Malaria

detailed description on malaria

1. malaria Dr. Yuva Sri Sai Anumula Assistant Professor Department of Pharmacy Practice Nirmala College of Pharmacy

2. CONTENTS DEFINITION HISTORY EPIDEMIOLOGY ETIOLOGY RISKFACTORS VECTOR MODE OF TRANSMISSION LIFECYCLE AND PATHOGENESIS SYMPTOMS LABORATORY INVESTIGATIONS DIAGNOSIS COMPLICATIONS TREATMENT PREVENTION

3. DEFINITION The term “malaria” originates from the Italian mala aria , meaning “bad air” in 18 th century. When the term was coined, it was commonly believed that malaria was caused by breathing in bad air. Formerly called ague or marsh fever due to its association with swamps and marshland. Malaria is a life threatening vector borne-disease disease caused by plasmodium protozoa which is transmitted via bites of an infected female anopheles mosquito. Uncomplicated malaria : symptomatic malaria without signs of vital organ dysfunction.

4. HISTORY • One of the oldest known diseases. • King Tut died of malaria. • Malaria has been infecting humans for over 50,000 years. • References to malaria have been recorded for nearly 6000 years, starting in China. • Used to be common in Europe and North America. • First advances in malaria were made in 1880 by a French army doctor

5. It was discovered more than 100 years ago A French army doctor working in the mili tary hospital of Constantine in Algeria—observed parasites inside red blood cells of malaria patients and proposed for the first time that a protozoan caused disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. Charles Louis Alphonse Laveran 4

6. RONALD ROSS DISCOVERS THE ROLE OF MOSQUITOS AND TRANSMISSION Scottish Physician Sir Ronald Ross discovered that M osquit o was the vector for malaria in 1898. First effective medicine was discovered by Pierre Pelletier and Joseph Caventou . This medicine is called quinine, which comes from the bark of cinchona trees in Peru. No effective vaccine: only immunity is a result of multiple infections.

7. Epidemiology   Around 300-500 million clinical cases of malaria are reported every year, of which more than a million die of severe and complicated cases of malaria.  Malaria is known to kill one child every 30 sec, 3000 children per day under the age of 5 years.  Malaria ranks third among the major infectious diseases in causing deaths after pneumococcal acute respiratory infections and tuberculosis, and accounts for approximately 2.6% of the total disease burden of the world.

8. Epidemiology (cont.)   It mainly occurs throughout tropical regions  515 million clinical cases per year  An estimated 655,000 people died from malaria in 2010  with two-thirds of these occurring in sub-Saharan Africa  especially amongst children and pregnant women  the incidence of malaria was greatly reduced between 1950 and 1960  but since 1970 there has been resurgence.

9. INDIA • 95 % malaria prone area • 1.5 – 2 million cases annually. • The incidence of malaria in India accounted for 58% of cases in the South East Asia Region of WHO. • In 2014, there were 1.07 cases of malaria in million, 0.70 cases of plasmodium falciparum in million and 535 deaths due to malaria. • 21.98% - high transmission areas. (High transmission > 1 case/ 1000 popln) • 92% of cases & 97% of death – north-eastern states, Chhattisgarh, Jharkhand, M.P, Gujarat, Orissa, A.P, W. P, Karnatka. • API has declined from 3.29 (1995) to .85 (2012)

10. ETIOLOGY Malaria is caused by a parasite called Plasmodium, which is transmitted via the bites of infected mosquitoes The genus Plasmodium contains over 200 species of that at least 11 species infect humans. Most important are: Plasmodium falciparum Plasmodium malariae Plasmodium ovale Plasmodium vivax Plasmodium knowlesi Among those infected, P. falciparum is the most common species identified (~75%) followed by P. vivax (~20%). Transmission of Malaria do not occur <16 c and >33 c Do not occur > 2000 meters altitude.

11. SPECIES CHARACTERISTICS PV PO PM 72 PF Periodicity(hrs.) Parasites/Ml RBC Age 48 50 48 20-50 9-30 6-20 Old No 50-2000 Any Young Young Hyponozoite Duration (yrs.) Yes Yes No 1.5-5 1.5-5 3->50 1-2

12. Who is at Risk?   Most people who get malaria are travelers or people who live in an area with malaria transmission.  Young children and pregnant women.  Poor people that live in rural areas who lack knowledge, money and the access to health care.

13. Vector   Female mosquitos of genus Anopheles are primary hosts and transmission vectors.  There are approximately 460 recognized species  Over 100 can transmit human malaria  Only 30 – 40 commonly transmit parasites of the genus Plasmodium  Anopheles gambiae is one of the best known which transmits Plasmodium falciparum

14. Vector (cont.)   Only female mosquitoes feed on blood while the males feed on plant nectar and do not transmit the disease.  The females of Anopheles genus prefer to feed at night  They start searching for a meal at dusk and continue throughout the night until they take a meal

15. MODE OF TRANSMISSION • Malaria is caused by a type of microscopic parasite that's transmitted most commonly by mosquito bites. • Other transmission: • From mother to unborn child • Through blood transfusions • By sharing needles used to inject drugs

16. LIFE CYCLE AND PATHOGENESIS 1 Pre erythrocytic schizogony 2 Erythrocytic Schizogony 3 Gametogony 4 Exoerythrocytic schizogony

17. Pre erythrocytic cycle Sprozoites undergo developemtnal phase in the liver cell   Sprozoites are elongated and spindle shaped become rounded inside the liver parenchyma Multiple nuclear divisions develop to Schozonts   A Schizont contains 20,000 – 50,000 merozoites.

18. DR.T.V.RAO MD 19

19. Period of Pre erythrocytic cycle 1 P.vivax 8 days     2 P.falciparum – 6 days 3 P.malariae - 13 – 16 days, 4 P.ovale 9 days On maturation Liver cells ruputure Liberate Merozoites into blood stream

20. Affinity of Parasite to Erythrocytes P.vivax P.malariae P.ovale    Infectes only young or Old Erythocytes P.falciparum Infects all age groups  Also adhere to the endothelial lining of Blood vessesl Causes the obstruction, Thrombosis and Local Ischemias

21. Erythrocytic Schizogony Liberated Merozoites penetrate RBC   Three stages occur 1 Trophozoites 2 Schizont 3 Merozoite

22. Erythrocytic cycle Ruptured red cells release Merozoites which attack new red cells  Continue with Schizogony Repeated cycles will continue   In P.falciparum - infected erythrocytes with Schizonts aggregate in the capillaries of brain and other internal organs  Only ring forms are seen in the blood smears 

23. Trophozoites After invasion grow and feed on hemoglobin   Blue cytoplasm and red nucleus, Called as Signet ring appearance Hence called ring form 

24. Schizont When the Trophozoite is fully developed becomes compact.     Malarial pigments are scattered through the cytoplasm The Nucleus is large and lies at the periphery starts dividing. Becomes Schizont

25. Exo Erythrocytic Schizogony Some Sprozoites do not undergo sporogony in the first instance    But go into resting stage called as Hypnozoites,( hibernation ) Within 2 years reactivate to form Schizonts release Merozoites and attack red cell and produce relapses Absent in P falciparum 

26. Gametogony Merozoites differentiate into Male and female gametocytes Macrogametocytes also called female gametocytes Microgametocyte also called as male gametocytes    They develop in the red cells Found in the peripheral blood smears Microgametocyte of all species are similar in size    Macro gametocytes are larger in size. 

27. Mosquito cycle A definitive Host – Mosquito

28. Mosquito cycle Sexual cycle Sexual cycle will be initiated in the Humans by the formation of Gametocytes  female Anopheles  Develop further in the Mosquito Only mature sexual forms are capable of further development in Mosquito In midgut one Microgametocyte develops into 4- 8 thread like filamentous structures named Micro gametes   From one macrogametocyte only one macrogamete is formed 

29. Events in Mosquitos Fertilization occurs when a Microgametocyte penetrate into Macrogametocyte   Fertilized macrogametocyte is known as ZYGOTE ZYGOTE matures into OOKINETE OOKINETE to OOCYST  

30. Formation of Sporozoites in Mosquitos. OOCYST matures with large number of Sporozoites ( A few hundred to thousands.)     OOCYST ruptures and release SPOROZOITES in the body cavity of Mosquito There is a specific predilection for salivary glands Now capable to transmit the infection to new Host

31. Incubation Period  It is usually 7 to 30 days.  Reduced in p. falciparum  Increased in p. malariae

32. CLINICAL PRESENTATION

33. Signs & symptoms:  The pathology and clinical manifestations associated with malaria are almost exclusively due to the asexual erythrocytic stage parasites.  Tissue schizonts and gametocytes cause little, if any, pathology..

34.  Plasmodium infection causes an acute febrile illness which is most notable for its periodic fever paroxysms occuring at either 48 or 72 hour intervals.  The severity of the attack depends on the Plasmodium species as well as other circumstances

35.  Sometimes the incubation periods can be prolonged for several months in P. vivax, P. ovale, and P. malariae .  All four species can exhibit non-specific prodromal symptoms a few days before the first febrile attack.  These prodromal symptoms are generally described as 'flu-like ' and include: headache, slight fever, muscle pain, anorexia and nausea.  The symptoms tend to correlate with increasing numbers of parasites.

36.  In contrast to the other three species, P. falciparum can produce serious disease with mortal consequences.  This increased morbidity and mortality is due in part to the high parasitemias associated with P. falciparum infections.  These potentially high parasitemias are due in part to the large number of merozoites produced and the ability of P. falciparum to invade all erythrocytes.

37. Disease Severity and Duration vivax ovale malariae falciparum Initial Paraoxysm moderate to moderate to severe mild severe Severity severe Average Parasitemia (mm 3 ) 50,000- 500,000 20,000 9,000 6,000 Symptom Duration (untreated) 3-8weeks 2-3 weeks 3-24 weeks 2-3 weeks Maximum Infection Duration (untreated) 12-20 months 5-8 years ++ 20-50 years 6-17 months Anemia + ++ ++++ Complications renal cerebral

38. Clinical Features   P. falciparum (malignant tertian):  It is the most dangerous of the malarias  Onset is insidious, with malaise, headache and vomiting… commonly mistaken for influenza  The fever has no particular pattern.  Jaundice is common due to hemolysis & hepatic dysfunction  There is hepatosplenomegaly  Anemia develops rapidly

39. Clinical Features   P. vivax & P. ovale (benign tertian):  In many cases the illness starts with several days of continued fever before the development of classical bouts of fever on alternate days. Fever starts with a rigor. The patient feels cold and the temperature rises to about 40 C. After an hour hot or flush phase begins. It lasts several hours and gives way to profuse perspiration and a gradual fall in temperature. The cycle is repeated 48 hours later.  Anemia develops slowly

40. How Malaria present Clinically  Stage 1(cold stage)  Chills for 15 mt to 1 hour  Caused due to rupture from the host red cells escape into Blood  Preset with nausea, vomitting,headache  Stage 2(hotstage)  Fever may reach upto 40 c may last for several hours starts invading newer red cells.

41. Clinical Malaria  Stage 3(sweating stage) Patent starts sweating, concludes the episode Cycles are frequently Asynchronous Paroxysms occur every 48 – 72 hours In P.malariae pyrexia may last for 8 hours or more and temperature my exceed 41 c

42. Clinical Features   P. malariae infection (quartan):  This is usually associated with mild symptoms and bouts of fever every third day. Parasitemia may persist for many years with the occasional recurrence of fever, or without producing any symptoms.

43. Malaria Paroxysm • paroxysms associated with synchrony of merozoite release • between paroxysms temper- ature is normal and patient feels well • falciparum may not exhibit classic paroxysms (continuous fever) tertian malaria quartan malaria DR.T.V.RAO MD 40

44. Laboratory Investigations of Malaria

45. Diagnostic Tools for Human Infections with Malaria  Blood film examination( Microscopy)  QBC system  Rapid Diagnostic Tests" (RDTs)  PCR ( determine the species of plasmodium)

46. Thin and Thick smear

47. Blood collected with sterile technique

48. Microscopy Malaria parasites c an be identified by examining under the microscope a drop of the patient's blood, spread out as a "blood smear" on a microscope slide. Prior to examination, the specimen is stained (most often with the Giemsa stain ) to give to the parasites a distinctive appearance. This technique remains the gold standard for laboratory confirmation of malaria 

49. Microscopic demonstration still the Gold standard in Diagnosis Blood smear stained with Giemsa’s stain

50. QBC system has evolved as rapid and precise method in Diagnosis The QBC Malaria method is the simplest and most sensitive method for diagnosing the following diseases.  Malaria  Babesiosis  Trypanosomiasis (Chagas disease, Sleeping Sickness)  Filariasis (Elephantiasis, Loa-Loa)  Relapsing Fever (Borreliosis) 

51. Principle of QBC System

52. Appearance of Malarial parasite in QBC system

53.   Detects circulating malaria antigens in whole blood.  Most often use a dipstick or cassette format, and provide results in 2-15 minutes.  The only FDA cleared rapid malaria test. These "Rapid Diagnostic Tests" (RDTs) offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not available Antigen Detection Methods are Rapid and Precise

54. How the test works?   The test targets the histidine-rich protein II (HRPII) antigen specific to P. falciparum and a pan-malarial antigen (aldolase), common to all four malaria species capable of infecting humans - P. falciparum, P. vivax, P. ovale, and P. malariae.  It is intended to aid in the rapid diagnosis of human malaria infections and to aid in the differential diagnosis of Plasmodium falciparum infections from other less virulent malarial infections. Negative results must be confirmed by thin / thick smear microscopy.

55. Serology Serology detects antibodies against malaria parasites, using either indirect immunofluorescence (IFA) or enzyme- linked immunosorbent assay (ELISA). Serology does not detect current infection but rather measures past experience. 

56. Newer Diagnostic methods Molecular Diagnosis Parasite nucleic acids are detected using polymerase chain reaction (PCR). This technique is more accurate than  microscopy. However, it is expensive, and requires a specialized laboratory (even though technical advances will likely result in field-operated PCR machines).

57. Other Laboratory Findings Normocytic anemia of variable severity. Liver function tests may be abnormal Presence of protein and casts in the Urine of children with P.malariae is suggestive of Quartan nephrosis.    In severe Falciparum malaria with renal damage may cause oliguria and appearance of casts, protein, and red cells in the Urine 

58.  chest x-ray : helpful if respiratory symptoms are present  CT scan : to evaluate evidence of cerebral edema or hemorrhage

59. Diagnosis

60. Diagnosis   Clinical  Fever, sweat, chills, headache and muscle pain  Serology  PCR  ELISA  Blood Film (gold standard)  Banana-shaped intraerythrocytic gametocytes identify P. falciparum  Enlarged erythrocytes with Schuffner’s dots are characteristics of P. vivax  Schuffner’s dots in ovale-shaped red blood cells are characteristic of P. ovale  Band-form trophozoites are seen in P. malariae

61. Periodicity can be clue in Diagnosis and species relation  Malaria tertiana: 48h between fevers (P. vivax and ovale)  Malaria quartana: 72h between fevers (P. malariae)  Malaria tropica: irregular high fever (P. falciparum)

62. Complication of malaria

63.  Malaria is probably the only infection that can be treated in just three days , yet that kills millions every year .  Malaria may become a medical emergency by rapidly progressing to complications and death.  Early diagnosis & proper management can prevent serious complication.  Most complications have similar pathogenesis .

64. Predisposing factors for complications (1.) Extremes of age. (2.) Pregnancy, especially in primigravidae and in 2nd half of pregnancy. (3.) Immuno suppressed - patients on steroids, anti- cancer drugs, immunosuppressant drugs. (4.) Immuno compromised - patients with advanced tuberculosis and cancers. (5.) Splenectomy. (6.) Lack of previous exposure to malaria (non-immune) or lapsed immunity (7.) Pre-existing organ failure.

65. Complications of P. falciparum Complications of P. vivax / P. malaria malariae ◦ Cerebral malaria ( coma ) ◦ Convulsions ◦ Rupture of spleen ◦ Hepatic dysfunction ◦ Thrombocytopenia ◦ Severe anemia ◦ Hyperpyrexia ◦ Severe anemia ◦ Metabolic (Lactic) Acidosis ◦ jaundice ◦ nephropathy malarial ◦ renal failure (Black water fever) ◦ Pulmonary odema & ARDS ◦ hypoglycemia ◦ Hypotention & shock ◦ Bleeding & clotting disorder ◦ haemoglobinuria ◦ hyperparasitemia ◦ Associated infection

66. Why Falciparum Infections are Dangerous  Can produce fatal complications, 1.Cerebral malaria 2.Malarial hyperpyrexia 3.Gastrointestinal disorders. 4.Algid malaria (SHOCK) 5 Black water fever can lead to death

67. Pernicious Malaria  Is a life threatening complication in acute falciparum malaria  It is due to heavy parasitization  Manifest with 1 Cerebral malaria – it presents with hyperpyrexia, coma and paralysis. Brain is congested 2 Algid malaria – presents with clammy skin leading to peripheral circulatory failure.

68. Cerebral malaria For a diagnosis of cerebral malaria, the following criteria should be met: (i.) Deep, unarousable coma: Motor response to noxious stimuli is non-localising or absent. (ii.) Exclusion of other encephalopathies . (iii.) Confirmation of P. falciparum infection all patients with P. falciparum malaria with neurological manifestations of any degree should be treated as cases of cerebral malaria.

69. HAS HH Causes of neurological manifestations in malaria: ◦ High-grade fever ◦ Antimalarial drugs ◦ Hypoglycemia ◦ Hyponatremia ◦ Severe anaemia

70. Pathogenesis of Cerebral malaria  High cytokine levels could be toxic on their own  High levels of cytokine also enhance the second process thought to be responsible for cerebral malaria: sequestration of infected RBCs

71. Cerebral Malaria  Present with Hyperpyrexia It is characterized by changes in the level of consciousness, Convulsions.  Paralysis and other complications Can lead to coma Brain appears congested

72. Management of cerebral malaria : manage airway Phenobarbitone IM, 10-15 mg/kg body weight should be given y to prevent convulsions Antimalarial treatment: (see the dose)

73. Shock : Hypotension in malaria could be due to many reasons: ◦ Dehydration due to high-grade fever, excessive sweating and inadequate fluid intake. ◦ Dehydration due to vomiting and/or diarrhoea. ◦ ◦ ◦ ◦ Pulmonary oedema . Metabolic acidosis . Associated Gram negative septicemia . Massive gastrointestinal haemorrhage

74. Metabolic (Lactic) Acidosis  Increased production of lactic acid by parasites  Decreased clearance by the liver  Most importantly the combined effects of several factors that reduce oxygen delivery to tissues . . . Marked reductions in the deformability of uninfected RBCs may compromise blood flow through tissues Dehydrated and hypovolemia can exacerbates microvascular obstruction by reducing perfusion pressure Destruction of RBCs and anemia further compromises oxygen delivery

75. Acute Pulmonary Odema:  It is a fatal complication of severe falciparum malaria with more than 50% mortality .  In a few patients it could be due to fluid overload  increased permeability of pulmonary capillaries.  Sequestration of red cells and clogging of pulmonary microcirculation and disseminated intravascular coagulation DIC  more common in patients with hyperparasitemia , renal failure and pregnancy .

76. Black water fever  Massive intravascular hemolysis  Due to P. falciprum  Severe acute hemolytic anemia  RBC=1-2*106 /ml  Hemoglobinuruia  Increase bilirubin  Acute tubcular necrosis & Hb casts

77. Black Water Fever  In malignant malaria a large number of the red blood corpuscles are destroyed. Haemoglobin from the blood corpuscles is excreted in the urine, which therefore is dark and almost the colour of cola

78. Renal Failure : Renal dysfunction in falciparum malaria can be due to many factors: ◦ Renal failure in malaria is caused by renal cortical vasoconstriction and resultant hypoperfusion, sequestration and resultant acute tubular necrosis due to microvascular obstruction and due to massive intravascular hemolysis in blackwater fever .

79. Anemia : In falciparum malaria, anemia can develop rapidly due to profound hemolysis The degree of anemia correlates with parasitemia and schizontemia More serious in children and pregnant . Bleeding disorder : ◦ Thrombocytopenia ◦ Disseminated intravascular coagulation DIC

80. Hypoglycemia: Hypoglycemia in malaria may be asymptomatic Therefore, hypoglycemia, which is easily treatable, may be missed Causes: ◦ 1. Increased consumption of glucose by the host and the growing parasites. ◦ 2. Failure of hepatic gluconeogenesis and glycogenolysis as a result of impaired liver function and acidemia and hyperinsulinemia ◦ 3. Stimulation of pancreatic insulin secretion by drugs like quinine . More than one of these factors may be at play in a given patient

81. Rupture of spleen: . It is more common in vivax malaria than falciparum malaria . occur in up to 0.7% of the patients . Rupture occurs in acute, rapid, hyperplastic enlargement of spleen . Patients present with abdominal pain, fever, tachycardia, prostration and rapidly developing anemia and hypotension. . Ultra sound evaluation of abdomen and paracentesis of the abdomen can confirm the diagnosis . Treatment includes replacement of fluid and blood, laparotomy and splenectomy

82. Complication due to medication Vomiting Dizziness Itching ( chloroquine ) Abdominal pain Convulsion ( chloroquine , quinine, meflequine ) Coma ( chloroquine , quinine) Hypoglycemia ( quinine) Anemia , jaudice ,Haemoglobinuria ( primaquine in pt with G6PD deficiency ) Fever HAJ by

83. Sequestration & cytoadherence  Rosetting (adhesion of infected RBCs to other RBCs) and clumping (adhesion between infected cells) was first observed in in vitro culture

84. How long Malaria infection can lost in Man  Without treatment P.falciparum will terminate in less than 1 year.  But in P.vivax and P.ovale persist as hypnozoites after the parasites have disppeared from blood.  Can prodce periodic relapses upto 5 years  In P.malariae may last for 40 years ( Called as recrudescence X relapse ) Parasites survive in erythrocytes Liver ?

85. Malaria Relapses  In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks ("relapses") after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites (" hypnozoites ") that may reactivate.

86. Management

87. TREATEMENT

88. Where Microscopy Result Is Not Available Within 24 Hours And Monovalent RDT Is Used

89. THE PHARMACOLOGY OF ANTIMALARIALS Class Class Definition Examples Class Definition Examples Definition Examples Blood schizonticidal drugs Act on (erythrocytic) stage of Quinine, artemisinins, the parasite thereby amodiaquine, chloroquine, terminating clinical illness lumefantrine, tetracycline a , atovaquone, sulphadoxine, clindamycin a , proguanil a Tissue Act on primary tissue forms of Primaquine, pyrimethamine, schizonticidal drugs plasmodia which initiate the erythrocytic stage. They block further proguanil, tetracycline development of the infection Gametocytocid Destroy sexual forms of the Primaquine, artemisinins, quinine b al drugs parasite thereby preventing transmission of infection to mosquitoes a Slow acting, cannot be used alone to avert clinical symptoms b Weakly gametocytocidal

90. THE PHARMACOLOGY OF ANTIMALARIALS (cont.) Class Definition Examples Class Definition Examples Class Definition Examples Hypnozoitocidal drugs These act on persistent Primaquine, liver stages of P.ovale and P.vivax which cause recurrent illness tafenoquine Sporozontocidal drugs These act by affecting further development of chlorguanil gametocytes into Primaquine, proguanil, oocytes within the mosquito thus abating transmission

91. 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.  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  Once the patient can tolerate oral therapy, treatment should be switched to a complete dosage of Riamet (artemether/lumefantrine) for 3 day.  Pregnant women & child < 8yrs old: Clindamycin (10mg/kg twice daily). Both drug can be given for 7 days.  Reconstitute with 5% Sodium Bicarbonate &  Dilute injection quinine in 250ml od D5% shake 2-3min until clear solution obtained. Then add 5ml of D5% or 0.9%NaCl to create total volume of 6ml. and infused over 4hrs.  Infusion rate should not exceed 5 mg salt/kg  Slow IV injection with rate of 3-4ml/min or IM injection to the anterior thigh. per hour.  The solution should be prepared freshly for each administration & should not be stored.

92. 2. Treatment of uncomplicated p.falciparum Preferred regime Alternative regime Artemether plus lumefantrine(Riamet) Quinine sulphate (300mg/tab) (1 tab: 20mg artemether/120mg lumefantrine) Weight Day 1 Group Day 2 Day3 Day 1-7: Quinine 10mg salt/kg PO Q8H 5-14kg 1 tab stat then 8hr 1 tab Q12H 1 tab Q12H Plus *Doxycycline (3.5mg/kg once a day) later 15-24kg 2 tab stat then 8hr 2 tab Q12H 2 tab Q12H OR later 25-34kg 3 tab stat then 8hr 3 tab Q12H 3 tab Q12H *Clindamycin (10mg/kg twice a day) later *Any of these combinations should be given for 7 days. Doxycycline: Children>8yr Clindamycin: Children<8yr >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

93. Treating Drug Resistance in P.falciparum Should be treated with  Quinine sulphate plus single dose of Combination Drug Pyramethamine and Sulphodoxine ( Fansidar ) Other Alternatives 1 Quinine plus Doxycycline or Tetracycline 2 Quinine plus Clindamycin Newer alternatives 1 Mefloquine and Halofantril.

94. Children under 5 kg or below 4 months should not be given Riamet instead treat with the following regimen (see table) . Dosage and administration Plasmodium falciparum for young infant Weight group Age Group Artesunate or *Quinine Oral ** IM first dose Quinine 10 mg/kgTDS for 4 days then 15-20 mg/kg TDS for 4 days ***Oral Artesunate 1.2 mg/kg or IM Arthemeter 1.6 mg/kg) 0 - 4 months Artesunate 2mg/kg/day day 2 to day 7 <5 kg 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

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

96. 4. Treatment of malaria caused by p . vivax, p. ovale or p. malariae. CHLOROQUINE PRIMAQUINE (150 mg base/tab) 25 mg (7.5 mg base/tab) base/kg divided over 3 days  Start concurrently with Day 1 Day 2 Day 3 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 5mg base/kg base/kg Q24H 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.

97. Treatment in specific population & situations Specific Preferred regime Alternative regime populations Pregnancy Quinine plus clindamycin to be given for Artesunate plus Clindamycin 7 day 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 Chloroquine : ClCr<10ml/min-50% of normal dose. Impairment 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.

98. 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.

99. 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 Correct with 50% dextrose (as infusion fluids). Check conc. <2.8mmol/L) 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

100. Immediate clinical management of severe manifestations and complications of P. falciparum malaria (cont.) Definitive clinical features Immediate management/treatment Acute renal failure (urine  Exclude pre-renal causes by assessing hydration status. output <400ml in 24hrs  Rule out urinary tract obstruction by abdominal in adults or 0.5ml/kg/hr, examination or ultrasound. failing to improve after rehydration & a serum creatinine of  Give intravenous normal saline  If in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis. >265 μ mol/L) 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  Suspect septicaemia, take blood for cultures; give systolic blood pressure parenteral broad-spectrum antimicrobials, correct

101. 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.

102. CHEMOPROPHYLAXIS • Indicated for travellers travel to endemic areas Short term chemoprophylaxis (up to 6 weeks) Doxycycline : 100 mg once daily for adults and 1.5 mg/kg once daily for children(contraindicated in children below 8 years). The drug should be started 2 days before travel and continued for 4 weeks after leaving the malarious area. • Chemoprophylaxis for longer stay (more than 6 weeks) Mefloqiune: 250 mg weekly for adults and should be administered two weeks before, during and four weeks after exposure.

103. 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 1/2 3/4 1 13 - 24 kg 25 - 35 kg 2 - 7 yrs 8 - 10 yrs 36 and above 11 yrs and above

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

105. Prevention

106. PREVENTION   Medications (will be mentioned in treatment )  Vector control  Mosquito nets and bedclothes  Immunity (natural & vaccines)  Education

107. Vector Control   Efforts to eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the United States and southern Europe, but vector control programs, in conjunction with the monitoring and treatment of infected humans, eliminated it from those regions.  Malaria was eliminated from most parts of the USA in the early 20th century by use of the pesticide DDT.

108. Mosquito nets   Mosquito nets help keep mosquitoes away from people and greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier and they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITNs) are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net. Since the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.

109. Immunity   Natural immunity occurs, but only in response to repeated infection with multiple strains of malaria.  A completely effective vaccine is not yet available for malaria, although several vaccines are under development.  SPf66 was tested extensively in endemic areas in the 1990s, but clinical trials showed it to be insufficiently effective.  Other vaccine candidates, targeting the blood-stage of the parasite's life cycle, have also been insufficient on their own.  Several potential vaccines targeting the pre-erythrocytic stage are being developed.

110. Vaccines  First proposed in 1960s, still nothing fully effective Difficulties include :  Intracellular parasites  Polymorphism and clonal variation  Parasite induced immunosuppression  Antigenic variation  Evaluation and trials difficult to interpret  High level of parasite mutation

111. Education   Education in recognizing the symptoms of malaria has reduced the number of cases in some areas of the developing world by as much as 20%.  Recognizing the disease in the early stages can also stop the disease from becoming a killer.  Education can also inform people to cover over areas of stagnant, still water which are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people.  This is most put in practice in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas.

112. WHAT ARE WAY S TO PREVENT MOSQUITO BITES? • Use mosquito repellants. • Wear long pants and long sleeves. • Wear light-colored clothes. • Use window screens • Use bed nets. DR.T.V.RAO MD 54

113. INSECTICIDE-TREATED NETS (ITNS) • What is happening here? • What needs to happen within six months? • Can you think of any practical challenges? Source: HEPFDC, 2009. DR.T.V.RAO MD 55

114. ORIGINAL ERADICATION PLANS • Interruption of transmission of main species infecting humans by DDT spraying • Malaria disappears spontaneously in under 3 years Source: Gabaldon DR.T.V.RAO MD 56

115. OTHER WAY S TO PREVENT MALARIA Who is at the highest risk of malaria? • Travelers to an area high in malaria • Travelers often take prophylactic (preventive) medicines to prevent malaria. • Pregnant women (especially those with HIV) • Pregnant women are given intermittent preventive treatment. They are given at least 2 doses of a malaria drug during their pregnancy. • Young children • How can you protect young children? DR.T.V.RAO MD 57

116. MILESTONES . Sir Bhore Committee Report 1946 1953 1958 1971 1977 1995 1977 1999 2002 . National Malaria Control Program . National Malaria Eradication Program . Urban Malaria Scheme . Modified Plan Of Operation . Malaria Action Program . Enhanced Malaria Control Program . National Anti Malaria Program . National Health Policy . National Vector Borne Disease Cont Program 2004 . Intensified Malaria Control Project . National Rural Health Mission 2005 2005

117. NATIONAL MALARIA CONTROL PROGRAMME 1953 OBJECTIVES • To bring down malaria transmission • To hold down malaria transmission at low level ACHIEVEMENT • Decline in incidence from 75 million to only 2 million in 1958

118. NATIONAL MALARIA ERADICATION PROGRAMM 1958 OBJECTIVE  To eradicate malaria from India in 7 to 9 years ACTIVITIES  Spraying operation  Fortnightly active case detection  Radical treatment  Investigation of positive cases and remedial measures ACHIEVEMENTS  Lowest ever incidence of 0.1 million in 1965  No reported deaths due to malaria

119. URBAN MALARIA SCHEME 1971 In 139 towns in 19 states and union territories. OBJECTIVES a) To prevent deaths due to malaria. b) Reduction in transmission and morbidity. NORMS The towns should have a minimum population of 50,000. The API should be 2 or above. The towns should strictly implement the civic by-laws to prevent/eliminate domestic and peri-domestic breeding places.

120. Control Strategies under Urban Malaria Scheme: -Parasite control -Vector control Parasite control: Treatment is done through passive agencies viz. hospitals, dispensaries both in private & public sectors and private practitioners. In mega cities malaria clinics are established by each health sector/ malaria control agencies viz. Municipal Corporations, Railways, Defence services Vector control comprises of the following components Source reduction Use of larvicides Use of larvivorous fish Space spray Minor engineering Legislative measure Aerosol Space Spray Space spraying of pyrethrum extract (2%) in 50 houses in and around every malaria and dengue positive cases to kill the infective mosquitoes is recommended. Town –biologist State-additional director (malaria/filaria) Central level-director NVBDCP

121. MODIFIED PLAN OF OPERATION 1977 OBJECTIVES • Prevention Of Death Due To Malaria • Reduction Of Morbidity Due To Malaria • Retention Of Achievements Gained So Far • Re-classification Of Endemic Areas • Based On • API Less T Pa idence ater Than 2 • Areas With API > 2 •Spraying •Entomological Assessment •Surveillance •Treatment Of Cases •Decentralization Of Laboratory Services At-phc •Establishment Of Ddcs And Ftds

122. • Areas With Api < 2 • Focal Spraying • Surveillance And Treatment • Follow Up • Epidemiological Investigation

123. MALARIA ACTION PROGRAMME 1995 RESURGENCE OF MALARIA (RAJASTHAN/MANIPUR/NAGALAND/ASSAM/WB/MAHARASHTRA) EXPERT COMMITTEE 1994 HIGH RISK AREAS IDENTIFIED FTD MICROSCOPY FACILITY 30,000 POPULATION 1,000 POPULATION

124. ELEMENTS Early diagnosis and prompt treatment Sustainable preventive measures including vector control Prevention of epidemics Regular assessment HIGH RISK AREAS High API High proportion of pf cases Reported death due to malaria SPR doubled SPR >5%

125. ENHANCED MALARIA CONTROL PROJEC 1997 • With World Bank Assistance • 1997-2003, Extn To 2005 Objectives . Effective contro l of malaria . Bring down malaria morbidity . Prevention of death due to malaria . Consolidation of gain achieved so far Selection Of Phc-criteria . API>2 for last 3 yrs . P . Falciparum >30% of cases . 25% tribal population . Death due to malaria

126. MAIN COMPONENTS • Early case detection and treatment • Selective vector control and personal protection • Health education and community participation PLAN OF ACTION • Synthetic pyrethroids • Bed nets • Rapid diagnostic kits • Arteether injections • Blister packs • Funds for training

127. NATIONAL AN MALARIA PROGRAMME 1999 OBJECTIVES • Reduce malaria morbidity and mortality by 50% TARGETS AND INDICATORS • ABER>10% • API 1.3 or less • 25% reduction in morbidity and mortality by 2010 • 50% reduction in morbidity and mortality by 2012

128. NATIONAL VECTOR BORNE DISEASE CONTROL PROGRAMME • Launched in year 2003-04 • Major vector borne diseases- • Malaria • Filaria • Kala-azar • Japanese Encephalitis • Dengue / Dengue Hemorrhagic fevers • Chikungunya Integrated accelerated action towards • Reducing mortality on account of Malaria, Dengue and JE by half

129. INTENSIFIED MALARIA CONTROL PROJECT Launched in July 2005 with assistance of global fund for AIDS,TB and malaria in NE states,Odisha,Jharkhand and WB. OBJECTIVES: 1-Increase access rapid diagnosis and treatment through community participation 2-Reduce transmission by used of insecticide treated bednets and larvivorous fish 3-Enhance awareness about malaria control 4-To promote community,NGO,private sector participation

130. • Indoor residual spraying or IR S is the process of sprayin g the inside of dwellings with an insecticide to kil l mosquitoes that spread malaria . • The main purpose of IRS is to reduce transmission by reducing the survival of malaria vectors entering houses or sleeping units. Effectiveness of IRS depends on: • Target area • Selection of Insecticides • Change of Insecticide • Insecticide formulations used under NVBDCP 1. DDT( Dichloro-diphenyl-trichloroethane) 2. Organophosphorus (OP) compounds 3. Synthetic Pyrethroids

131. • An insecticide-treated net is a mosquito net that repels, disables and/or kills mosquitoes coming into contact with insecticide on the netting material. There are two categories of ITNs: • • A conventionally treated net is a mosquito net that has been treated by dipping in a WHO-recommended insecticide. • • A long-lasting insecticidal net is a factory-treated mosquito net made with netting material that has insecticide incorporated within or bound around the fibres.

132. • Specific Objectives: Reduce human contact, reduce morbidity, prevent deaths, promote community participation, modalities for social marketing through public-private partnership. • Synthetic Pyrethroids mainly two Deltamethrin(2.5%) at a dosage of 25mg/m2 and cyfluthrin (5%) at 50mg/m2.

133. • Environmental control : Good water management practices are best. Could be Temporary and Permanent. • Biological control : Fishes, Insects, Protozoans, Arthropods, Bacteria, Fungi & viruses. • Genetic control : Genetic Engineering like Transgenic Mosquito. • Chemical control : Given high priority in Operational Measures.

134. : Bacillus thuringiensis and B. sphaericus - Predatory mosquito larvae ( Toxorhynchites ) - Copepods ( Macrocyclops albidus )

135. INTEGRATION UNDER NRHM At Village Level  Monthly meetings of Village Health & Sanitation Committee serve as a platform for health education and counseling of community. Involvement of ASHA as-  Surveillance worker to inform any increase in fever cases including Dengue/ Chikungunya and J.E.  FTD for early detection of suspected malaria cases and treatment.  Linkage between ANC services and prevention & treatment of malaria.  Organizer, motivator and trainer in village level meetings/training workshops.

136. MDG 6 COMBAT HIV/AIDS, MALARIA AND OTHER DISEASES Target 6c: Halt and begin to reverse the incidence of malaria and other major diseases 6.6 Incidence and death rates associated with malaria 6.7 Proportion of children under 5 sleeping under insecticide-treated bed nets 6.8 Proportion of children under 5 with fever who are treated with appropriate anti-malarial drugs

137. • Integrated Disease Surveillance Project(IDSP) - The Project with weekly fever alerts is increasingly providing early warning signals on malaria outbreaks. • Other Vector borne diseases - Dengue & malaria control activities overlap in many Urban areas, Malaria & kala-azar in few districts of Jharkhand. • Reproductive and Child Health - ANC services utilized in distribution of LLINs to pregnant women.

138. • Global Fund for AIDS, TB & Malaria(GFATM) supported Intensified Malaria Control Project( IMCP ): • It was for a period of 5years from July 2005 to June 2010. Implemented in 106 districts in 10 states. • It helped to achieve 23.4% decline in Malaria Incidence. • IMCP-II has been initiated for a period of five years (2010- 2015).

139. • Approved for 5years(March 2009-Dec 2012). Total financial outlay Rs.1000 Crore. • Being implemented in 93 malarious districts of eight states including Andhra Pradesh . • Provides additional Support for procuring ACT, LLIN’s, Provision of additional manpower.

140. ROLL BACK MALARIA • RBM is a global partnership founded in 1998 by (WHO), (UNDP), (UNICEF) and the World Bank with the goal of halving the world's malaria burden by 2010. • It forges consensus among key actors in malaria control, harmonises action and mobilises resources to fight malaria in endemic countries and to improve and support capacity to scale up action against malaria.

141. • RBM's four pillars of action ROLL BACK MALARIA is promoting four main strategies to pursue its goal of halving the world's burden of malaria by 2010. The strategies are evidence-based • Prompt access to treatment • Insecticide-treated mosquito nets (ITNs) • Prevention and control of malaria in pregnant women • Malaria epidemic and emergency response

142. Vaccines developed are basically of three types: • Pre-erythrocytic stage vaccine • Blood stage vaccine and • Transmission blocking vaccine • SPf-66 —1 st malaria vaccine that was tried in clinical trials in 1990s. • RTS,S - Most successful vaccine candidate. • On July 25 th 2015 World's first malaria vaccine got a green light from European drugs regulators who recommended it should be licensed for use in babies in Africa at risk of the mosquito-borne disease. • The shot, called RTS,S or Mosquirix developed by British drugmaker GlaxoSmithKline in partnership with the PAT H Malaria Vaccine Initiative, would be the first licensed human vaccine against a parasitic disease.