Malaria presentation

Introduction, epidemiology, global trends, Indian setting, pathogenesis, life cycle, clinical manifestations, investigations, treatment regimen, prevention.

1. DEPARTMENT OF PAEDIATRICS, OWAISI HOSPITAL AND RESEARCH CENTRE, DECCAN COLLEGE OF MEDICAL SCIENCES, HYDERABAD.

2. HISTORY The name “malaaria” (meaning bad air in Italian) was first used in English in 1740 by H. Walpole when describing the disease. The term was shortened to “malaria” in the 20th century. C. Laveran in 1880 was the first to identify the parasites in human blood. In 1889, R. Ross discovered that mosquitoes transmit malaria. Historical record suggests malaria has infected humans since the beginning of the mankind.

3. Since 2000, substantial progress has been made in fighting malaria. According to the latest estimates, between 2000 and 2015, malaria case incidence was reduced by 41% and malaria mortality rates by 62%. At the beginning of 2016, malaria was considered to be endemic in 91 countries and territories, down from 108 in 2000. Despite this remarkable progress, malaria continues to have a devastating impact on people’s health and livelihoods. Updated estimates indicate that 212 million cases occurred globally in 2015, leading to 429 000 deaths, most of which were in children aged under 5 years in Africa. WHO WORLD MALARIA REPORT 2016

4. Recognising the need to hasten progress in reducing the burden of malaria, WHO developed the Global Technical Strategy for Malaria 2016–2030 (GTS), which sets out a vision for accelerating progress towards malaria elimination. The WHO strategy is complemented by the Roll Back Malaria advocacy plan, Action and investment to defeat malaria 2016–2030 (AIM). Together, these documents emphasise the need for universal access to interventions for malaria prevention, diagnosis and treatment; that all countries 1 should accelerate efforts towards malaria elimination; and that malaria surveillance should be a core intervention.

5. The GTS and AIM also recognise the importance of innovation and research and a strong enabling environment, and share the same global targets for 2030 and the same milestones for 2020 and 2025, as shown in Table 1.1. The time frame of the GTS and AIM is aligned with that of the Sustainable Development Goals (SDGs)

6. GLOBAL MALARIA BURDEN

7. ETIOLOGY 4 species of the genus Plasmodium namely P. viva, P. falciparum, P. ovale, P. malariae are mainly responsible for malaria. Of these, first two account for nearly all the cases of malaria in India. Few cases of P. ovale are reported in Orissa. The disease is not seen 2000 m above sea level and thrives in high humidity with ambient temperature between 20 to 30 degrees centigrade.

8. VECTOR The disease is transmitted by female anopheline mosquito with Anopheles stephensi and Anopheles culicifacies as the main vectors in urban and rural areas, respectively.

9. EPIDEMIOLOGY The disease initially restricted to rural areas of eastern and northeastern state of India has also spread to the central and arid western parts of the country. Thereafter due to unplanned expansion of the megacities and town, urban malaria starting as a minor problem, has expanded to contribute about 10% of total malaria cases. The magnitude of the problem was further enhanced by P. falciparum developing resistance to first- line drug Chloroquine (CQ). CQ resistant falciparum , first detected in northeastern part of India, has spread across. At present about 80 districts of 21 states of India report CQ resistant falciparum malaria.

10. Resistance to second line antimalarial drugs Sulfadoxine- pyrimethamine (SP) has been reported from seven northeastern states, Orissa and few districts of West Bengal. Factors responsible for resistance include unplanned development, deforestation, population movement, infrastructure deficiency, and haphazard use of antimalarial drugs, and presumptive treatment based on clinical signs alone.

11. LIFE CYCLE OF PLASMODIUM Plasmodium species have a complex life cycle that enables them to survive in different cellular environments in the human host (asexual phase) and the mosquito (sexual phase). There is a two- step process in humans, with the 1st phase in hepatic cells (exoerythrocytic phase) and the 2nd phase in the red cells (erythrocytic phase). The exoerythrocytic phase begins with inoculation of sporozoites into the bloodstream by a female anopheles mosquito. Within minutes, the sporozoites enter the hepatocytes of the liver, where they develop and multiply asexually as a schizont .

12. After 1-2 weeks, the liver cells rupture and release thousands of merozoites into the circulation. The tissue schizonts of P. falciparum , P. malariae and apparently P. knowlesi rupture once and do not persist in the liver. There are 2 types of tissue schizonts for P. ovale and P. vivax. The primary type ruptures in 6-9 days, and the secondary type remains dormant in the liver cell for weeks, months, or as long as 5 years before releasing merozoites and causing relapse of infection. The erythrocytic phase of Plasmodium asexual development begins when the merozoites from the liver enters the erythrocytes. Once inside the erythrocyte, the parasite transforms into the ring form, which then enlarges to become a trophozoite . These latter two stages can be identified with Giemsa stain on blood smear, the primary means of confirming the diagnosis of malaria.

13. The trophozoites multiply asexually to produce a number of small erythrocytic merozoites that are released into the bloodstream when the erythrocyte membrane ruptures, which is associated with fever. Over time, some of the merozoites develop into male and female gametocytes that complete the Plasmodium life cycle when they are ingested during a blood meal by the female anopheline mosquito. The male and female gametocytes fuse to form a zygote in the stomach cavity of the mosquito. After a series of further transformations, sporozoites enter the salivary gland of the mosquito and are inoculated into a new host with the next blood meal.

14. PATHOGENESIS Four important pathologic processes have been identified in patients with malaria: Fever Anemia Immunopathologic events Tissue Anoxia

15. Fever occurs when erythrocytes rupture and release merozoites into the circulation. Anaemia is caused by hemolysis, sequestration of erythrocytes in the spleen and other organs, and bone marrow suppression. In contrast to malaria caused by P. ovale, P. vivax and P. malariae, which usually results in parasitemias of less than 2%, malaria caused by P. falciparum can be associated with parasitemia levels as high as 60%. The differences in parasitemia reflect the fact that P. falciparum infects both immature and mature erythrocytes, while P. ovale and P. vivax primarily infect immature erythrocytes and P. malariae infects only mature erythrocytes.

16. Immunopathologic events include excessive production of pro inflammatory cytokines, such as TNF, that may be responsible for most of the pathology of the disease, including tissue anoxia; polyclonal activation resulting in both hypergammaglobulinemia and the formation of immune complexes; and immunosuppression. Cytoadherence of infected erythrocytes to vascular endothelium occurs in P. falciparum malaria and may lead to obstruction of blood flow and capillary damage, with resultant vascular leakage of blood, protein, and fluid and tissue anoxia. In addition, hypoglycaemia and lactic acidemia are caused by anaerobic metabolism of glucose.

17. The cumulative effects of these pathologic processes may lead to cerebral, cardiac, pulmonary, intestinal, renal and hepatic failure.

18. IMMUNITY IN RELATION TO MALARIAL INFECTION Immunity after plasmodium species infection is incomplete. Repeated episodes of infections occur because the parasite has developed a number of immune evasive strategies, such as intracellular replication, vascular cytoadherence that prevents infected erythrocytes from circulating through spleen, rapid antigenic variation, and alteration of the host immune system resulting in partial immune suppression. Several alterations in erythrocyte physiology prevent or modify malarial infection.

19. Erythrocytes containing Haemoglobin S (sickle erythrocytes) resist malaria parasite growth, erythrocytes lacking Duffy blood group antigen are resistant to P. vivax, and erythrocytes containing haemoglobin F (fetal haemoglobin) and ovalocytes are resistant to P. falciparum. In hyper-endemic areas, newborns rarely become ill with malaria, in part because of passive maternal antibody and high levels of fetal haemoglobin. Children from 3 months to 5 years of age have little specific immunity to malaria species and therefore suffer most.

20. RECRUDESCENCE Often due to incomplete treatment some erythrocytic form of parasite survives in human host and only with time it multiplies and produces recurrence of symptoms of malaria. This is especially seen in cases of P. falciparum malaria and is known as recrudescence. It can be seen as long as 10 weeks following treatment.

21. CLINICAL MANIFESTATIONS The usual incubation periods are 9-14 days form P. falciparum, 12-17 days from P. vivax, 16-18 days for P. ovale and 18-40 days for P. malariae. Children and adults are asymptomatic during the initial phase of malaria infection. A prodrome of 2-3 days is noted in some patients during which non specific symptoms, like headache, fatigue, anorexia, myalgia, slight fever and pain in chest, abdomen, and joints, are noted and high index of suspicion is necessary to detect malaria during this time.

22. Fever is most important feature of malaria and comes in paroxysms alternating with periods of fatigue. Febrile paroxysms are characterised by high fever, sweats, nausea, vomiting, diarrhoea, pallor and jaundice. Paroxysms coincide with the rupture of schizonts that occurs in every 48 hours with P. vivax and P. ovale, resulting in fever spikes every other day. Rupture schizonts occur every 72 hours in P. malariae, resulting in fever spikes on every 3rd or 4th day. Periodicity is less apparent with P. falciparum and mixed infections and may not be apparent early on infection, when parasite broods have not yet synchronised.

23. Distinct physical signs may include splenomegaly (common), hepatomegaly and pallor due to anaemia. Typical laboratory findings include anaemia, thrombocytopenia and a normal or low leukocyte count. The ESR is often elevated. Plasmodium falciparum is the most severe form of malaria and is associated with higher density of parasitemia and a number of complications. The most common serious complication is severe anaemia (Hb < 5gm/dL), which also is associated with there malaria species.

24. WHO CRITERIA FOR SEVERE MALARIA, 2000 IMPAIRED CONSCIOUSNESS PROSTRATION RESPIRATORY DISTRESS MULTIPLE SEIZURES JAUNDICE HEMOGLOBINURIA ABNORMAL BLEEDING SEVERE ANEMIA CIRCULATORY COLLAPSE PULMONARY EDEMA

25. Congenital malaria is acquired from the mother prenatally or perinatally and is a serious problem in tropical areas. In endemic areas, congenital malaria is an important cause of abortions, miscarriages, still births, premature births, intrauterine growth retardation and neonatal deaths. Congenital malaria usually occurs in the offspring of a non immune mother with P. vivax or P. malariae infection, although it can be observed with any of the human malaria species. The 1st sign or symptom most commonly occurs between 10 and 30 days of age (range 14 hours to several months). Fever, restlessness, drowsiness, pallor, jaundice, poor feeding, vomiting, diarrhoea, cyanosis and hepatosplenomegaly are primarily noted.

26. DIAGNOSIS Diagnosis of malaria in our country is mainly based on symptoms due to lack of proper infrastructure. With the development of rapid antigen tests, which are cost- effective and does not require expertise considerable reduction of unnecessary treatment is possible. In all cases of malaria all out efforts should be given to diagnose malaria with all possible means before commencing treatment. However, in complicated malaria or malaria with danger signs presumptive treatment may be started before confirmation after collecting blood for examination.

27. Light microscopy of well- stained thick and thin films by a skilled microbiologist has remained the “gold standard” for malaria diagnosis. Thick films are nearly ten times more sensitive for diagnosis of malaria as larger amount of blood is there in a given area as compared to thin films. Species identification is better with thin films as morphology of the parasite and red blood cells are well- preserved.

28. Timing of the sample collection should be as soon as malaria is suspected. It can be collected any time irrespective of fever and not necessarily only at the height of the fever. Collection should be before administration of antimalarials which causes detection of parasites difficult due to its morphological alteration. Smears should be prepared soon after collection which enables adherence of films to the slide and cause minimal distortion of parasites and red cells. In blood collected with anticoagulant films should be prepared within 2 hours for best results.

29. Smear should be examined with 100X oil immersion objective. A minimum of 100 fields should be examined before concluding the slide to be negative. Once negative, samples may be examined for at least three consecutive days where clinical suspicion of malaria persists.

30. RAPID DIAGNOSTIC TESTS Rapid diagnostic tests (RDT) are immunochromatographic (ICT) test to detect Plasmodium specific antigens in blood sample. Test employ monoclonal antibodies directed against targeted parasite antigens.

31. Targeted Antigens in Currently Available RDTs Histidine rich protein- II (HRP-II) is actively secreted by asexual stages and young gametocytes of Plasmodium falciparum but not by mature gametocytes. A metabolic enzyme Parasite lactate dehydrogenase (pLDH) is produced by all four species of Plasmodia, both asexual and sexual (gametocytes) stages, provided they are viable. Monoclonal antibodies produced against this antigen are of three groups. One specific for P. falciparum and the second specific for P. vivax. The other is pan specific antibody which reacts with all the four species of plasmodia, i.e. vivax, falciparum, ovale and malariae but unable to separate them individually.

32. Commercially available kit can detect falciparum, vivax and other malaria but cannot differentiate ovale and malariae malaria. Certain new antigens like Plasmodium aldolase- an enzyme of the glycolytic pathway produced by all four species has been recently developed.

33. Role of RDTs in the Diagnosis of Malaria in our Country. In comparison to high transmission areas, malaria in our country occurs less frequently, in all age groups and almost always symptomatic. Drug resistance including multi drug resistance has started developing in our country is laboratory confirmation of malaria is an essential component of disease management. Expert microscopic diagnosis is available in central level of healthcare system like in metro cities but it is often unreliable and unavailable in areas with poor health facilities. So, RDTs will be useful in following situations in our country.

34. In far away communities with poor healthcare facilities where microscopic diagnosis is not available. Also in areas where laboratory service is inadequate, of an unacceptable standard or not available at odd hours. In places where quality microscope is available, RDTs and microscopy can run in parallel. RDTs will provide rapid or screening diagnosis whereas microscopy reserved for resolution of confusing cases, confirmation of negative result in RDTs with high clinical suspicion of malaria. US FDA has approved RDT with a note that negative results by the RDT in case of high clinical suspicion be confirmed by microscopy. In some cases of severe and complicated malaria peripheral parasitemia may be negative due to sequestration but RDTs are expected to provide evidence of antigenemia.

35. According to the New National Drug Policy of Malaria (2008) that the fever cases clinically suspected for malaria should be preferable investigated for confirmation of malaria by microscopy or RDT so as to ensure full therapeutic dose with appropriate drug to all confirmed cases. So in conclusion RDTs permit on the spot confirmation of malaria even at the peripheral healthcare system by unskilled health worker with minimal training. Rationale use of RDTs as a complement to microscopy might offer following benefits: Early treatment will reduce mortality and morbidity In multi drug resistance areas expensive drugs and drug combination will be given only to those who need them. Avoidance of unnecessary treatment will reduce drug pressure and delay progress of drug resistance.

36. DIFFERENTIAL DIAGNOSIS The differential diagnosis of malaria is broad and includes viral infections such as influenza and hepatitis, sepsis, pneumonia, meningitis, encephalitis, endocarditis, gastroenteritis, pyelonephritis, brucellosis, leptospirosis, tuberculosis, typhoid fever, amoebic liver abscess, Hodgkin disease and collagen vascular diseases.

37. BASIS OF ANTIMALARIAL TREATMENT Malaria in children has some unique features. Young children below 5 years whose passive immunity wanes and as yet to develop sufficient immune of their own are most vulnerable. Falciparum malaria can be rapidly progressive and can develop rapid clinical deterioration hence this group needs constant monitoring. Children can tolerate antimalarial drugs better than adults and their symptoms resolve more quickly following successful treatment.

38. The main aim of antimalarial treatment in children, which is also the basis of National Antimalarial Programme, is to prevent morbidity and mortality by early diagnosis and prompt treatment (EDPT). Unfortunately in our country prompt treatment is mostly presumptive based on clinical diagnosis. It is interesting to note that in the year 2000 out of 86.46 million blood smear examination throughout the country on presumptive diagnosis of malaria, slide positivity rate (SPR) was found to be only 2.32%. Extrapolating from this data, it is evident that the use of presumptive treatment of malaria has the potential to facilitate resistance by greatly increasing the number of patients who are treated unnecessarily.

39. Treatment Regimen of Uncomplicated Malaria Treatment regimens are to be tailored specifically according to the resistance pattern of the region under consideration. According to the Directorate General of Health Services, National Vector Borne Disease Control Programme ACT (AS+SP) combination in falciparum malaria is being implemented in 117 districts (i.e. 50 highly endemic districts of states namely Andhra Pradesh, Chattisgarh, Jharkhand, Madhya Pradesh and Orissa + 67 in Northeastern states) in addition to 253 PHCs of 46 districts included on the basis of chloroquine resistance status. However, in view of gradually increasing resistance it has been suggested that all falciparum cases may be treated with ACT both in public and private health care system to win the war against on going drug resistance.

40. DRUG SENSITIVITY RECOMMENDED TREATMENT P. vivax and chloroquine sensitive P. falciparum Chloroquine 10 mg base/kg stat orally followed by 5 mg/kg at 6, 24 and 48 hours ( total dose 25 mg/kg) OR Chloroquine 10mg/ kg base stat orally followed by 10mg/kg at 24 hours and 5 mg/ kg at 48 hours (total 25mg/kg base). In case of vivax malaria to prevent relapse Primaquine should be given in a dose of 0.25 mg/kg once daily for 14 days. In case of falciparum malaria a single dose of primaquine (0.75 mg/kg) is given for gametocytocidal action. RECOMMENDED TREATMENT IN CHLOROQUINE SENSITIVE MALARIA * Chloroquine should not be given on empty stomach and in high fever. Bring down the temperature first. If vomiting occurs within 45 minutes of a dose of CQ that particular dose is to be repeated after taking care of vomiting by using antiemetic. As Primaquine can cause haemolytic anaemia in children with G6PD deficiency, they should be preferably screened for the same prior to starting treatment. As infants are relatively G6PD deficient it is not recommended in this age group and children with 14 days regimen should be under close supervision to detect any complication. In cases of borderline G6PD deficiency once weekly dose of primaquine 0.6-0.8 mg/kg is given for 6 weeks.

41. ANTIMALARIAL COMBINATION THERAPY To improve outcome and halt the threat of resistance to mono therapy WHO recommends combination of antimalarials for the treatment of falciparum malaria. Antimalarial combination therapy is simultaneous use of two or more blood schizonticidal drugs with independent mode of action and thus unrelated biochemical target in the parasite. To reap the benefit of combination therapy the partners should be individually effective. This mutual protection will prevent or at least delay emergence of resistance to individual drugs.

42. According to WHO, one of the partners in combination therapy will be Artemisinin and its derivatives hence known as artemisinin- based combination therapy (ACT). The reason for choosing artemisinin is its rapid clearance of parasitemia and resolution of symptoms. They reduce the parasite number by approximately 10,000 (10 4 ) in each asexual cycle. The second important reason is its rapid elimination from the body so that the residual concentration of the drug doesn’t provide a selective filter for resistant parasites. The other reason being its lack of serious adverse effects and absence of significant resistance till date.

43. In 3 days ACT regimen artemisinin is present in the body during two asexual parasite life cycles each lasting for 2 days. This treatment reduces the number of parasites in the body by a factor approximately one hundred million (10 4 X 10 4 = 10 8 ). The complete clearance of the parasites is dependent on the partner medicine being effective and persisting at parasiticidal concentration until all the infecting parasites have been killed. Thus the partner compound is to be relatively slowly eliminated. As a result of combination therapy the artemisinin component is protected from resistance by the partner medicine provided it is efficacious and partner medicine is in turn protected by the artemisinin derivative.

44. The following ACTs are currently available in our country: Artesunate (AS) + SP Artesunate + MQ Artesunate + Lumefantrine Of these Artesunate + Lumefantrine is available as co-formulated tablets and lumefantrine is not available as mono therapy. So it has been never used alone for the treatment of malaria. Other combinations are available separately.

45. DRUG SENSITIVITY RECOMMENDED TREATMENT CQ resistant P. falciparum Artesunate 4 mg/kg of body weight orally once daily for 3 days and a single dose administration of SP as 25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine on day 1 OR Artesunate as above and mefloquine 25 mg/kg of body weight in two divided doses (15 mg/kg and 10 mg/kg) on day 2 and day 3. OR Co-formulated tablets containing 20 mg of artemether and 120 mg of lumefantrine can be used as a six dose regimen orally twice a day for 3 days. For 5-14 kg body weight 1 tablet at diagnosis, again after 8-12 hours and then daily on day 2 and day 3. For 15- 24 kg body weight same schedule with 2 tablets. For 25- 35 kg body weight and above same schedule with 3 and 4 tablets respectively. A single dose of Primaquine (0.75 mg/kg) is given for gametocytocidal action. Recommended treatment in CQ resistant P. falciparum * Currently there are insufficient safety and tolerability data on mefloquine at its recommended dosage 25 mg/kg body weight in children. Mefloquine shares cross resistance with Quinine which is still an active drug in our country. Health planners of our country do no advocate use of mefloquine. Advantage of artemether/ lumefantrine combination is that lumefantrine is not available as mono therapy and has never been used alone for the treatment of malaria. Lumefantrine absorption is enhanced by co-administration with fatty food like milk.

46. DRUG SENSITIVITY RECOMMENDED TREATMENT Multi-drug resistant P. falciparum, i.e. both to CQ and SP Quinine 10 mg salt/kg/dose orally three time daily for 7 days + Tetracycline (above 8 years) 4 mg/kg/dose 4 time daily for 7 days. OR Doxycycline (above 8 years) 3.5 mg/kg once a day for 7 days. OR Clindamycin 20 mg/kg/day in two divided doses for 7 days. In case of developing Chinconism, Quinine 10 mg salt/ kg/ dose orally 3 times daily for 3- 5 days + Tetracycline (above 8 years) 4 mg/kg/dose 4 time daily for 7 days. OR Doxycycline (above 8 years) 3.5 mg/kg once a day for 7 days. OR Clindamycin 20 mg/kg/day in two divided doses for 7 days. OR Artemether/ Lumefantrine combination orally as mentioned above. OR Artemether/ Mefloquine combination orally as mentioned above. A single dose of primaquine above 1 year age (0.75 mg/kg) is given for gametocytocidal action. Recommended treatment of Multi drug resistant P. falciparum (both to CQ & SP) * Doxycycline is preferred to tetracycline as it can be given once daily and does not accumulate in renal failure. One of the drawbacks of quinine therapy is its long course. Unsupervised and ambulatory setting may decrease patients compliance and many patients might not complete the full course of prescribed therapy. Fortunately children tolerate quinine better than adults.

47. MANAGEMENT OF SEVERE MALARIA IN CHILDREN Severe life-threatening malaria is nearly always due to P. falciparum. All cases with severe manifestations are to be treated in the same line of complicated malaria with injectable antimalarials irrespective of the species. High degree of suspicion of severe malaria is of utmost importance and any delay in initiation of treatment can be fatal. It should be treated as a medical emergency at highest level of facility available preferable in an intensive care setting. Confirmation of the diagnosis is preferable but one should not delay the treatment if it needs more than an hour. Effective therapy in children with severe malaria includes antimalarial chemotherapy, supportive management and management of complications. All these three interventions are equally important and to be taken care of simultaneously.

48. DRUG DOSAGE Quinine 20 mg salt/kg (loading dose) diluted in 10 ml of isotonic fluid/ kg by infusion over 4 hours, then 12 hours after the start of loading dose give a maintenance dose of 10 mg salt/ kg over 2 hours. This maintenance dose should be repeated in every 8 hours, calculated from beginning of previous infusion, until the patient can swallow, then quinine tablets, 10 mg salt/kg 8 hourly to complete a 7 day course of treatment (including both parenteral and oral). Tetracycline or Doxycycline or Clindamycin is added to quinine as soon as the patient is able to swallow and should be continued for 7 days. If controlled IV infusion cannot be administered the quinine salt can be given in the same dosages by IM injections in the anterior thigh (not in buttock). The dose of the quinine should be divided between two sites, half the dose in each anterior thigh. If possible, IM should be diluted in normal saline to a concentration of 60-100 mg salt/mL (quinine is usually available as 300 mg/mL). Tetracycline or Doxycycline or Clindamycin should be added as above. Artesunate 2.4 mg/kg IV stat then at 12 and 24 hours, then once a day. Parenteral antimalarials should be used for a minimum of 24 hours, once started irrespective of the patients ability to swallow oral medication and thereafter, complete the treatment by giving a course of: Artemether + Lumefantrine Artesunate + SP Artemether 3.2 mg/kg (loading dose) IM, followed by 1.6 mg/kg daily. Parenteral antimalarials should be used for a minimum of 24 hours, once started irrespective of the patients ability to swallow oral medication and thereafter, complete the treatment by giving a course of: Artemether + Lumefantrine Artesunate + SP DRUG AND DOSAGE OF ANTIMALARIALS IN COMPLICATED AND SEVERE MALARIA * Loading dose of quinine should not be used if the patient has received quinine, quinidine or mefloquine within preceding 12 hours. Alternatively, loading dose can be administered as 7 mg salt/kg IV infusion over 30 minutes, followed immediately by 10 mg salt/kg diluted in 10 mL isotonic fluid/ kg by IV infusion over 4 hours. Quinine should not be given by bolus or push injection. Infusion rate should not exceed 5 mg salt/ kg/ hour. If there is no clinical improvement after 48 hours of parenteral therapy the maintenance dose of quinine should be reduced by one-third to one-half, i.e. 5-7 mg salt/kg. Quinine should not be given subcutaneously as this may cause skin necrosis. Artesunate 60 mg/ampoule is dissolved in 0.6 mL of 5% sodium bicarbonate diluted in 3-5 mL with 5% dextrose and given immediately by IV bolus. Artemether is dispensed in 1 mL ampule containing 80 mg of artemether in peanut oil.

49. SUPPORTIVE MANAGEMENT Rapid clinical assessment with respect to level of consciousness (use Blantyre coma scale), blood pressure, rate and depth of respiration, anaemia, state of hydration and temperature. Thick and thin blood smears should be made. Minimal investigation should include packed cell volume (PCV), blood glucose and lumbar puncture especially in cerebral malaria. If LP is delayed proper ABX cover for meningitis must be given. ABX may also be considered if any secondary infection is suspected, which is common in severe malaria. Start IV antimalarials after drawing blood. Good nursing care with proper positioning, meticulous attention to airways, eyes, mucosa and skin should be done. Appropriate fluid therapy is to be given. For unconscious patients nasogastric tube is to be inserted to reduce the risk of aspiration.

50. Oxygen therapy and respiratory support is to be given if necessary. In case of shock resuscitate with normal saline or Ringer lactate by bolus infusion. Avoid under or over hydration. Convulsions should be treated with Diazepam. Hyperpyrexia should be treated with tepid sponging, fanning and paracetamol. Close monitoring of the vital signs preferably every 4 hours to be done till the patient is out of danger. Also maintain intake output chart and watch for hemoglobinuria. Monitoring of the response to treatment is essential. Detail clinical examination with particular emphasis on hydration status, temperature, pulse, respiratory rate, blood pressure and level of consciousness is to be given. Blood smear examination on every 6-12 hours for parasitemia for first 48 hours is needed.

51. In case of quinine parasite count may remain unchanged or even rise in first 18-24 hours which should not be taken as an indicator of quinine resistance. However, parasite count should fall after 24 hours of quinine therapy and should disappear within 5 days. In case of artemisinin derivatives parasite count usually comes down within 5-6 hours of starting therapy. Asexual parasitemia generally disappears after 72 hours of therapy. Poor prognosis is suggested by high parasite densities (above 5% RBC infected or parasite density >250000/ uL). At any parasitemia prognosis worsens if there is predominance of more parasite stages. If more than 20% of the parasite contain visible pigment (mature trophozoites and schizonts) the prognosis worsens. Poor prognosis is also indicated if more than 5% of the peripheral blood polymorphonuclear leukocyte contain visible malaria pigment. In follow- up cases add iron and folic acid.

52. MANAGEMENT OF COMPLICATIONS OF MALARIA Of the various complication of falciparum malaria the common and important ones in children as follows: Cerebral Malaria Severe anemia Respiratory distress (acidosis) Hypoglycaemia

53. Cerebral Malaria Initial presentation is usually fever followed by inability to eat or drink. The progression to coma or convulsion is usually very rapid within one or two days. Convulsions may be very subtle with nystagmus, salivation or twitching of an isolated part of the body. Effort should be given to exclude other treatable causes of coma (e.g. bacterial meningitis, hypoglycaemia). Patients should be given good nursing care, convulsions should be treated with diazepam/ midazolam and avoid harmful adjuvant treatment like corticosteroids, mannitol, adrenaline and phenobarbitone.

54. Severe Anaemia Children with hyper parasitemia due to acute destruction of red cells may develop severe anaemia. Packed red cell transfusion should be given cautiously when PCV is 12% or less, or haemoglobin is below 4 gm%. Transfusion should also be considered in patients with less severe anaemia in the presence of respiratory distress (acidosis), impaired consciousness or hyper parasitemia. (>20% of RBCs infected)

55. Lactic Acidosis Deep breathing with in drawing of lower chest wall without any localising chest signs suggests lactic acidosis. It usually accompanies cerebral malaria, anaemia or dehydration. Correct hypovolemia, treat anaemia and prevent seizures. Monitor acid base status, blood glucose and urea and electrolyte level.

56. Hypoglycaemia It is common in children below 3 years especially with hyper parasitemia or with convulsion. It also occurs in patients treated with quinine. Manifestations are similar to those of cerebral malaria so it can be easily overlooked. Monitor blood sugar on every 4-6 hours. If facilities to monitor blood glucose are not available assume hypoglycaemia in symptomatic patient and treat accordingly. Correct hypoglycaemia with IV dextrose (25% dextrose 2-4 ml/kg by bolus) and it should be followed by slow infusion of 5% dextrose containing fluid to prevent recurrence.

57. Hyperpyrexia High fever is common in children and may lead to convulsion and altered consciousness. Tepid sponging, fanning and paracetamol 15 mg/kg should be given.

58. Hyper parasitemia It is specially seen in non- immune children associated with severe disease. Consider exchange transfusion/ cytapheresis if greater than 20% of RBCs are parasitised.

59. Circulatory Collapse (Algid Malaria) In case of circulatory collapse suspect gram negative septicaemia, send blood cultures before starting antibiotics. Resuscitate with judicious use of fluids.

60. Spontaneous Bleeding and Coagulopathy (DIC) Usually seen in non-immune children which should be treated with vitamin- K, blood or blood products as required.

61. Prevention One of the main pillars of prevention is vector control which may be by chemical control, biological control and personal protective measure taken up by individuals or community. Indoor spraying has been there for a long time but mosquitoes developed resistance to it. Aerosol spray at day time and fogging with malathion are other methods of chemical control. Use of mosquito larvivorous fish in tanks and other water bodies where mosquitoes breed are ways of biological control. As mosquito bites from dusk to dawn, evening use of repellant cream, coils, and mats are effective in preventing bite and also wearing long sleeve clothes are helpful. Sleeping under insecticide treated bed-nets of breeding places, proper storage of water and reducing of unplanned construction will go in a long way to prevent mosquito breeding. Finally it is the participation of the community in these activities is essential.

62. Chemoprophylaxis Chemoprophylaxis is necessary for all visitors to and residents of the tropics who have not lived there since infancy, including children of all ages. Healthcare providers should consult the latest information on resistance patterns before prescribing prophylaxis for their patients. CQ is given in the few remaining areas of the world free of CQ resistance. In areas where CQ resistance is seen, Atovaqoune- proguanil, mefloquine or doxycycline may be given as chemoprophylaxis.

63. Malaria Vaccine Despite considerable effort it seems a good vaccine against malaria is far from reality. A number of liver- stage antigen including circumsporozoites protein of P. falciparum were developed as vaccine candidate but none proved to be effective. Of the blood stage vaccine, SPf66 developed in Columbia which contains a mixture of synthetic peptides of sporozoites and ring infected erythrocytes showed some promise initially but failed in trials conducted in Africa. Transmission blocking vaccines directed against gametocytes are also in the line. Finally multi stage vaccines are also under study but none of the report shows any hope in near future.

64. –TOM FRIEDEN “Our progress against malaria is impressive. But vigilance remains a critical ingredient to protect the health of all people.”