Malaria clinical

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Malaria clinical

  1. 1. MALARIA – Pathophysiology,Clinical features, Management &EpidemiologyRumala MorelDepartment of ParasitologyUniversity of PeradeniyaY3S2
  2. 2. Objectives• Name the parasites causing human malaria worldwideindicating those present in Sri Lanka.• Describe the life cycle - recapitulation• Describe the pathological and clinical consequences ofthe erythrocytic cycle including relapse & recrudescence• Malaria diagnosis - recapitulation• Name the anti malarial drugs in common use anddescribe the mode of action of each – recapitulation• Describe the current malaria situation in Sri Lanka• Describe the preventive and control measures used byAnti Malaria Campaign in Sri Lanka
  3. 3. World map of current malaria incidence2.4 Billion Population at risk1 million children die every year
  4. 4. 5 Plasmodium spp. causing HUMAN MALARIA3. P.malariaeband form1. P.falciparumsmall rings2. P.vivaxlarge rings & schizonts4. P.ovalered cell has oval shapeFound in SL Not in SLCommonSpeciesworldwide5. P.knowlesiMonkey parasite.Human diseaseSouth-East Asia
  5. 5. 5th Human Malaria ParasitePlasmodium knowlesiRapidly multiply –Quotidian 24hErythrocytic cycleEarly Trophozoites:small rings similar toP.falciparumLate Trophozoites :band-forms likeP.malariae
  6. 6. PREPATENT PERIOD:Interval between infection anddemonstration of parasitesINCUBATION PERIODInterval between infection andclinical signs/symptoms11-12 days2-3 days more(about 2 weeks)
  7. 7. PATHOPHYSIOLOGYPathology is due to erythrocytic cycleA). Destruction of RBCs – haemolysis anaemiareleases endotoxins, malaria pigmentB). Host reaction:1. IMMUNOPATHOLOGYBalance betweenpro-inflammatory & anti-inflammatory cytokines2. hyperplasia of RES system -splenomegaly & hepatomegaly
  8. 8. Red Blood CellsruptureRelease parasite endotoxinsGlycosyl Phosphatidyl Inositol (GPI)Activate MACROPHAGE-MONOCYTE systemPro inflammatory Cytokines:TNF, interleukin-(IL-1), interferon-γ, IL-6, IL-8,macrophage colony-stimulating factor , lymphotoxin,superoxide and nitric oxide(NO)Symptoms: FEVER, malaise, headache,nausea and vomiting, diarrhea, anorexia, body aches,thrombocytopenia, immunosuppression, coagulopathy, CNS symptoms
  9. 9. Plasmodial DNApresented by hemozoinRelease ofproinflammatorycytokinesInduce COX-2-upregulatingprostaglandinsFEVER
  10. 10. after the infection gets established for about a weekMALARIA FEBRILE PAROXYSMSCLASSIC THREE STAGES :–1. Cold stage – chills (15 min – 1hour)2. Hot stage – High fever 106 ºF (2 - 6 hours)accompanied byhead aches, vomiting, delirium,anxiety, restlessness3. Sweating stage - profuse sweating and fever subsides(2-4 hours).
  11. 11. FEVER with chills & rigorsPalpableSPLEENANAEMIASevere anaemia = leading causeof death in children withfalciparum malaria.
  12. 12. CLINICAL FEATURESDepends on parasite species, parasitaemia,host immunity1. FEVER -intermittent with chills & rigors48h cycle- Pf, Pv, PoTertian72h cycle - PmQuartan1 3day 1 42. SPLENOMEGALY3. ANAEMIA
  13. 13. D 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 7 8P falciparum P vivax , P ovale P malariaeFever patterns in malariatertian periodicity uncommonin primary attack of PfTertian Quartan
  14. 14. ANAEMIA normocytic, normochromic(1). Major mechanism =haemolysis of parasitized cells(2). Phagocytosis of non parasitized cellsSplenic clearance - rigidity of RBCsimmune clearance(3). Dyserythropoiesis inbone marrow
  15. 15. Haemoglobinutilization byparasiteHaem + parasite proteinMalaria pigment(haemozoin)globinHaemozoin induction of apoptosis inerythroid cells in the bone marrowDYSERYTHROPOIETIC ANAEMIA
  16. 16. Severe falciparummalariaGambian 3yr oldcerebral malaria& opisthotonosDysconjugate (asymmetric)gaze in comatose Gambianchild with cerebral malaria
  17. 17. Infected RBCs get sequestered in capillaries ofvital organs eg. brain, liver, kidneyMechanical obstruction of microcirculation= obstruction of small blood vesselseg. capillaries, post – capillary venulesP. falciparum – Pathophysiology of Severe Malaria1. Cytoadherence of parasitized RBCs = RBCs withmature parasites stick to blood vessel walls in deep organsSEQUESTRATION
  18. 18. Interfere with microcirculation1. Tissue hypoxia2. Nitric oxide [NO] release2. Rosetting = Parasitized RBCs stick touninfected RBCsP. falciparum – Pathophysiology of Severe Malaria3. Rigid parasitized RBCs get stuck in narrowedcapillary lumen
  19. 19. 1. Cytoadherence (mainly)2. Rosetting3. Rigid parasitized RBCsP. falciparum - MechanismsofMicrocirculatory Obstruction
  20. 20. (1).Rosetting (2). EndothelialCytoadherenceVASCULAR OBSTRUCTION HYPOXIA
  21. 21. Ischaemia &Tissue hypoxiaCytoadherence , Rosetting & Rigid RBCsBlock capillaries & post capillary venulesNO = Nitric Oxide releaseOxidative damage to tissue
  22. 22. Severe Malaria• Impaired level ofconsciousness, COMA• Convulsions• Generalized andlocalizedneurological signsCerebralPathogenesis Clinical FeaturesRenal• Acute tubular necrosis -sluggish blood flow and hypotension.•Intravascular haemolysis•Oliguria• Haemoglobinuria• Acute Renal Failure [ARF]Sluggish flow caused bysticky knobs on parasitizedredcells leading to stagnanthypoxia and vascular damage.
  23. 23. Severe Malaria: Common Clinical Manifestations 2Pathogenesis Clinical FeaturesIncreased pulmonarycapillary permeability• Cough• Pulmonary oedema[ARDS]•Bronchopneumonia•Elevated serum enzyme levels•Prolonged prothrombin timeJaundice(mainly haemolytic)BleedingRespiratoryHepatic
  24. 24. Severe Malaria: Common Clinical Manifestations 3BLOOD Severe anaemia – Hb < 5g/dlHypoglycaemiaAcidaemiaShockDisseminated Intravascular Circulation [DIC]Multiple Organ Dysfunction [MODS]
  25. 25. 1. Impairment of consciousnessGlasgow Coma Scale [adults] & Blantyre Scale [children]2. Prostration – inability to sit unassisted in a child.In infant not old enough to sit, inability to feed[on examination - not just told in history]3. Hyperparasitaemia >4% in non-immune [SL]SEVERE MALARIA – 2000 WHOTreat any patient as SEVERE MALARIAif physician is worried about Signs & SymptomsBUT
  26. 26. Severe Malaria
  27. 27. Cerebral malaria -P falciparumAfrica - cerebral malaria common in children (6m to 3 yrs)high mortality - survivors, 10% have neurological sequelae
  28. 28. Brain in cerebral malaria-autopsy specimenperivascularhaemorrhageParasitized RBCsfillingvenules/capillaries
  29. 29. Liver in chronic malaria:dark colour is due to malarialpigment in macrophagesANAEMIA in recurrent malaria• hypersplenism• severe dyserythropoeisis - ineffectiveerythropoeisis in bone marrow
  30. 30. HAEMOGLOBINURIA (blackwater fever)often due to G6PD deficiency& oxidant drugs eg. Primaquinequinine therapy - immune lysisIntravascular haemolysis
  31. 31. Post-malarianeurological syndromesFollowing cerebral malaria <than in other encephalopathies – 3% inadults & 10-20% in childrenHemiparesis, cortical blindness, tremor,cranial N palsy?subtle persistent cognitive/behaviouraleffects2-3 wks after P vivax uncomplicated malaria.Self limiting – few wksCerebellar Ataxia in Sri Lanka
  32. 32. Hyperreactive malarialsplenomegaly syndrome(Tropical splenomegalysyndrome)massive spleensseen in endemic areasOverproduction ofpolyclonal IgMimmune response
  33. 33. Malaria in ChildrenSevere Pf – rapid progression <1d feverP/CComaConvulsionsAcidosisHypoglycaemiaSevere anaemiaHigh risk of dying - ifRespiratory distress (acidotic breathing)Deep coma
  34. 34. Malaria in PregnancyAreas with UNSTABLE Malaria (SL)Higher maternal mortality&fetal lossMOTHERoSevere anaemiaoAcute pulmonaryoedemaoHypoglycaemiaBABYoPremature birthsoLow Birth WeightHigher Neonatal Mortality
  35. 35. RELAPSE OR RECRUDESCENCE?Reappearance of clinical symptomsfollowing a period of being wellRecrudescence: 2- 4 weeks „specially in PfDue to presence of asexual blood stages that arenot cleared - Inadequate treatment or drugresistanceRelapse: 3- 6 weeks - Pv, PoDue to hypnozoite activation merozoites>% hypnozoites - relapses over longer term
  36. 36. Clinical symptomsparasitiaemiasubpatentLiver schizogony-hypnozoitesRecrudescence & RelapseFever thresholdMicroscopic thresholdRecrudescence Relapse 3-6 wks later1st attack
  37. 37. MALARIA ENDEMICITYSTABLE OR UNSTABLE TRANSMISSION Hyper/holo endemic High anopheline bitingfrequency Severe malaria in6 months -3 yrs age Older – asymptomaticparasitaemic[PREMUNITION] Pregnancy – severemalaria Spleen rate .50% inchildren 2-9yrsUNSTABLE MALARIA[Sri Lanka,Thailand, Cambodia]Meso / hypoendemicSevere malaria in all agesCerebral malaria > commonSpleen rate in children<50%STABLE MALARIA[AFRICA]
  38. 38. Laboratory diagnosisDiagnosis confirmed by finding parasites/productsin blood using microscopy/ Antigen detection RDTs1. Microscopy - thin /thick blood film x3 (if –ve repeat 12-24h)THICK FILM (3-5l) – Very SensitiveLimit of detection 10-20 p/l =0.002% parasitaemiaTHIN FILM (1l) - accurate species identification2. Antigen detection - parasite derived products - proteinsenzymes3. PCR – identify DNA (for research only)
  39. 39. In falciparum malaria- peripheral parasitaemiacould underestimate the total parasite burdenThe parasites causing the clinical symptoms areSEQUESTERED in the capillaries of deep organsie. microvascular circulationIn synchronous cycles, peripheral parasitaemiacould even be negativeRepeat blood films daily – 3 consecutive days
  40. 40. 42Microscopy – identify parasiteThin & Thick film x3 Consecutive daysGOLD STANDARDTHICK FILM(3-5 l)Very SensitiveLimit of detection 10-20 p/lCan quantify against WBCsTHIN FILM(1l)Accurate species identification
  41. 41. 43Disadvantages1. Need trained experienced personnel2. Can’t do in fieldMicroscopyAdvantages1. Less costly2. High sensitivity3. Can quantify
  42. 42. 44ANTIGEN DETECTIONRAPID DIAGNOSTIC TESTS [RDTs]Dipstick/card methods1. Most useful commercial tests detectingBOTH Pf + PvDetectsparasite Lactate dehydrogenase ( pLDH)depends on LIVE parasitesCAN USE TO TEST DRUG RESISTANCE
  43. 43. 2. RDTs – sensitivity is low(won’t detect below 100 – 200 parasites/μl)45ANTIGEN DETECTIONRAPID DIAGNOSTIC TESTS [RDTs]WHO malaria RDT performance evaluation - Round 21. High costDisadvantagesAdvantages1. Easy to do in field2. Don’t need trained persons
  44. 44. The leaves of Artemisia annua,(China) are the source of artemisininCinchona (Peru) –QuinineAnti - malarials
  45. 45. Malaria Treatment in Sri LankaVivax malaria1. Chloroquine –blood schizonticide2. Primaquine – Killshypnozoites &gametocytesFalciparum MalariaCombination therapy to limitDevelopment of drug resisitanceCO-ARTEMETHER[Artemether & Lumefantrine]& PrimaquineSevere Pf – Quinine
  46. 46. Pregnant women in 1st trimesterExclusively breastfeedingChildren weighing < 5 kg„Coartem‟ is contraindicated for:-Treatment = Quinine
  47. 47. ANTIMALARIAL RESISTANCEDEFINITION“Ability of a parasite strain to survive or multiplyin spite of administration of a drug at usualor higher than usual dose.( where drug failure due to defective intake/absorption / metabolism has been excluded)”P falciparum –Multi Drug Resistance(MDR) – combinationtherapyP vivax - resistance tochloroquine in a few areasRESISTANCE 3 grades :R1 (low grade)R ll (high)R lll (no response)
  48. 48. P.falciparum – map of chloroquine resistance
  49. 49. Assessment of TherapeuticResponse to Anti-malarials(1) Parasite Clearance Time (PCT)Time between beginning the anti-malarialtreatment and the first –ve blood film(2) Fever Clearance Time (FCT)Time from beginning anti- malarial treatmentuntil the patient is apyrexial [no fever]
  50. 50. Prevention & Control of MalariaInterrupt transmission @ different stages1. MAN3. PARASITE2. VECTOR
  51. 51. A. Prevent Man-Vector Contact / Reduce VectorPopulationmost useful strategies Insecticide impregnated bed nets Residual insecticide spraying ofhousesPrevention & Control of MalariaB. Reduce Parasite PopulationTreatment of patients –Gametocytocides (Primaquine) also to preventtransmission
  52. 52. Still experimentalMultistage, multi component -anti sporozoite, liver stages, merozoite,ring infected erythrocytesTransmission blocking – anti gametocyteAnti disease not anti parasitic –So as not to prevent infection &reduce natural immunity = PremunitionDNA vaccinesVaccines
  53. 53. Prevention & Control of Malaria in SLMinistry of Health – Anti Malaria CampaignELIMINATION of Malaria transmission in SL by 201556200,000 cases in 200023 in 2012(99.99% reduction)2012 lowest number ofmalaria cases since1963Dramatic reduction of microscopically confirmed case loadhttp://www.malariacampaign.gov.lk
  54. 54. 57Prevention & Control of Malaria in SLhttp://www.malariacampaign.gov.lkMost detected by1. Activated Passive Case Detection (APCD) –hospitals in endemic areaalso1. Active Case Detection (ACD) and Mobile malariaclinics – home visits
  55. 55. MALARIA DAY WALKGlobal fund - grant to eliminatemalaria in SL given toTEDHA= Tropical and EnvironmentalDiseases and Health Associates
  56. 56. Clinical features of severe falciparum malariaincludeA. Severe anaemiaB. Acute pulmonary oedemaC. HypoglycaemiaD. ComaE. ConvulsionsT=ABCDE
  57. 57. ReferencesLook at these websites• World health Organization: WHO - www.who.int/• Centers for Disease Control and Prevention (cdc)website : www.cdc.gov/Books1. Manson’s Tropical Diseases – 22nd Ed2. Worms & Human Disease – Ralph Muller & DerekWakelin

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