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Malaria . dr surya


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Malaria . dr surya

  1. 1. MALARIA
  2. 2. Why The Concern About Malaria? > 1/3rd of world’s population (2.1 billion) live in MALARIOUS areas One million deaths (mostly African children) in 2008 Malaria can decrease GDP by 1.3% in countries with high disease rates Non-immune travelers very vulnerable to the disease. WHO FactSheet April 2010.
  3. 3. Concern……contd. 1.5 Million laboratory confirmed cases annually Half cases are due to P. falciparum Rising resistance to Chloroquine (CHQ) Avilability of Rapid Diagnostic Tests (RDT) National Drug Policy on Malaria, NVBDC. 2010.
  4. 4. Malarial Endemecity in India In most parts of the country about 90%, malaria is unstable. In North-Eastern States efficient malaria transmission is maintained during most months of the year. Intermediate level of stability is maintained in eight states (Andhra Pradesh, Jharkhand, Gujarat, Madhya Pradesh, Chhatisgarh, Maharashtra, Orissa and Rajasthan).
  5. 5. Transmission Man is the only important reservoir Vector is female Anopheles mosquito Temperature: > 68º F and < 86º F, Rainfall: thrive in tropical areas Altitude: rarely exist above 2000 meters (e.g. J&K) Terrain: coastal areas and lowlands with lots of freshwater breeding sites Transmission also possible through: Blood transfusion (Short incubation period) Contaminated needle Organ transplant Congenital (<5% of newborns of infected mothers)
  6. 6. Pathogenesis RBC destruction Immune complexes and mediators Capillary permeability Tissue hypoxia
  7. 7. Acute Symptoms Parasites density reach about 50 per micro liter Classical cyclic paroxysm: Cold stage: chills and shaking (15-60 minutes) Hot stage: warm, headache, vomiting (2-6 hours) Sweating stage: weakness (2-4 hours) Feel well for period of time, then cycle repeats itself
  8. 8. Severe Malaria Most of these are attributable to P. falciparum (90 percent), but P. vivax and P. knowlesi can also cause severe disease
  9. 9. Severe Falciparum Malaria Also known as Complicated malaria or Malignant Tertian malaria Mortality rate of ~0.1% - appropriately treated, uncomplicated falciparum malaria Mortality rate >30% - multiple vital organ dysfunction A hospital study from Jabalpur showed that 27% of severe malaria were having cerebral malaria of whom 1/4th died. Journal, Indian Academy of Clinical Medicine Vol. 2, No. 3 July-September 2001
  10. 10. Profile of severe malaria in India Characteristics Frequency Mortality Cerebral malaria 76% 22% Severe anemia 34% 56% Hypoglycemia 21% 40% Jaundice 15% 57% Renal failure 8% 75% Blackwater fever 6% 66% Algid malaria 4% 50% Indian Pediatrics 2003; 40:939-945
  11. 11. Severe Falciparum Malaria Presence of asexual parasitaemia + ≥ 1 of the following Cerebral malaria/unarousable coma : • Not attributable to any other cause in a patient with falciparum malaria. • Coma should persist for at least 30 minutes after a generalized convulsion. Severe anemia : • Normocytic normochromic anemia with haematocrit < 15% or • hemoglobin < 5 gm/dl Renal failure : • Urine output < 400 ml/24 hrs (adults) and < 1.2 ml/kg/hr (children) • No improvement with rehydration and • S. creatinine level > 3 mg/dl. Working group of WHO,2001
  12. 12. Severe Falciparum Malaria (cont…) Acute respiratory distress syndrome (ARDS) Hypoglycemia  < 40 mg/dl (2.2mmol / l) Hypotension/shock (Algid malaria):  Systolic B.P. < 50 mmHg in children aged 1-5 years or  < 80 mmHg in adults, with cold, clammy skin Bleeding/disseminated intravascular coagulation (DIC) Convulsion : Repeated generalized convulsions > 2 within 24 hrs, despite cooling. Acidosis/acidaemia :  Arterial pH < 7.25 or plasma bicarbonate level of < 15 mmol/l.  Venous lactate level of > 15 mmol/l. Macroscopic haemoglobinuria (According to the working group of WHO,2001)
  13. 13. Who is at risk for complicated malaria? High-transmission areas, Young children, Pregnant females and Visitors (of any age) from non-endemic areas. Non-transmission / low-transmission areas Travelers returning, with undiagnosed malaria infection, from any area where P. falciparum transmission occurs.
  14. 14. The processes involved are Sequestration • Cytoadherence(Pf EMP1) • Vascular endothelial ligands  ICAM in brain,  chondroitin sulfate in placenta and  CD36 in most other organs • Rosetting • Decreased RBC Deformability Inflammatory response
  15. 15. The standard clinical case definition of cerebral malaria includes the following criteria Blantyre coma score ≤2 P. falciparum parasitemia (any density) No other identifiable cause of coma (eg, hypoglycemia, meningitis, or a post-ictal state) ( WHO guidelines for the treatment of malaria. Geneva, World Health Organization, 2010.}
  16. 16.      Score   Eye movement   Watches or follows  1  Fails to watch or follow  0  Best motor response   Localizes painful stimulus  2  Withdraws limb from painful stimulus  1  No response or inappropriate response  0  Best verbal response   Cries appropriately with pain, or, if verbal, speaks  2  Moan or abnormal cry with pain  1  No vocal response to pain  Total Fully conscious children score 5; children who do not respond to painful stimuli score 0. Response to pain should be assessed via firm nailbed pressure, sternal pressure, and pressure over the supraorbital ridge. Blantyre coma score ≤2 is associated with mortality.  Molyneux, ME, Taylor, TE, Wirima, JJ, Borgstein, A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med 1989; 71:441    
  17. 17. Cerebral Malaria Clinical feature Children (African) Adults Onset Rapid Insidious Seizures More common (in 80%) In 20 % Neurological signs Brainstem signs, raised ICP,retinal changes Symmetrical upper motor neuron signs Mortality 18.6% 20% Sequelae 11% <5% Lancet Neurol 2005; 4: 827–40
  18. 18. Malarial Retinopathy Common in children with cerebral malaria(60%) Papilloedema, and multiple retinal hemorrhages Whitening of the macula (spares the central fovea), peripheral retina and retinal vessels Bad prognostic indicator Lancet Neurol 2005; 4: 827–40
  19. 19. Acute renal failure (ARF)Pathogenesis Renal cortical vasoconstriction  Micro vascular obstruction due to sequestration  Dehydration and hypovolemia (reversible)  Massive intravascular hemolysis in blackwater fever Common in adults, rare in children Manifests as ATN (renal cortical necrosis never develops)
  20. 20. Black water fever Earlier, mortality was high (20% to 30%) Presently, mortality is much lower. Black or dark brown or red urine Transient Resolves without complications (mostly). In severe cases ATN develops from massive hemolysis. Transfused blood is also rapidly haemolysed where plasma may also be red. The patient often has a slate grey appearance.
  21. 21. Anemia Results from Accelerated red cell destruction Removal by the spleen Ineffective erythropoiesis.
  22. 22. Metabolic acidosisCauses: renal failure primary lactic acidosis (more common) Lactic acidosis results from : Anaerobic glycolysis due to micro vascular obstruction. Failure of hepatic and renal lactate clearance. Production of lactate by the parasite. Venous lactate concentration BEST PROGNOSTIC INDICATOR (4 hours after admission) >5mmol/l has bad prognosis Trans R Soc Trop Med Hyg. 1994 Jan-Feb;88(1):67-73
  23. 23. Hypoglycemia• Caused by: o ↑ requirement due to anaerobic glycolysis. o ↑ metabolic demands of febrile illness. o Obligatory demand of parasites. o Failure of hepatic gluconeogenesis and glycogenolysis o Quinine stimulated insulin secretion Occurs in 8% of adults and 30% of children (particularly problematic in pregnant women and children) Poor prognosis. Mortality rate as high as 40%.
  24. 24. Pulmonary edema/ARDS May develop even after several days of antimalarial therapy Results from increase in pulmonary vascular permeability which is not reflected in other vascular beds. Cause of increased permeability is not known Mortality >80%
  25. 25. Diagnosis Clinical diagnosis Lab. Diagnosis Microscopy Thick film - presence/absence Thin film - morphology/species Fluorescent microscopy (acridine orange) Capillary – fluorescence (QBC assay) Other Rapid Diagnostic Tests (RDTs) Antigen capture( pfHRP2, pLDH)  PCR
  26. 26. Microscopic diagnosis Gold standard Sensitivity : 5-10 parasites/μl Thick smear : rapid diagnosis Thin smear : species identification Other advantages: Platelets, toxic granules, anemia If negative, repeat 6 times 6 hourly. Indian pediatrics 2005
  27. 27. Microscopy….contd.. Collection of blood sample before administration of antimalarials not necessarily during fever Examination done in 100x oil immersion using giemsa stain, minimum of 100 fields examined before concluding slide negative
  28. 28. Microscopy….contd.. o Why parasites not detected in peripheral smear ? o sequestration in deep vascular bed o partially treated patients o prophylactic antimalarial treatment o inexperienced microscopist o poor quality staining o Slide Positivity Rate lower in 1-3 yrs age group Indian pediatrics 2005/ June 1999
  29. 29. Rapid Diagnostic Tests Histidine-rich protein 2 of P. falciparum water soluble protein, produced by the asexual stages/gametocytes of P. falciparum, expressed on the RBC surface. remain in the blood for at least 28 days after the initiation of antimalarial therapy detect asexual parasitemia of >40 parasites/µL Sensitivity 92.7% Specificity 99.2% In AIIMS study 97% & 100% (Indian J. Med. Res. Jan 1999) Limitations:  Doesn’t detect P. vivax  Positivity after treatment (from 6 to 31 days )  Cross-reaction between RA factor and HRP2 antigen Lancet Infect Dis 2006; 6: 582–88
  30. 30. Rapid Diagnostic Tests….contd.. Plasmodium aldolase Enzyme of the parasite glycolytic pathway expressed by the blood stages of all Plasmodium : pan- specific: the pan malarial antigen (PMA) Parasite lactate dehydrogenase (pLDH) glycolytic enzyme produced by live parasites different isomers of pLDH for each of the 4 species exist detect a parasitemia of >100 to 200 parasites/µL
  31. 31. The Quantitative Buffy Coat (QBC)Test  Glass haematocrit tube, pre-coated with acridine orange is filled with 55-65 μl of blood with a precisely made cylindrical float suspended in it.  Centrifugation at 12,000 rpm separates cells based on their densities which form wide bands due to the float  RBC containing Plasmodia are less dense, concentrate just below the leukocytes, at the top of the erythrocyte column  Parasites contain DNA, takes up the acridine orange stain, appear as bright specks of light under fluorescent light  Sensitivity of 83% and specificity of 94%  Very useful to detect ≤100 parasites/μl of blood J Commun Dis. 1999 Mar;31(1):19-22. WBC RBC RBC with Plasmodium
  32. 32. PCR & ELISAPolymerase chain reaction (PCR) 10-fold more sensitive than microscopy, Sensitivity to detect 1.35 to 0.38 parasites/µL for P. falciparum and 0.12 parasites/µL for P. vivax Sensitivity of 95% and specificity of 99% ELISA Antibodies to asexual blood stages appear a few days after malarial infection and are undetectable in 3-6 months after treatment. Sensitivity of 78.1% and specificity of 94.9% Lancet Infect Dis 2006; 6: 582–88
  33. 33. Flow cytometry It detects a metabolic end-product of plasmodium in WBCs (DiOC1), or parasite DNA (Hoechst 33342) Found to be useful in indicating a diagnosis of malaria during routine blood counts with automatizer. Sensitivity 95% and specificity of 88%. Cytometry. 2001 Oct 1;45(2):133-40.
  34. 34. Upcoming techniques Intraleucocytic malaria pigment Pigment-containing neutrophil count is a marker of disease severity in childhood malaria (Trans R Soc Trop Med Hyg. 1998 (Jan-Feb); 92(1):54-56) Mass spectrometry Sensitivity of 10 parasites/µL of blood
  35. 35. Guiding factors Treatment should be guided by three main factors: The infecting Plasmodium species, The clinical status and age of the patient, The drug susceptibility of the infecting parasites as determined by the geographic area where the infection was acquired.
  36. 36. Aims of treatment Providing complete cure (clinical and parasitological) of malaria cases  Prevention of progression of uncomplicated malaria into severe malaria and thereby reduce malaria mortality  Prevention of relapses by administration of radical treatment  Interruption of transmission of malaria by use of gametocytocidal drugs  Preventing development of drug resistance by rational treatment of malaria cases National Drug Policy on Malaria, NVBDC. 2010.
  37. 37. ACT: artemether + lumefantrine Artesunate plus amodiaquine/ mefloquine/ sulfadoxine-pyrimethamine (available in India) dihydroartemsinin + piperaquine (DHA+PPQ) (NA in India) Second-line antimalarial treatment: alternative ACT known to be effective in the region AS plus tetra/doxy/ clinda for 7 days quinine plus tetra/doxy/ clinda for 7 daysGuidelines for the treatment of malaria. 2nd ed. WHO. 2010
  38. 38. Treatment of severe malaria AS: 2.4 mg/kg IV or IM (0, 12 and 24 h and then once a day), or, Quinine: 20 mg/kg (may be omitted) on admission (IV infusion or divided IM injection) followed by 10 mg/kg 8 hourly (infusion rate should not exceed 5 mg salt/kg per hour), or, Artemether: 3.2 mg/kg IM given on admission and then 1.6 mg/kg per day (IM drug has erratic absorption, hence, less preferred) Parenteral treatment in severe malaria cases should be given for minimum of 24 hours National Drug Policy on Malaria, NVBDC. 2010. Guidelines for the treatment of malaria. 2nd ed. WHO. 2010
  39. 39. Treatment of severe malaria After parenteral artemisinin therapy, patients will receive a full course of oral ACT for 3 days Those patients who received parenteral Quinine therapy should receive: Oral Quinine 10mg/kg three times a day for 7 days (including the days when parenteral Quinine was administered) + Doxy 3mg/kg once a day or Clinda 10mg/kg 12-hourly for 7 days (Doxy is contraindicated in pregnant women and children under 8 years of age), or, ACT National Drug Policy on Malaria, NVBDC. 2010.
  40. 40. Antimalarial Combination therapy Antimalarial combination therapy (CT) : simultaneous use of two or more blood schizonticidal drugs with different biochemical targets in the parasites and independent modes of action Artemisinin-based combination therapy (ACT) is antimalarial combination therapy with an artemisinin derivative as one component of the combination
  41. 41. Rationale for ACT Widely established resistance to chloroquine and sulfadoxine-pyrimethamine; Theoretical basis of CT are:  Protect individual drug against occurrence of resistance  To decrease rate of decline in efficacy  Interrupt spread of resistant strains  Decrease transmission in a region
  42. 42. Why Artemisinins? ● Short half-life hence good for combination ● Rapid substantial reduction of the parasite biomass ● Rapid resolution of clinical symptoms ● Effective action against multi-drug resistant P. falciparum ● Reduction of gametocyte carriage ● Few reported adverse effects
  43. 43. For children, artesunate 2.4 mg/kg BW IV or IM given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended treatment. Artemether, or quinine, is an acceptable alternative if parenteral artesunate is not available: artemether 3.2 mg/kg BW IM given on admission then 1.6 mg/kg BW per day ; or quinine 20 mg salt/kg BW on admission (IV infusion or divided IM injection), then 10 mg/kg BW every 8 h; infusion rate should not exceed 5 mg salt/kg BW per hour
  44. 44. Intravenous artesunate has been shown to significantly reduce the risk of death from severe malaria compared to intravenous quinine (6 trials, 1938 participants; RR 0.62, 95% CI 0.51–0.75; high quality evidence). Intravenous artesunate was associated with a lower risk of hypoglycaemia (2 trials, 185 participants; RR 0.46, 95% CI 0.25–0.87; low quality evidence
  45. 45. Among 1461 patients in Bangladesh, India, Indonesia, and Myanmar randomized to receive artesunate or quinine, lower mortality was observed among those who received artesunate (15 versus 22 percent, respectively; risk reduction 34 percent ( Dondorp A, Nosten F, Stepniewska K, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366:717.) Among 5425 children in Africa with severe malaria randomized to receive therapy artesunate or quinine, lower mortality was observed among those who received artesunate (8.5 versus 10.9 percent, respectively; risk reduction 22.5 percent)  Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376:1647.
  46. 46. Degree of resistance (WHO) Smears on day 2, 7 and 28 are done to grade the resistance as R1 to R3. In a case of normal response parasite count to fall to 25% of pre-treatment value by 48 hours and smear should be negative by 7 days.
  47. 47. Drug resistance of P. falciparum The drug resistance of P. falciparum to chloroquine is widespread. However for SP, low to moderate level resistance is observed in north-east states, in kolar district in Karnataka, and one district each in Madhya Pradesh and West Bengal respectively. Quinine resistance is limited to few places of North-East states only.
  48. 48. Classification of Treatment Outcome 1. Early treatment failure (first 3 days), 2. Late treatment failure (4th -28th day)  Late clinical failure,  Late parasitological failure, and 1. Adequate clinical and parasitological response.  Absence of parasitemia on day 28 irrespective of axillary temperature without previously meeting any 0f the criteria of treatment failure Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva, World Health Organization, 2003 (document WHO/HTM/RBM/2003.50)
  49. 49. Early t/t failure  danger signs/sev. malaria in day 1-3 + parasitaemia  day 2 parasitaemia > day 0 count irrespective of axillary temp  parasitaemia on day 3 with axillary temperature ≥ 37.5o C  day 3 parasitaemia ≥ 25% of day 0 Late t/t failure  Late clinical failure  danger signs/severe malaria > day 3 + parasitaemia, w/o previously meeting any of the criteria of early treatment failure  parasitaemia + axillary temperature ≥ 37.5o C (or history fever) (day 4-28), w/o previously meeting any of the criteria of early treatment failure.  Late parasitological failure  Parasitaemia (day 7-28) + axillary temperature < 37.5o C, w/o previously meeting any of the criteria of early treatment failure
  51. 51. SUPPORTIVE MEASURESIf there is suspicion of meningitis in a case of ? cerebral malaria, LP should be done In malaria endemic areas particularly, where parasitaemia is common in the young age group, it is often impossible to rule out septicaemia in a shocked or severely ill obtunded child. Blood culture Empirical antibiotic treatment
  52. 52. SUPPORTIVE MEASURES Anemia Ideally fresh blood should be transfused In high transmission settings, for children with a haemoglobin level of <5 g/100 ml (haematocrit <15%) In low-transmission settings, a threshold of 20% (haemoglobin 7 g/100ml) is recommended.
  53. 53. Acute renal failure (ARF) Management Correction of dehydration Diuretic therapy Hemodialysis is preferred over peritoneal dialysis If facilities are not available for hemodialysis, peritoneal dialysis can still be tried. If ARF >2 days, maintenance dose of quinine should be reduced by 30 to 50% while artemisinin or chloroquine require no change
  54. 54. Exchange blood transfusion (EBT)The rationale : Removing infected red blood cells and lowering the parasite burden Reducing rapidly both the antigen load and the burden of parasite- derived toxins, metabolites and toxic mediators produced by the host; Replacing the rigid unparasitized red cells by more deformable cells and therefore alleviating microcirculatory obstruction. Carries a significant risk Although only the circulating relatively non-pathogenic stages are removed – and this is also achieved rapidly with artemisinin derivatives
  55. 55. Exchange Transfusion Has not been proven beneficial in an adequately powered randomized controlled trial CDC recommends for persons with a parasite density of more than 10% or if complications such as cerebral malaria, non-volume overload pulmonary edema, or renal complications exist. The parasite density should be monitored every 12 hours until it falls below 1%, which usually requires the exchange of 8-10 units of blood in adults.
  56. 56. Poor Prognostic indicatorsClinical indicators ● Age under 3 years ● Deep coma ● Witnessed or reported convulsions ● Absent corneal reflexes ● Decerebrate/decorticate rigidity or opisthotonos ● Clinical signs of organ dysfunction (e.g. renal failure, pulmonary edema) ● Respiratory distress (acidosis) ● Circulatory collapse ● Papilloedema and/or retinal changes World Health Organization. In : Management of severe malaria – A practical handbook. 2nd edition. Geneva. 2000; 1-69.
  57. 57. Poor Prognostic indicatorsLaboratory indicators Hyperparasitaemia leukocytosis (>12 000/μl) Mature pigmented parasites (>20% of parasites) Peripheral blood polymorphonuclear leukocytes with visible malaria pigment (>5%) High CSF lactic acid (>6 mmol/l) and low CSF glucose Raised venous lactic acid (>5 mmol/l) More than 3-fold elevation of serum enzymes (aminotransferases) Increased plasma 5'-nucleotidase Low antithrombin III levels Very high plasma concentrations of (TNF) >100pg/ml World Health Organization. In : Management of severe malaria – A practical handbook. 2nd edition. Geneva. 2000; 1-69.
  58. 58. Take Home Message Incidence of P. falciparum malaria and complicated malaria is rising in India Antimalarial resistance is wide spread and increasing Don’t give presumptive treatment Use ACTs for uncomplicated falciparum malaria Don’t use monotherapies In India artesunate-amodiaquine is suitable (areas with CQ and SP resistance, but not MDR)
  59. 59. Take Home Message Artesunate is better than quinine in severe malaria (new dose schedule) Use high loading dose of quinine (20 mg/kg) For vivax malaria chloroquine is to be used as resistance is not wide spread Use Primaquine for 14days for radical cure in P. VIVAX Newer drugs and vaccine are new rays of hope
  60. 60. Dr Surya Kumar
  61. 61. Classification of Treatment Outcome