seminar on Malaria

nkpsims and lmh nagpur by dr praman kushwah

1. Malaria Dr. Shyam Kartikey Dwivedi Moderator-Dr. Rohinie Dhokane

2. History of malaria

3. Malaria History and Introduction Epidemiology of malaria in India Life cycle of plasmodium and pathophysiology of malaria Clinical features and severe malaria Differential diagnosis Complications Diagnosis Treatment Prevention

4. Ancient History of Malaria Malaria parasites have been with us since the dawn of time. They probably originated in Africa (along with mankind), and fossils of mosquitoes up to 30 million years old , show that the malaria vector, the malaria mosquito, was present well before the earliest history.

5. Malaria and Man

6. Hippocrates and Malaria Hippocrates, a physician born in ancient Greece, today regarded as the " Father of Medicine ", was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived.

7. Malaria Name is derived from Italian Mal’ aria or bad air Malaria continues to be most important cause of fever and morbidity in the Tropical world

8. History – Events on Malaria 1880 - Charles Louis Alphose Lavern discovered malarial parasite in wet mount 1883 - Methylene blue stain - Marchafava 1898 - Roland Ross - Life cycle of parasite transmission, wins Nobel Prize in 1902 1948 - Site of Exoerythrocytic development in Liver by Shortt and Garnham

9. Major Developments in 20 th Century 1955 - WHO starts world wide malaria eradication programme using DDT 1970 – Mosquitos develop resistance to DDT Programme fails 1976 – Trager and Jensen in vitro cultivation of parasite 1948 - Site of E1948 - Site of Exoerythrocytic dev in Liver by Shortt and Garnham xoerythrocytic dev in Liver by Shortt and Garnham

10. Lavern and Ronald Ross Pioneered the Events on Malaria

11. Nobel Prizes in Malaria The discovery of this parasite in mosquitoes earned the British scientist Ronald Ross the Nobel Prize in Physiology or Medicine in 1902. In 1907, Alphonse Lavern received the Nobel prize for his findings that the parasite was present in human blood.

12. Introduction Malaria is probably one of the OLDEST DISEASES known to mankind that has had profound impact on our history. It is a huge social, economical and health problem, particularly in the tropical countries. Malaria is a vector -borne infectious disease caused by single-celled PROTOZOAN PARASITES of the genus Plasmodium. Malaria is transmitted from person to person by the bite of female mosquitoes.

13. Female Anopheles Mosquitos transmit Malaria

14. Global problem

15. What causes Malaria Malaria is caused by a parasite called Plasmodium , which is transmitted via the bites of infected mosquitoes. In the human body, the parasites multiply in the liver, and then infect red blood cells. Transmission of Malaria do not occur <16 c and >33 c Do not occur > 2000 meters altitude.

16. Malaria Kills more people than AIDS Malaria kills in one year what AIDS kills in 15 years. For every death due to HIV/AIDS there are about 50 deaths due to malaria. To add to the problem is the increasing drug resistance to the established drug.

17. Who is at risk? young children pregnant women people with HIV/AIDS international travelers from non-endemic areas   immigrants from endemic areas and their children  

18. Know malaria and why Malaria is an acute and chronic illness characterized by paroxysms of fever, chills, sweats, fatigue, anemia, and splenomegaly . Malaria is of overwhelming importance in the developing world today, with an estimated 300 to 500 million cases and more than 1 million deaths each year . Most malarial deaths occur among infants and young children.

19. 4 species of Plasmodium were known to cause malaria in humans: P . falciparum, P . malariae , P . ovale , and P . vivax . In 2004 P. knowlesi (a primate malaria species) was also shown to cause human malaria.

20. Epidemiology of malaria in I ndia Season : most common in July-November Definitive host : Anopheles mosquito Intermediate host : Man Vector : Anopheles culicfacies (rural) and Anopheles stephensi (urban) Type Incubation period P vivax 8-17 days (14days) P falciparum 9-14 days (12 days) P malariae 18-40 days (28 days) P ovale 16-18 days (17 days)

21. Modes of malaria transmission Bite of female anopheline mosquitoes: Infective form: sporozoites Infection of blood of a malaria patient containing asexual forms- ‘ trophozoite ’ induced malaria Trasfusion malaria Congenital malraia Malaria in drug addicts

22. Hosts involved in transmission of malaria Man Female anopheles mosquito Secondary host Primary host Intermediate host Definitive host Asexual cycle Sexual cycle Schizogony Sporogony

23. Life Cycle of Malaria

24. Human cycle of plasmodium 1 . Pre Erythrocytic Schizogony Development of sporozoites in liver parenchyma Liberated merozoites are called as cryptozoites No clinical manifestation; no pathological changes Blood is sterile 2 . Erythorcytic schizogony Parasite resides inside RBCs; passes through stages of T rophozoite , S hcizont , Merozoite Parasitic multiplication brings clinical attack of malaria

25. 3 . Gametogony Some merozoites develop in RBCs of spleen and bone marrow to form ‘Gametocytes ’ 4. Exo Erythorocytic Schizogony Persistence of late tissue phase in liver Seen in P vivax and P ovale Cause relapses in Vivax and Ovale malaria Liberated merozoites are known as ‘ Phanerozoites ’

26. Mosquito cycle of plasmodium 1. Completion of gametogomy Exflagellation of microgamete and maturation of gametes Fusion of gametes form Zygote; Zygote matures to Ookinite 2. Sporogony Ookinite develops into oocyst On 10 th day of infection, oocyst ruptures, relasing sporozoites ; sporozoites reach salivary glands Mosquito at this stage is capable of transmitting infection.

27. Once inside the erythrocyte , the parasite transforms into the ring form , which then enlarges to become a trophozoite . These latter 2 forms can be identified with Giemsa stain on blood smear, the primary means of confirming the diagnosis of malaria

28. Pathological process Fever Anaemia Immunogenic events Tissue anoxia Hypoglycemia and lacticacidemia due to anaerobic metabolism of glucose

29. Fever – due to rupture of infected erythrocytes and release of merozoites in the circulation Anaemia – due to sequestration of infected erythrocytes into spleen and other organs and bone marrow supression

30. Tissue anoxia – due to cytoadherence of infected RBC in the capillary (p. falciparum ) , obstruction of capillary Immunogenic events – due to proinflammatory mediators, TNF, and polyclonal activation resulting hyper gama globulinemia and the formation of immunecomplex and immunosupression

31. Cumulative effect of these pathologic process leads to cerebral, cardiac, pulmonary, renal and hepatic failure

32. Natural immune mechanism prevents malaria, Sickle cell, fetal hemoglobin New born has passive maternal antibody and HbF

33. The age between 3 months to 5 years is potentially fatal

34. Febrile paroxysms are characterized by high fever, sweats, and headache, as well as myalgi a , back pain, abdominal pain, nausea, vomiting, diarrhea, pallor

35. Paroxysms coincide with the rupture of schizonts that occurs every 48  hr with P. vivax and P. ovale , resulting in fever spikes every other day - tertian malaria every 72  hr with P. malariae , resulting in fever spikes every 3rd or 4th day- quartan marlaria Periodicity is less apparent with P . falciparum and mixed infections travelers from nonendemic regions

36. Children with malaria often lack typical paroxysms and have nonspecific symptoms , including fever (may be low-grade but is often greater than 104°F ), headache, drowsiness, anorexia, nausea, vomiting, and diarrhea. Signs - splenomegaly (common), hepatomegaly, and pallor due to anemia. Typical laboratory findings include anemia, thrombocytopenia , and a normal or low leukocyte count. The erythrocyte sedimentation rate (ESR) is often elevated

37. Symptoms Signs Lab Fever Splenomegaly Anemia Headache hepatomegaly Thrombocytopenia Drowsiness Pallor Normal/ low TLC Anorexia Elevated ESR Nausea Vomiting Diarrhea

38. Severe malaria WHO has identified 10 complications of P. falciparum malaria that define severe malaria Impaired consciousness Prostration Multiple seizures Respiratory distress Pulmonary edema Jaundice Hemoglobinuria Abnormal bleeding Severe anemia Circulatory collapse 123 CNS 45 RS 6789 Hematological 10 CVS

39. The most common serious complication is severe anemia. Serious complications that appear unique to P. falciparum include cerebral malaria, acute renal failure, respiratory distress from metabolic acidosis, algid malaria and bleeding diatheses . P. falciparum is the most severe form of malaria and is associated with higher density parasitemia and a number of complications

40. Unique complications of P.falciparum Cerebral malaria Algid malaria ARF Respiratory distress due to metabolic acidosis Bleeding diatheses

41. P.vivax commonly occur with P.falciparum P.malariae associated with nephrotic syndrome

42. Congenital malaria Clinical features- symptoms appear within 10-30 days of life but average is 14hrs to several months Fever Poor feeding Restlessness Drowsiness Vomitting Diarrhoea

43. Signs- pallor Icterus Cynosis Hepatosplenomegaly

44. Complications Abortion Miscarriage IUGR Premature birth Neonatal death

45. Parasite and RBCs P. falciparum - immature and mature erythrocytes P. ovale and P. vivax - immature erythrocytes P . malariae - only mature erythrocytes.

46. Diagnosis Fever or unexplained systemic illness History of travel from endemic area with previous year ,think about malaria untill proven otherwise

47. Diagnosis The diagnosis of malaria Giemsa -stained smears of peripheral blood or rapid immunochromatographic assay. Stains used for diagnosis Giemsa stain > Wright stain or Leishman stain.

48. Thick and Thin blood smears The concentration of erythrocytes on a thick smear is 20-40 times that on a thin smear and is used to quickly scan large numbers of erythrocytes. The thin smear allows for positive identification of the malaria species and determination of the percentage of infected erythrocytes and is useful in following the response to therapy

49. Diagnosis A single negative blood smear does not exclude malaria. Most symptomatic patients with malaria will have detectable parasites on thick blood smears within 48 hr.

50. Dignostic feature of malaria Ring stage- immature tropozyte Mature tropozyte Schizont Gametocyte

51. Differential diagnosis Viral infections such as influenza and hepatitis, Sepsis, Pneumonia, Meningitis, encephalitis, Endocarditis , Gastroenteritis, Pyelonephritis , Babesiosis , brucellosis, leptospirosis , Tuberculosis, Relapsing fever, Typhoid fever, Yellow fever, Amebic liver abscess, Hodgkin disease, and Collagen vascular disease

52. Complications Severe malarial anemia (hemoglobin < 5 g/ dL ) is the most common severe complication of malaria in children. Anemia- hemolysis removal of infected erythrocytes by the spleen and impairment of erythropoiesis The primary treatment -blood transfusion.

53. Diagnosis for P.falciparum H/O travel within one month from endemic area Parasitemia more then 2% Ring form with double chromatin dots Erythrocytes infected with more then one parasite

54. Cerebral malaria Cerebral malaria is defined as the presence of coma in a child with P. falciparum parasitemia and an absence of other reasons for coma. Cerebral malaria is associated with long-term cognitive impairment in children. Physical findings- high fever, seizures, muscular twitching, rhythmic movement of the head or extremities, contracted or unequal pupils, retinal hemorrhages, hemiplegia, absent or exaggerated deep tendon reflexes, and a positive Babinski sign. LP - increased pressure and cerebrospinal fluid protein with no pleocytosis and normal glucose and protein concentrations. Treatment – antimalarial medications Supportive treatment of seizures and hypoglycemia.

55. Facts to remember Severe disease and death from P. vivax are usually due to severe anemia and sometimes to splenic rupture. P . ovale malaria is the least common type of malaria. P . malariae is the mildest and most chronic of all malaria infections. Nephrotic syndrome is a rare complication of P. malariae infection that is not observed with any other human malaria species . Nephrotic syndrome associated with P. malariae infection is poorly responsive to steroids .

56. Terminology Recrudescence after a primary attack may occur from the survival of erythrocyte forms in the bloodstream. merozoites from an exoerythrocytic source in the liver - P. vivax and P. ovale , or persistence within the erythrocyte - P . malariae , P . falciparum(rare). Congenital malaria is acquired from the mother prenatally or perinatally . Causes - abortions , miscarriages, stillbirths, premature births, intrauterine growth retardation, and neonatal deaths . Presentation - between 10 and 30 days of age (range 14 hr to several months of age). Signs and symptoms - fever , restlessness, drowsiness, pallor, jaundice, poor feeding, vomiting, diarrhea, cyanosis, and hepatosplenomegaly.

57. New malaria treatment guidelines in India Uncomplicated malaria Uncomplicated P. vivax - Chloroquine for 3 days (Day 1: 10 mg/kg + Day 2: 10 mg/kg + Day 3: 5mg/kg) + Primaquine 0.25 mg/kg daily for 14 days Uncomplicated P. falciparum- Artesunate (4 mg/kg body weight) daily for 3 days and sulfadoxine pyrimethamine (25 mg/kg + 1.25 mg/kg body weight) on Day 0; + Primaquine 0.75 mg/kg body weight single dose on day 2 Mixed Infections (P. vivax + P. falciparum)- Full course of artemisinin -based combination therapy (ACT) + Primaquine 0.25 mg/kg daily for 14 days

58. 1. Treatment of severe falciparum malaria Preferred regime Alternative regime IV Artesunate (60mg): 2.4mg/kg on admission, followed by 2.4mg/kg at 12h & 24h, then once daily for 7 days. Once the patient can tolerate oral therapy, treatment should be switched to a complete dosage of Riamet ( artemether / lumefantrine ) for 3 day. IV Quinine loading 7mg salt /kg over 1hr followed by infusion quinine 10mg salt/kg over 4 hrs, then 10mg salt/kg Q8H or IV Quinine 20mg/kg over 4 hrs, then 10mg/kg Q8H . Plus Adult & child >8yrs old: Doxycycline (3.5mg/kg once daily) or Pregnant women & child < 8yrs old: Clindamycin (10mg/kg twice daily). Both drug can be given for 7 days. Reconstitute with 5% Sodium Bicarbonate & shake 2-3min until clear solution obtained. Then add 5ml of D5% or 0.9%NaCl to create total volume of 6ml. Slow IV injection with rate of 3-4ml/min or IM injection to the anterior thigh. The solution should be prepared freshly for each administration & should not be stored. Dilute injection quinine in 250ml od D5% and infused over 4hrs. Infusion rate should not exceed 5 mg salt/kg per hour.

59. 2. Treatment of uncomplicated p.falciparum Preferred regime Alternative regime Artemether plus lumefantrine ( Riamet ) (1 tab: 20mg artemether /120mg lumefantrine ) Quinine sulphate (300mg/tab) Weight Group Day 1 Day 2 Day3 Day 1-7: Quinine 10mg salt/kg PO Q8H Plus * Doxycycline (3.5mg/kg once a day) OR * Clindamycin (10mg/kg twice a day) * Any of these combinations should be given for 7 days. Doxycycline : Children>8yr Clindamycin : Children<8yr 5-14kg 1 tab stat then 8hr later 1 tab Q12H 1 tab Q12H 15-24kg 2 tab stat then 8hr later 2 tab Q12H 2 tab Q12H 25-34kg 3 tab stat then 8hr later 3 tab Q12H 3 tab Q12H >34kg 4 tab stat then 8hr later 4 tab Q12H 4 tab Q12H Take immediately after a meal or drink containing at least 1.2g fat to enhance lumefantrine absorption. Add primaquine 0.75mg base salt/kg single dose if gametocyte is present at any time during treatment.

60. Dosage and administration Plasmodium falciparum for young infant Age Group Weight group Artesunate or *Quinine 0 - 4 months <5 kg ** IM first dose Artesunate 1.2 mg/kg or IM Arthemeter 1.6 mg/kg) ***Oral Artesunate 2mg/kg/day day 2 to day 7 Oral Quinine 10 mg/ kgTDS for 4 days then 15-20 mg/kg TDS for 4 days Source: Malaria in Children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University. ** Preferably Artesunate/Artemether IM on day 1 if available *** When Artesunate/Artemether IM is unavailable, give oral Artesunate from day 1 to day 7 * Treat the young infant with Quinine when oral Artesunate is not available Children under 5 kg or below 4 months should not be given Riamet instead treat with the following regimen (see table) .

61. 3. Treatment of malaria caused by p.knowlesi & mixed infection (p. falciparum + p. vivax) Treat as p. falciparum

62. Important notes Riamet tablets should be taken with or after food.  Patient with acute malaria re frequently averse to food , the dose may be taken with fluid and encourage patient to resume normal eating as soon as food can be tolerated. Watch all patients swallowing the first dose of Riamet® and observe for 1 hour after the intake. In the event of vomiting within one hour of administration, a repeat dose should be taken. For small children Riamet® can be crushed, diluted in water and then put either directly into the mouth using a syringe or given with a spoon. Riamet may cause fatigue and dizziness. Warn patient not to drive or use machines. Instruct patient to report signs/symptoms of QT interval prolongation.

63. 4. Treatment of of malaria caused by p . vivax, p. ovale or p. malariae. CHLOROQUINE (150 mg base/tab) 25 mg base/kg divided over 3 days PRIMAQUINE (7.5 mg base/tab) Day 1 Day 2 Day 3 Start concurrently with CHLOROQUINE 0.5 mg base/kg Q24H for 2 weeks Take with food Check G6PD status before start primaquine In mild-to-moderate G6PD deficiency, primaquine 0.75 mg base/kg body weight given once a week for 8 weeks. In severe G6PD deficiency, primaquine is contraindicated and should not be used. 10mg base/kg stat, then 5mg base/kg 5mg base/kg Q24H 5mg base/kg Q24H 1 tab of chloroquine phosphate 250mg equivalent to 150mg base. Calculation of dose for chloroquine is based on BASE, not SALT form. 1 tab of primaquine phosphate contains 7.5mg base.

64. Treatment in specific population & situations Specific populations Preferred regime Alternative regime Pregnancy Quinine plus clindamycin to be given for 7 day Artesunate plus Clindamycin for 7 days is indicated if first line treatment fails Lactating women Should receive standard antimalarial treatment (including ACTs) except for dapsone , primaquine and tetracyclines , which should be withheld during lactation Hepatic impairment Chloroquine : 30-50% is modified by liver, appropriate dosage adjustment is needed, monitor closely. Quinine : Mild to moderate hepatic impairment-no dosage adjustment, monitor closely. Artemisinins : No dosage adjustment Renal Impairment Chloroquine : ClCr <10ml/min-50% of normal dose. Hemodialysis , peritoneal dialysis: 50% of normal dose. Continuous Renal Replacement Therapy( CRRT) : 100% of normal dose. Quinine : .ClCr 10-50ml/min : Administer Q8-12H, CLCr <10ml/min : administer Q24H,Severe chronic renal failure not on dialysis : initial dose: 600mg followed by 300mg Q12H, Hemo - or peritoneal dialysis: administer Q24H ,Continuous arteriovenous or hemodialysis : Administer Q8-12H. Artemisinin : no dosage adjustment.

65. Treatment of complications of malaria Severe & complicated falciparum or knowlesi malaria is a medical emergency that requires intervention and intensive care as rapidly as possible. Fluid , electolyte glucose & acid-base balance must be monitored.Intake & output should be carefully recorded.

66. Immediate clinical management of severe manifestations and complications of P. falciparum malaria Definitive clinical features Immediate management/treatment Come (Cerebral malaria) Monitor & record level of consciousness using Glaslow coma scale, temperature, respiratory, and depth, BP and vital signs. Hyperpyrexia (rectal body temperature >40°C) Treated by sponging, fanning &with an antipyretic drug. Rectal paracetamol is preferred over more nephrotoxic drugs (e.g. NSAIDs) Convulsions A slow IV injection of diazepam(0.15mg/kg, maximum 20mg for adults). Hypoglycaemia (glucose conc. <2.8mmol/L) Correct with 50% dextrose (as infusion fluids). Check blood glucose Q4-6H in the first 48hrs. Severe anaemia ( hb < 7g/dl) Transfuse with packed cells. Monitor carefully to avoid fluid overload. Give small IV dose of frusemide , 20mg, as necessary during blood transfusion to avoid circulatory overload. Acute pulmonary oedema Prop patient upright (45°), give oxygen, give IV diuretic (but most patient response poorly to diuretics), stop intravenous fluids. Early mechanical ventilation should be considered.

67. Immediate clinical management of severe manifestations and complications of P. falciparum malaria (cont.) Definitive clinical features Immediate management/treatment Acute renal failure (urine output <400ml in 24hrs in adults or 0.5ml/kg/hr, failing to improve after rehydration & a serum creatinine of >265 μ mol/L) Exclude pre-renal causes by assessing hydration status. Rule out urinary tract obstruction by abdominal examination or ultrasound. Give intravenous normal saline If in established renal failure add haemofiltration or haemodialysis , or if unavailable, peritoneal dialysis. Disseminated intravascular Coagulopathy (DIVC) Transfuse with packed cell, clotting factors or platelet. Usual regime: Cryoprecipitate 10units,platelets 4-8units, fresh frozen plasma(10-15ml/kg). For prolonged PT, give vitamin K, 10mg by slow IV injection. metabolic acidosis Infuse sodium bicarbonate 8.4% 1mg/kg over 30min and repeat if needed. if severe, add haemodialysis . Shock (hypotension with systolic blood pressure <70mmHg) Suspect septicaemia , take blood for cultures; give parenteral broad-spectrum antimicrobials, correct haemodynamic disturbances.

68. Monitoring & follow-up Blood smear should be repeated daily (twice daily in severe infection). Within 48-72 hr after start of treatment, patients usually become afebrile and improve clinically except in complicated cases. All patients should be investigated with repeated blood film of malarial parasite one month upon recovery of malarial infection, to ensure no recrudescence.

69. Prevention Avoid mosquito bites: Wearing long sleeves, trousers. Insecticide Treated Bednets Repellent creams or sprays.

70. Chemoprophylaxis Indicated for travellers travel to endemic areas in Malaysia. Mefloquinine 250mg weekly (up to 1 year) or doxycycline 100mg daily (up to 3 month), to start 1 week before and continue till 4 weeks after leaving the area.

71. Dosing schedule for mefloquine Weight Age No of tablets per week < 5 kg < 3 months Not recommended 5 - 12 kg 3 - 23 months 1/4 13 - 24 kg 2 - 7 yrs 1/2 25 - 35 kg 8 - 10 yrs 3/4 36 and above 11 yrs and above 1

72. Dosing schedule for doxycycline Weight in kg Age in years No of tablets < 25 < 8 Contraindicated 25 - 35 8 - 10 ½ 36 - 50 11 - 13 ¾ 50+ 14+ 1

73. Tx failure of uncomplicated A failure to clear malarial parasitaemia and/or resolve clinical symptoms despite the administration of an antimalarial. So while drug resistance may lead to treatment failure, not all treatment failures are caused by drug resistance. Treatment failure can also be the result of incorrect dosing, problems of treatment adherence (compliance), poor drug quality, interactions with other drugs, compromised drug absorption, or misdiagnosis of the patient. Apart from leading to inappropriate case management, all these factors may also accelerate the spread of true drug resistance by exposure of the parasites to inadequate drug levels.

74. Tx failure for uncomplicated malaria Treatment failures within 14 days of initial treatment should be treated with a second-line antimalaria. the following second-line treatments are recommended, in order of preference: ■ an alternative ACT known to be effective in the region, ■ artesunate plus tetracycline or doxycycline or clindamycin (given for a total of 7 days), ■ quinine plus tetracycline or doxycycline or clindamycin (given for a total of 7 days).

75. Complicated malaria Initial treatment Parenteral Artemisin derivatives ( Artesunate , Artemether , Arteether ) or Parenteral Quinine Once patient can take Oral therapy Those on parenteral Artemisin derivatives: oral ACT(full course) ACT- A rtesunate Sulfalene Pyrimethamine C ombination T herapy Those on parenteral Quinine: oral quinine+Doxycycline 7 days Complicated malaria in pregnancy I trimester: parenteral quinine II and III trimester: Parenteral Artemisin derivatives

76. Prevention Malaria prevention consists of Reducing exposure to infected mosquitoes and C hemoprophylaxis Chemoprophylaxis is necessary for all visitors to and residents of the tropics who have not lived there since infancy, including children of all ages. Health care providers should consult the latest information on resistance patterns before prescribing prophylaxis for their patients.

77. Chemoprophylaxis Short term chemoprophylaxis (<6 weeks): Doxycycline(2 days before to 4 weeks after leaving area) Long term chemoprophylaxis (> 6 weeks): Mefloquine (2 weeks before to 4 weeks after leaving area)

78. Thank you