Malaria

A detailed presentation about malaria.
REFFERENCE-API TEXT BOOK OF MEDICINE,HARRISON
Presentation by DR JAYASOORYA P G,JUNIOR RESIDENT DEPARTMENT OF GENERAL MEDICINE,AZEEZIA MEDICAL COLLEGE,TRIVANDRUM,KERALA,INDIA

1. AZEEZIA MEDICAL COLLEGE DEPARTMENT OF GENERAL MEDICINE

2. MALARIA Dr JAYASOORYA P G JUNIOR RESIDENT DEPARTMENT OF GENERAL MEDICINE

3. Sir RONALD ROSS Awarded nobel prize for physiology or medicine in 1902 for his work on transmission of Malaria

4. Malaria is a results of complex interaction between the host ,plasmodium parasite ,female anopheles mosquito vector and the environment

5. Epidemiology and aetiology Caused by protozoan parasite-genus plasmodium 150 species of plasmodium-they infect mammals , birds,reptiles Human malaria-only 5 species- P.falciparum,vivax,ovale,malariae,knowelesi Transmission-female anopheles mosquito >90 % death-in sub-Saharan Africa-young childrens of <5 years About 4% cases globally-d/t vivax –but outside Africa continent vivax infection is 41% P knowlesi -monkey parasite-cause of human malariae in forested areas of malasia and indonesia

6. India contribute 6% of global malaria cases According to NVBDCP -2/3 rd cases in india are due to P falciparum and rest due to vivax in 2015 Ovale,malaria,knowlesi –cases reported sporadically from various parts of india India achieved near elimination of cases in 1970-but resurge of cases due to relaxation of control measures,development of chloroquine resistance to P falciparum,development of insecticide resistance by mosquito vectors

7. Two host for malaria.Asexual life cycle in human host (intermediate host),sexual life cycle in female anopheles mosquito (definite host) Infected female anopheles mosquito inoculate few sporozoite into skin—which circulate in human body and reach liver to intiate exoerythrocytic stage—within liver hepatocyte,sporozoite mature into hepatic schizont,which rupture and release merozoite into circulation. In vivax and ovale hypnozoite (dormant liver form) form from these merozoite Merozoite invade RBC and intiating erythrocytic shizogony,develop into early trophozoite (ring form),late trophozoite to mature schizont within 48-72 hours,and lead to rupture of RBC and release 6-30 merozoite

8. They in turn infect new RBC and repeat the process. Few merozoite develop to male and female gametocyte within human. Upon mosquito bite male and female gametocyte fuse and form zygot within female anopheles mosquito gut (sexual phase) Zygote elongate to ookinete and penetrate the gut wall and forms oocyte where development of sporozoite takes place. Sporozoite then migrate to salivary gland and reside until next human bite ,ready to be inoculated

9. Sporogony (from ingestion of gametocyte to formation of sporozoite )-takes 8-21 days depending on temperature Thus to transmit malaria-mosquito has to survive >7 days Sporogony is not completed at cooler temperature ( ie <16 c for vivax and <21 c for falciparum).so transmission does not occur below these temperature or at high altitude

10. Pathogenesis Infected RBCs lose their deformability and results in intravascular haemolysis Mechanisms in severe malaria- cytoadherence,agglutination,rosetting,cytokine network Cytoadherence -infected RBCs containing schizonts develop sticky knobs,which make them adhere to the venular and capillary endothelium of brain,lungs,liver,kidney,gut Agglutination –infected RBCs adhere to other infected RBCs Rosetting -infected RBCs adhere to uninfected RBCs Because of these phenomin there is microvascular blockage resulting in tissue hypoxia and organ dysfunction

11. Cytokine network – proinflamatory and immunomodulatory cytokines are activated in acute malaria which evoke fever and are implicated in severe malaria. P vivax induces more inflammation compared to P falciparum for given parasite density

12. RBC changes,Haemoglobin variants and protection against malaria Haemoglobin S, haemoglobin C, haemoglobin E, alpha thalassemia-protection from severe life threatening P falciparum malariae Risk is reduces 70% by homozygous HbC and 90% by heterozygous HbS (SICKLE CELL TRAIT) This protection is from severe malaria and largely absent for P falciparum infection Mechanism- haemoglobinopathies interfere with parasite metabolism,restrict the growth of parasite or expression of adhesion molecule Duffy blood group antigen is the receptor for P vivax binding of RBCs. Most west Africans and people with duffy negative phenotype are resistant to P vivax

13. Clinical features Hippocrates –first explain symptoms of malaria and periodicity of fever Periodicity –depends on duration of erythrocytic phase of life cycle,febrile paroxysms-coincide with rupture of erythrocytic shizont P knowlesi -quotidian fever-every day P falciparum,vivax,ovale -tertian fever-fever occur every third day P malariae-quartan fever-fever every 4 th day

14. Typically malarial fever paroxysm has A)cold stage(20-60 min)-where individual experience intense chills and rigors B)Hot stage (2-6 hours)-where temperature may reach upto 40 c C)Wet stage/Diaphoresis(20-30 min) associated with profuse sweating

15. Other symptoms Nonspecific Head ache,bodyache,cough,vomiting,diarrhea

16. Clinical examination Pallor,mild jaundice,hepatomegaly,splenomegaly

17. Atypical presentation seen in Extremes of age Pregnancy Immunocompromised individuals Individuals with comorbidities Hence high index of suspicion is warranted in endemic areas and malaria must be rule out in all febrile patients

18. Severe malaria Malaria with evidence of any organ dysfunction as per WHO defined severity criteria anytime during acute illness is severe malaria c/f-altered sensorium,convulsions,oliguria,deep jaundice,shock,DIC,bleeding manifestations,breathlessness Mortality (in severe falciparum malaria) if untreated-100%,mortality with treatment-10-20 %

19. Cerebral malaria Present with impaired consciousness with or without convulsions in the absence of hypoglycemia Usually focal neurological deficit and neck stiffness are absent More common in children Due to cytoadherence and sequestration

20. Severe anaemia Children>adult Due to intravascular haemolysis

21. Jaundice Commonest complication in patients with severe malaria Mild jaundice and indirect hyperbilirubinemia -due to haemolysis Some severe malaria-deep jaundice,conjugated hyperbilirubinemia,transaminitis -d/t liver dysfunction Due to cytoadherence and sequestration in vital organs in addition to inflammatory mediators

22. Hypoglycemia Results from failure of hepatic gluconeogenesis and increased consumption of glucose by both host and malarial parasite Quinine and quinidine are powerfull secreatagogue and compound the problem Hypoglycemia is asignificant problem in children and pregnant women

23. ACUTE KIDNEY INJURY Due to hypovolemia d/t vomiting,dehydration,sequestration of parasite,sepsis,hypotension,haemoglobinuria (d/t Intravascular haemolysis ) M.c in adult Non- oliguric,metabolic acidosis,hyperlactemia Black water fever-severe intravascular haemolysis resulting in dark coloured urine haemoglobinuria,and is often precipitated by quinine Early dialysis enhances the likely hood of a patients survival

24. ARDS Noncardiogenic pulmonary oedema is due to leaky capillaries M.C with P vivax > P falciparum ARDS may develop as a late manifestation even after parasite clearance

25. Severe P vivax malaria Complications-cerebral malaria,spontaneous bleeding,pulmonary oedema,ARDS,circulatory collapse/ shock,hyperbilirubinemia,severe anaemia,hemoglobinuria,renal failure,respiratory distress,metabolic acidosis,hypoglycemia Unlike P falciparum,vivax doesnot produce hyperparasitemia.And rarely reach parasitemia of 2% in the periphery,as it predominantly infect reticulocyte Significant P vivax biomass in extra vascular compartment such as bone marrow and spleen Splenic rupture is more common with P vivax

26. Malaria due to P ovale Mild acute attack Parasitemia persist for several years with occasional recrudescence of fever Cause glomerulonephritis and nephrotic syndrome in children

27. Malaria due to P ovale Mild malaria with potential to cause relapses

28. Malaria due to P knowlesi Full spectrum of illness including severe malaria(exception-cerebral malaria)

29. Chronic complications of malaria Tropical splenomegaly(hyperactive malarial splenomegaly) Quartan malarial nephropathy Recurrent malaria Malarial relapses

30. Tropical splenomegaly Its Hyperractive malarial splenomegaly Exposure to r/c malarial infection in endemic areas-abnormal immunological response-massive splenomegaly and hepatomegaly Defective CD8 lymphocyte function-marked stimulation of B lymphocyte-elevation of IgM and malarial antibodies Rx –long term Proguanil

31. Quartan malarial nephropathy Chronic or repeated infection with P malaria causes immune complex mediated glomerulonephritis and resulted in nephrotic syndrome Poor response to antimalarial agents,glucocorticoids,cytotoxic drugs

32. Recurrent malaria Reappearance of parasitaemia after a clearance following acute malaria Recrudescence –appearance of parasitaemia from blood stage of parasite Relapse –appearance of parasitaemia from the activation of dormant hypnozoites from the liver Reinfection –appearance of parasitaemia because of new infection following a mosquito bite

33. Malarial relapses Hypnozoites,the dormant liver forms in P vivax and ovale –produce relapses upto 2 years Frequent relapses can induce severe anaemia ,especially in children and pregnant women

34. Differential Diagnosis Dengue fever Scrub typhus Leptospirosis Influenza Viral hepatitis Meningoencephalitis Sepsis

35. Diagnosis Perepheral smear examination QBC(quantitative buffy coat) examination Immunochromatographic test Molecular diagnosis Other lab test Glucose 6 phosphatase dehydrogenase activity

36. Perepheral blood smear examination Gold standerd for diagnosis-demonstration of asexual forms of parasite in stained peripheral blood smear After a negative smear,if suspicion of malaria is high,repeat smear should be made Stains using- romanowsky stains like leishman stain and giemsa stain-both thick and thin smears are making Thick smears has more diagnostic sensitivity than thin smears-thick smear concentrate the parasite by 40-100 fold than thin smear Before thick smear is judged negative-minimum of 200 field should be examined under oil immersion

37. QBC examination Based on acridine orange staining of centrifuged peripheral blood sample in a micro haematocrit tube and examination under UV light source ( flurescence microscopy) Principle-centrifugation concentrate RBCs in a predictable area of QBC tube ,making detection easy and fast RBCs containing plasmodia –concentrate just below the leukocytes,at the top of erythrocyte coloumn -because RBC containing plasmodia are less dense than normal ones RBC which takes acridine orange stain-appear as bright specks of light among nonflurescing RBCs

38. Immuno chromatographic test These are rapid diagnostic test-detection of plasmodium antigen It’s a rapid and easy way to diagnose malaria in remote areas where microscopy is not available Parasite LDH(plasmodium antigen)-in P falciparum,vivax,ovale,malaria Plasmodium falciparum histidine rich protein 2 (PfHRP2) antigen is specific for P.falciparum Bivalent RDTs –differentiating vivax and falciparum

39. Molecular diagnostics PCR are more specific and sensitive for different species of plasmodia Costly So presently not indicated for case management of fever Using in –asymptomatic malaria in malaria control and elimination settings Antibody based malaria test has no role in diagnosis of acute malaria

40. Other lab test Normocytic normochromic anemia Thrombocytopenia Leukocytosis LFT-indirect hyperbilirubinemia with normal transaminase-s/o haemolysis Severe malaria-total bilirubin (>3) with elevation of direct bilirubin and mild elevation of liver enzyme RFT-usually normal,severe malaria RFT elevated with metabolic acidosis Coagulopathy with abnormal PT/APTT-S/o DIC-in severe malaria

41. G6PD Activity RBC G6PD activity <30 % of normal mean have G6PD deficiency and will experience haemolysis with primaquine

42. TREATMENT Treatment has to be intiated after confirmation of malaria by microscopy or RDT.Treatment is according to infecting species and severity

43. A)Treatment of uncomplicated malaria 1)Treatment of uncomplicated Falciparum malaria 2)Treatment of uncomplicated vivax malaria 3)Treatment of P.ovale ,P malariae,P knowlesi B)Treatment of severe Malaria C )Treatment of recurrent malaria D)Treatment of malaria in pregnancy

44. Treatment of uncomplicated Falciparum malaria Resistance to chloroquine Artemisin combination therapy (ACT) is indicated for Falciparum malaria Artemisin monotherapy banned in india -emergence of resistance Artemisinin with short half life has to be administrated with a partner drug with longer half life ,to prevent recrudescence Acute treatment of P.Falciparum should be followed by a single dose of primaquine 0.5mg/kg to kill the gametocyte to prevent transmission

45. ACT is not to be given in first trimester of pregnancy. SP-is not prescribed for children <5 month,and should treat with alternative ACT Primaquine is contraindicated in infants,pregnant women,G6PD deficiency In North Eastern india,P falciparum has developed resistance to SP. Hence SP cannot be used along with artemisinin (SP- Sulfadoxine + pyrimethamine )

46. Treatment of uncomplicated vivax malaria Areas where P vivax sensitive to chloroquine ,its treated with chloroquine P vivax in india remains sensitive to chloroquine 10 countries( Papua,new guinea,Thailand ) developed resistace to P vivax.such cases are managed with ACT.Sulfadoxine pyrimethamine is ineffective against P vivax Schizonticidal treatment with chloroquine should be followed by primaquine (a hypnozoitocidal )drug for 14 days to prevent relapses in all cases of P vivax malaria In G6PD deficiency individual,primaquine may induce haemolysis.In such patients , primaquine 0.75mg/kg administered weekly for 8 week with supervision and adequate patient counciling about symptoms of haemolysis

47. Treatment of P.ovale ,P malariae,P knowlesi P ovale should be treated as P vivax P malariae,P knowlesi should be treated as P falciparum

48. Treatment of severe Malaria It’s a medical emergency All severe malaria due to all plasmodia species are treated similarly DOC- parentral ACT

49. Treatment of severe falciparum malaria

50. Adjunct treatment of severe malaria Fluid management,oxygen and ventilator support –to prevent ARDS Prevention and treatment of hypoglycemia,transfusion of blood component therapy,management of kidney injury with dialysis Management of convulsions with diazepam and broad spectrum antibiotics in suspected bacterial infection until cultures are negative

51. Treatment of recurrent malaria Its not resistant malaria Its due to reinfection/recrudescence/relapse Currently no test to accurately identify the cause Recurrence due to vivax -high dose of primaquine (0.5-0.75 mg/kg/day) for 14 days Failure to take full course of primaquine –one of the reason for relapse-so ensure compliance to 14 days course of primaquine

52. Malaria in pregnancy ACT- contraindicated in first trimester Primaquine,doxycycline -contraindicated in throughout pregnancy and lactation

53. Prevention of malaria National frame work for elimination of malaria by 2030-programme by gov of india -it’s a multimodal approach to prevention 1)promoting awareness of malarial transmission,breading sites and preventive measures 2)Bite prevention-integrated vector control,bed nets and mosquito repellents 3)chemoprophylaxis for at risk individuals including travelers and intermittent preventive therapy in infants and pregnant women (practiced in Africa) 4)Diagnosis and early treatment of cases to reduce gametocyte production and transmission.Ensuring radical therapy in P vivax cases with primaquine

54. Malaria vaccine Immunity in malaria is species and stage specific

55. RTS,S/AS01 Vaccine( trade name- Mosquirix ) Against P falciparum malaria , Recombinant vaccine against pre- erythrocytic stage of the parasite Here P falciparum circumsporozoite protein are fused to hepatitis B surface antigen Three doses -IM –minimum 4 weeks between doses 4 th dose-recommended by WHO for large scale pilot implementation in sub-Saharan Africa

56. Thank you