationsAntiparasiticDrugsDrugs foramoebiasisMechanismofactionClinicalindicationsMetronidazole,tinidazole and orni-Bioactivated toform reduced cyto-DOCfortheamoebic colitis,dazoletoxicproductswhichdamageDNAamoebicliverabscess,andother(nitroimidazolecompound)extraintestinalamoebiasisDehydroemetineInhibits protein synthesisParenterally usedfor severe hepaticamoebiasis.ChloroquineProbably by concentrating in para-Usedforextraintestinalamoebiasis.site food vacuoles.Paromomycin (Aminoglycoside)Inhibits proteinsynthesis bybindingEffective luminalagentto16S ribosomal RNADiloxanide furoate (AcetanilideUnknown; it is thoughtto interfereEffectiveluminal agentcompound)withproteinsynthesislodoquinol (8-hydroxyquinolineUnknownLuminal agentcompound)Amphotericin BComplex and multifaceted.DOCfor NaegleriafowleriContd
Chapter 1 General Introduction: Parasitology 11 Immune evasion mechanisms Parasites involved By intracellular location Plasmodium spp, Babesia spp., Trypanosoma spp., Toxoplasma spp., Leishmania spp. and Microsporidia Enters an immunologically protected site soon after infection Plasmodium spp. entering into hepatocytes Leave the site where the immune response is already established Ascaris undergoes intestinal phase and migratory lung phase during its life cycle Survives in macrophages by preventing phago-lysosome fusion Leishmania, Trypanosoma and Toxoplasma Antigenic shedding (capping): Surface membrane antigens of the parasites bound to the antibodies undergo redistribution so that the parasite is covered by a folded membrane that later extrude as a cap containing most of the antibodies that were originally bound to the membrane Entamoeba histolytica, Trypanosoma brucei and Acylostoma caninum Antigenic variation: By change of antigenic composition, the parasites can be protected from the antibodies which are formed against the original antigens P. falciparum ( pf-EMP protein), Giardia and Trypanosoma brucei Antigenic mimicry: The adult fl ukes of Schistosoma get coated with the host red cell antigens and histocompatibility antigens, so that they are not recognized as foreign and live free from host attack Schistosoma spp. Inhibit antibody binding Schistosoma mansoni Lymphocyte suppression Schistosoma mansoni Polyclonal stimulation of lymphocytes P. falciparum, Trypanosoma brucei, Babesia, Trichinella and E. histolytica. Suppression of immune system Trypanosoma, Plasmodium and Lesimania Table 1.5: Immune evasion mechanisms of the parasites Antiparasitic Drugs Drugs for amoebiasis Mechanism of action Clinical indications Metronidazole, tinidazole and ornidazole (nitroimidazole compound) Bioactivated to form reduced cytotoxic products which damage DNA DOC for the amoebic colitis, amoebic liver abscess, and other extraintestinal amoebiasis Dehydroemetine Inhibits protein synthesis Parenterally used for severe hepatic amoebiasis. Chloroquine Probably by concentrating in parasite food vacuoles. Used for extra intestinal amoebiasis. Paromomycin (Aminoglycoside) Inhibits protein synthesis by binding to 16S ribosomal RNA Eff ective luminal agent Diloxanide furoate (Acetanilide compound) Unknown; it is thought to interfere with protein synthesis Eff ective luminal agent Iodoquinol (8-hydroxyquinoline compound) Unknown Luminal agent Amphotericin B Complex and multifaceted. DOC for Naegleria fowleri Table 1.6: Common antiparasitic drugs, their mechanism of action and clinical indications Contd. Chapter-01.indd 11 5/17/2014 5:48:08 PM
12Section1IntroductionContd...Drugsfor flagellatesMechanismofactionClinical indicationsIntestinal/GenitalFlagellatesGiardiasisBioactivated to form reduced cyto-Metronidazole and tinidazoleDOCforGiardiasistoxicproducts whichdamageDNANitazoxanideInterference with thePFORenzymedependentelectron transferreac-tion which is essentialforanaerobicenergymetabolism.FurazolidoneCross linking of DNAGiven tochildrenParomomycinProtein synthesis inhibitor in non-Can be given in pregnancyresistantcellsbybindingto16Sribosomal RNATrichomoniasisDOCfortrichomoniasis,giventoMetronidazoleortinidazoleBioactivatedto formreducedcyto-toxicproducts havingnitrogroupsboththepartnerswhich damageDNA.HemoflagellatesTrypanosomiasisChagas'diseaseNifurtimoxForms nitro-anion radical meta-Chagas'diseasebolite, which reacts with the nucleicacids of the parasite, causing asignificantbreakage in theDNABenznidazoleProductionoffreeradicals,towhichEffective in the treatment of reacti-Trypanosoma cruzi isparticularlyvated T.cruzi infections causedbysensitiveimmunosuppression(AIDSpatientsorpatientsoforgantransplants)SleepingsicknessPentamidineDOCfor East African sleepingAccumulatestomicromolalconcentrations within the parasitesicknessto kill it by inhibiting enzymes andinteracting with DNASuraminDOC for West African sleepingTrypanocidal activity; inhibitssicknessenzymes involved withtheoxi-dation of reduced NADHLeishmaniasisSodium stibogluconateInhibitionoftheparasite's glycolyticLeishmaniasisMeglumineantimoniateand fatty acid oxidative activityresulting in decreased reducingequivalentsfor antioxidantdefenseand decreased synthesis of ATPAmphotericinBComplex and multifacetedLeishmaniasisParomomycinProteinsynthesisinhibitorin non-Leishmaniasisresistantcellsbybindingto16SContd
12 Section 1 Introduction Drugs for fl agellates Mechanism of action Clinical indications Intestinal/Genital Flagellates Giardiasis Metronidazole and tinidazole Bioactivated to form reduced cytotoxic products which damage DNA. DOC for Giardiasis Nitazoxanide Interference with the PFOR enzyme dependent electron transfer reaction which is essential for anaerobic energy metabolism. Furazolidone Cross linking of DNA Given to children Paromomycin Protein synthesis inhibitor in nonresistant cells by binding to 16S ribosomal RNA. Can be given in pregnancy Trichomoniasis Metronidazole or tinidazole Bioactivated to form reduced cytotoxic products having nitro groups which damage DNA. DOC for trichomoniasis, given to both the partners Hemofl agellates Trypanosomiasis Chagas’ disease Nifurtimox Forms nitro-anion radical metabolite, which reacts with the nucleic acids of the parasite, causing a signifi cant breakage in the DNA Chagas’ disease Benznidazole Production of free radicals, to which Trypanosoma cruzi is particularly sensitive Eff ective in the treatment of reactivated T. cruzi infections caused by immunosuppression (AIDS patients or patients of organ transplants) Sleeping sickness Pentamidine Accumulates to micromolar concen trations within the parasite to kill it by inhibiting enzymes and interacting with DNA DOC for East African sleeping sickness Suramin Trypanocidal activity; inhibits enzymes involved with the oxidation of reduced NADH DOC for West African sleeping sickness Leishmaniasis Sodium stibogluconate Meglumine antimoniate Inhibition of the parasite’s glycolytic and fatty acid oxidative activity resulting in decreased reducing equivalents for antioxidant defense and decreased synthesis of ATP Leishmaniasis Amphotericin B Complex and multifaceted Leishmaniasis Paromomycin Protein synthesis inhibitor in nonresistant cells by binding to 16S ribosomal RNA Leishmaniasis Contd. Contd. Chapter-01.indd 12 5/17/2014 5:48:09 PM
13Chapter1General Introduction:ParasitologyContd..MiltefosineCan triggerprogrammedcelldeathLeishmaniasis(apoptosis)Drugs formalariaMechanismofactionClinicalindicationsChloroquineProbably,concentrating in parasiteDOC for uncomplicated benignfoodvacuoles,preventingthemalariapolymerizationofthehemoglobininto the toxic product hemozoinDOC forcomplicated orfalciparumArtemisininderivative(ArtemisininGeneratehighlyactivefreeradicalsmalariaorartemether orarte-ether)thatdamageparasitemembraneQuinineProbably similar tochloroquine;stillDOC forcomplicated orfalciparumnotclearmalariaMefloquineSameas chloroquineDOC forcomplicatedorfalciparummalariaPrimaquineGenerating reactive oxygen speciesDOC for relapse ofvivaxmalariaSulfadoxine-pyrimethamineInhibits theproduction ofenzymesDOC forcomplicatedorfalciparuminvolved in the synthesis offolic acidmalariawithin the parasitesLumefantrineAccumulation of heme and freeComplicated orfalciparum malariaradicalsDrugs forbabesiosisMechanismofactionClinicalindicationClindamycin plusquinineDOCfor severe babesiosisAtovaquoneplus azithromycinDOCformild babesiosisMechanismofactionDrugsfortoxoplasmosisClinicalindicationsCotrimoxazole(TrimethoprimInhibiting folate synthesis fromDOC for prophylaxis in HIV infectedsulfamethoxazole)PABA(paraaminobenzoicacid)peoplethus inhibiting purine metabolismSpiramycinInhibitionofproteinsynthesisintheDOC in pregnancycellduringtranslocationDrugsforCryptosporidiumMechanismofactionClinicalindicationsNitazoxanideInterfereswiththePFORenzyme-DOC for Cryptosporidium infectiondependentelectron-transferreactionwhich is essential to anaerobicmetabolisminprotozoanand bacterialspeciesDrugsforIsosporaandCyclosporaMechanismofactionClinicalindicationsCotrimoxazoleInhibiting folate synthesis fromDoC forIsosporaand Cyclospora(Trimethoprim-sulfamethoxazole)PABA(Paraaminobenzoicacid),thusinfectioninhibitingpurinemetabolismDrugs forcestodesMechanismofactionClinicalindicationPraziquantelIncreasesthepermeabilityofDOCforall cestodeinfectionsthe membranes of parasite cellstoward calcium ions which inducescontraction of the parasites,resulting inparalysis in thecontracted stateContd
Chapter 1 General Introduction: Parasitology 13 Miltefosine Can trigger programmed cell death (apoptosis) Leishmaniasis Drugs for malaria Mechanism of action Clinical indications Chloroquine Probably, concentrating in parasite food vacuoles, preventing the polymerization of the hemoglobin into the toxic product hemozoin DOC for uncomplicated benign malaria Artemisinin derivative (Artemisinin or artemether or arte-ether) Generate highly active free radicals that damage parasite membrane DOC for complicated or falciparum malaria Quinine Probably similar to chloroquine; still not clear DOC for complicated or falciparum malaria Mefl oquine Same as chloroquine DOC for complicated or falciparum malaria Primaquine Generating reactive oxygen species DOC for relapse of vivax malaria Sulfadoxine-pyrimethamine Inhibits the production of enzymes involved in the synthesis of folic acid within the parasites DOC for complicated or falciparum malaria Lumefantrine Accumulation of heme and free radicals Complicated or falciparum malaria Drugs for babesiosis Mechanism of action Clinical indication Clindamycin plus quinine DOC for severe babesiosis Atovaquone plus azithromycin DOC for mild babesiosis Drugs for toxoplasmosis Mechanism of action Clinical indications Cotrimoxazole (Trimethoprimsulfamethoxazole) Inhibiting folate synthesis from PABA (para aminobenzoic acid), thus inhibiting purine metabolism DOC for prophylaxis in HIV infected people Spiramycin Inhibition of protein synthesis in the cell during translocation DOC in pregnancy Drugs for Cryptosporidium Mechanism of action Clinical indications Nitazoxanide Interferes with the PFOR enzymedependent electron-transfer reaction, which is essential to anae robic metabolism in protozoan and bacterial species DOC for Cryptosporidium infection Drugs for Isospora and Cyclospora Mechanism of action Clinical indications Cotrimoxazole (Trimethoprim-sulfamethoxazole) Inhibiting folate synthesis from PABA (Para aminobenzoic acid), thus inhibiting purine metabolism DOC for Isospora and Cyclospora infection Drugs for cestodes Mechanism of action Clinical indication Praziquantel Increases the permeability of the membranes of parasite cells toward calcium ions which induces contraction of the parasites, resulting in paralysis in the contracted state DOC for all cestode infections Contd. Contd. Chapter-01.indd 13 5/17/2014 5:48:10 PM
14Section1IntroductionContd...NiclosamideNiclosamideuncouplesoxidativeAlternativedrugforcestodeinfectionsphosphorylationAlbendazoleCauseslossofthecytoplasmicmicroGiven for cysticercosis and hydatidtubulesleadingtoimpaireduptakediseaseof glucosebythe larval andadultstagesofthesusceptibleparasites,anddepletingtheirglycogenstoresDrugsfortrematodesMechanismofactionClinicalindicationDoC formost ofthetrematodePraziquantelIncreasesthepermeabilityofthemembranesofparasitecellstowardinfectionscalciumionswhichinducescontraction of the parasites, resulting inparalysis in thecontractedstateTriclabendazoleBinds tobeta-tubulinand preventDOCforFasciolahepaticaandFthe polymerization of the micro-giganticatubulesDrugs fornematodesMechanismofactionClinicalindicationIntestinal nematodesCausesloss ofthecytoplasmicmicro-DOCformostoftheintestinalnemaMebendazole oralbendazoletubules leading to impaireduptaketodesof glucose by the larval and theadultstages ofthe susceptibleparasites, and depleting theirglycogen storesActs as a depolarizing neuro-Pyrantel pamoateAlternativedrugforintestinalnemamuscular blocking agent, therebytodescausing sudden contraction,followed by spastic paralysis of thehelminthsIvermectinKills by interferingwith nervousMoreaffectivefordisseminatedsystem andmusclefunction, instrongyloidiasis.AlternativedrugforTrichuris infectionsparticularbyenhancing inhibitoryneurotransmission resulting inflaccidparalysisFilarial nematodesDiethylcarbamazine (DEC)An inhibitorofarachidonicacidDOCforlymphaticfilariasis,Loaloametabolismin microfilaria.ThisandMansonellainfectionsmakes themicrofilariamore suscep-tible to phagocytosisAlbendazoleCauses loss of the cytoplasmicAlternative drug forlymphaticmicrotubules leading to impairedfilariasis, Loa loa andMansonellauptake of glucose by the larval andinfectionsthe adult stages of the susceptibleparasites, and depleting theirglycogen storesContd
14 Section 1 Introduction Niclosamide Niclosamide uncouples oxidative phosphorylation Alternative drug for cestode infections Albendazole Causes loss of the cytoplasmic micro tubules leading to impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depleting their glycogen stores Given for cysticercosis and hydatid disease Drugs for trematodes Mechanism of action Clinical indication Praziquantel Increases the permeability of the mem branes of parasite cells toward calcium ions which induces contraction of the parasites, resulting in paralysis in the contracted state DOC for most of the trematode infections Triclabendazole Binds to beta-tubulin and prevent the polymerization of the microtubules DOC for Fasciola hepatica and F. gigantica Drugs for nematodes Mechanism of action Clinical indication Intestinal nematodes Mebendazole or albendazole Causes loss of the cytoplasmic micro - tubules leading to impaired uptake of glucose by the larval and the adult stages of the susceptible parasites, and depleting their glycogen stores DOC for most of the intestinal nematodes Pyrantel pamoate Acts as a depolarizing neuromuscular blocking agent, thereby causing sudden contraction, followed by spastic paralysis of the helminths Alternative drug for intestinal nematodes Ivermectin Kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission resulting in fl accid paralysis More affective for disseminated strongyloidiasis. Alternative drug for Trichuris infections Filarial nematodes Diethylcarbamazine (DEC) An inhibitor of arachidonic acid metabolism in microfilaria. This makes the microfi laria more susceptible to phagocytosis DOC for lymphatic fi lariasis, Loa loa and Mansonella infections Albendazole Causes loss of the cytoplasmic microtubules leading to impaired uptake of glucose by the larval and the adult stages of the susceptible parasites, and depleting their glycogen stores Alternative drug for lymphatic filariasis, Loa loa and Mansonella infections Contd. Contd. Chapter-01.indd 14 5/17/2014 5:48:11 PM