NEW CONCEPTS IN THE MANAGEMENT OF MALARIA

1. NEW CONCEPTS IN THE MANAGEMENT OF MALARIA

2. INTRODUCTION • Malaria is an ancient scourge of humanity. Although almost eradicated from the industrialized nations, malaria continues to extract a heavy toll of life and health in a substantial part of the world. Almost half the world's population lives in countries where the disease is endemic, and almost every country in the world encounters imported malaria. Malaria is the number one cause of morbidity in the countries of Africa and one of the major contributors to childhood deaths and the leading cause of mortality in the vulnerable group (children less than five years and pregnant women) in Sub-Saharan Africa.

3. The WHO estimated that about 2100 million people are at risk from Malaria, and the disease kills about 2 million people every year. (Half of these being children less than 5 years old). In addition, 3000 people die from malaria each day, ten new cases occurring every second. • Malaria is reported to account for ten percent of Africa’s disease burden. Five hundred and fifty cases are estimated to occur annually (75% stable transmission, 17% epidemic, 8% unstable transmission and non-malarial transmission areas). • Incidentally, 80% of malaria cases and 90% of deaths are recorded in Africa. They die because they lack access to health care, life-saving drugs and insecticide-treated –bednets.

5. ETIOLOGY • Malaria in humans is caused by plasmodium. .The species include • P falciparum; • P. malariae, • P. ovale, • P. vivax. • Transmission depends on the presence of and relationship between the three epidemiological factors. • Reservoir- man (for human plasmodia) • Agent of Infection- gametocytes of plasmodium • Vector of transmission- Anopheles mosquito

7. ETIOLOGY contd • It is however worthy of note that transmission of the parasite can also be transplacentally acquired and by blood transfusion

8. PATTERNS OF MALARIA ENDEMICITY • Stable Malaria- Malaria is transmitted all year round, but may have seasonal variation. Adults living here may acquire some immunity and are hence unlikely to develop severe malaria • Unstable Malaria- It is characterized by intermittent transmission that may be bi-annual or variable epidemic due to poor immunity against malaria • Malaria free-areas- No immunity whatsoever, hence all are prone to severe malaria

9. PROBLEMS OF MALARIA • -Increase in school absentism • -Low Birth Weight of babies of Infected mothers with risk of mortality in children, -Adolescents and pregnant women - Increasing resistance to commonly used drugs -Poor reporting

10. CLINICAL FEATURES • PATHOPHYSIOLOGY • LIFE CYCLE • Consist of 2 phases • 1.)Asexual Phase • 2.)Sexual Phase • These phases should however be well understood because various drugs used in the management of malaria are directed at specific forms of parasite in the two phases.

11. ASEXUAL PHASE • The bite of an infected mosquito introduces asexual forms of the parasite, called sporozoites, into the bloodstream. Sporozoites enter the hepatocytes and form schizonts, which are also asexual forms. Schizonts undergo a process of maturation and multiplication known as preerythrocytic or hepatic schizogony. • The bite of an infected mosquito introduces

12. In Plasmodium vivax and Plasmodium ovale infection, some sporozoites convert to dormant forms called hypnozoites, which can cause disease after months or years. Preerythrocytic schizogony takes 6-16 days, and results in the host cell bursting and releasing thousands of merozoites into the blood.

13. Relapses and recrudescences occur and may vary depending on the species of Plasmodium involved. P vivax and P ovale both give rise to hypnozoites in the liver. P vivax malaria may relapse for up to 3 years and P ovale for 1-1.5 years. P falciparum and P malariae do not form hypnozoites, so they do not have true relapses

14. However, the disease recrudesces because of surviving erythrocytic forms. While P falciparum can recrudesce for up to 1 year, P malariae may continue to cause clinical malarial attacks even 20 years after the original infection. Only the sporozoites (introduced by the mosquitoes themselves) can penetrate the liver cells.

15. Thus, if malaria is acquired by blood transfusion or transplacentally, no infection of the liver occurs and relapses do not occur.

16. Merozoites enter the erythrocytes and initiate another asexual reproductive cycle, known as erythrocytic schizogony. The parasite passes successively through the stages of trophozoite and schizont, ultimately giving rise to several merozoites. On maturation of these merozoites, the erythrocyte ruptures, releasing the merozoites and multiple antigenic and pyrogenic substances into the bloodstream.

17. These pyrogens stimulate the blood macrophages and endothelial cells to produce cytokines, the cause of fever. These merozoites again infect new erythrocytes. After a few cycles of this erythrocytic schizogony, some merozoites differentiate into the sexual forms: the male and female gametocytes.

18. SEXUAL PHASE • The merozoites destined to become male and female gametes differentiate into micro gametes and macro gametes respectively. Further development results in the formation of male and female gametocytes, when taken up by mosquito during a blood feed, the male and the female gametes fuse in the stomach of the mosquito.A Zygote is formed which develop through stages of ookinetes , oocytes and sporozoites. The latter moves to the salivary gland of the mosquito where they are inoculated into man to recommence the asexual cycle.

19. Incubation Period • Incubation period in malaria covers the time between infection and the first appearance of clinical signs. The length of the incubation period is usually between 9 and 30 days, depending on the infecting species (shortest for P.falciparum, longer for P.malariae). In some strains of P.vivax (P.v.hibernans) the incubation period may last some 8-9 months

20. RISK FACTORS • 1 ENVIRONMENTAL FATORS • The environment in Nigeria is favourable for transmission • Rain the amount of rain and the number of rainy days are important- 10 cm • Low Altitude 200m meters above sea level • High temperature 20-28 0C • High humidity 60% • 2. RACIAL FACTOR: People of all races are affected, with some exceptions. People of West African origin who do not have the Duffy blood group are not susceptible to P vivax malaria.

21. 3. AGE FACTOR: Partial immunity is developed after repeated attacks ofmalaria. Thus, older children and adults often have asymptomatic parasitemia, i.e, presence of plasmodia in the bloodstream without clinical manifestations of malaria. Most deaths resulting from malaria occur in children younger than 5 years. • 4. NUTRITIONAL FACTOR: Ironically malnourished children are noticed to have a lower incidence of cerebral malaria due to reduced amounts of ICAM-1 and CD46 on their cerebral endothelial cells to which the P. falciparum infected red blood cells bind

22. OTHERS • Socio-economic conditions like large scale population movements eg labour force coming from endemic areas to develop project areas. • Immune status as in Pregnancy

23. CLASSIFICATION OF MALARIA • Malaria can be classified into two main types • Simple / uncomplicated malaria.: This is a type of malaria that has no life threatening manifestation • Severe / complicated malaria.: Malaria with life threatening manifestation and complication.

24. CLINICAL FEATURES OF SIMPLE / UNCOMPLICATED MALARIA • It is often an acute disease, which clinically normally presents with • Fever. • Chills • Profuse sweating • Headache • Aching joints • General discomfort

25. CLINICAL FETAURES OF SEVERE MALARIA • A change of behaviour (confusion or drowsiness) • Altered consciousness or coma +++ • Multiple convulsions +++ • Hypoglycemia ++ • Severe Anaemia (haematocrit <20% or HB <5g/dl) ++ • Haemoglobinuria (coca-cola coloured urine) + • Jaundice + • Prostration +++ • Acidosis + • Oliguria or acute renal failure ± • Difficulty in breathing or pulmonary oedema ± • Circulation collapse or shock + • Bleeding tendency ± • Hyperpyrexia ++ • Hyperparasitemia ++ • Persistent vomiting ++ • An individual patient may have any one or any combination of complications listed above

26. FORMS OF SEVERE MALARIA • CEREBRAL MALARIA • ANAEMIA IN MALARIA • MALARIA NEPHROPATHY • ALGID MALARIA • BLACK WATER FEVER • CONGENITAL MALARIA

27. CHAPTER 2 • DIAGNOSIS AND PREVIOUS MANAGEMENT POLICY IN THE TREATMENT OF MALARIA

28. DIAGNOSIS • History: • General information as age, place of residence, history of travel within and outside the country • Main manifestation is FEVER. Clinical features vary from asymptomatic to mild to severe disease • Enquire about the following symptoms: • Characteristic history of fever associated with chills (feeling cold in older children), rigors (shaking of the body), or history of fever within the last two days prior to presentation, headache, joint weakness or tiredness • Also ask for the symptoms of other common childhood diseases • -cough, diarrhoea, ear pain and skin rashes within the last three months

29. Physical Examination • -Increased body temperature >37.20C • -Pallor • -Enlarged spleen ± liver • * In children under five, a clinical diagnosis is often sufficient for uncomplicated malaria. This is to forestall undue delay in commencing treatment. Malaria can be rapidly fatal in this age group.

30. Management • Establish an intravenous infusion • Correct hypoglycemia if present; 10% DW IV, 2-3 ml/kg over 1-2 minutes. Recheck blood glucose after 30 minutes and throughout course of management. • Assess fluid req. based on patients weight and set up appropriate volume to run in 1st 4 hours • Add the correct antimalarial drug in the correct dose according to the patients weight to the infusion fluid

31. Reduce body temperature • give paracetamol orally 20mg/kg/ dose • give paracetamol suppository • tepid sponge • expose to fan • Control convulsions • use paraldehyde IM 0.1 ml/kg /yr of life up to 5 mls • IV diazepam (titrated) • 7.).Consider the need for blood transfusion (PCV <15% /Hb <5gm/dl) • 8.) Decide whether a urinary catheter should be passed

32. . Lab Studies: • Take samples for PCV, E&U, blood smear for MP, LP, WBC, ESR • Examination of blood smear • Demonstration of the parasite in a smear of the blood definitely establishes the presence of malaria.

33. The presence of the asexual form must be established • A negative finding on examination does not rule out malaria. Only 50% of children with malaria are smear positive, even on repeated examination. • A positive finding on examination does not confirm malaria, especially in patients from an endemic area, in whom asymptomatic parasitemia often exists. • Both thick and thin films are essential. If the parasitemia is light, a thin film examination may miss the diagnosis. Thick films save time in diagnosis of scanty infections but make species identification of the parasite difficult. • Blood sample must be examined 8-12 hourly and only 3 consecutive negative samples are acceptable

34. Criteria suggestive of P. falciparum infection • Prominent non-pigmented ring forms • Double chromatin • Diagnostic crescent shaped gametocytes • The infected red cells are not enlarged and are without the pink stippling (Schuffner dots).

35. Enumeration of malaria parasite • In addition to definitive diagnosis of malaria and diagnosis of the specie of malaria parasites, microscopical examination also enables their number in a unit volume of blood to be determined. This becomes important for diagnosis, prognosis and follow-up. • OTHER TESTS INCLUDE • Serological tests • Dipstick tests • Molecular biological detection tests • Lumbar puncture is indicated to rule out meningitis in cerebral malaria and febrile seizures with malaria. • Severe P falciparum malaria is often associated with hypoglycemia. Lower blood glucose levels are associated with higher mortality rates.

36. PREVIOUS NATIONAL ANTIMALARIA TREATMENT GUIDELINES • The latest (2006) management guideline was released few weeks ago by WHO. The policy currently in use in Nigeria was adopted Feb, 2005. It is however important to highlight previous antimalarial drugs that were used before 2005. • These drugs are grouped into 2; • For simple / uncomplicated malaria • For severe / complicated malaria

37. Previous Classification of drugs for Simple malaria • First line drugs- chloroquine • Second line drugs- Amodiaquine, sulphadoxine+Pyrimethamine(Fansidar) • Third line drugs- Mefloquine,Halofantrine,Artemisinin and its derivatives

38. CHLOROQUINE. This was given orally and first dose in the presence of an health worker • Dose 1ST DAY: 10mg/kg • 2nd DAY: 10mg/kg • 3 rd DAY: 5mg/kg • It was effective against the erythrocytic forms of the parasite. It is not effective against hypnozoites. However, P falciparum developed widespread resistance to chloroquine. • It was only given parenterally where there was repeated vomiting despite measures to reduce vomiting • Interactions there were possible delayed or reduced absorption with co administration of antacids containing magnesium; cimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones) • Pregnancy - Safety for use during pregnancy was not established

39. SULFADOXINE/PYRIMETHAMINE (SP). • was used as a second line drug in CQ sensitive areas but as an alternative to first line in CQ resistant areas or in Px unable to tolerate CQ. Cannot be used in potentially severe cases being slowly acting • It has no activity against hypnozoites and gametocytes. • It is contra indicated in pregnancy. • c.)HALOFANTHRINE • was a 3rd line drug in CQ and SP failures. It is cardio toxic. Its absorption may be erratic following oral administration but better absorbed after a fatty food. • was contraindicated in involvement of a cardiac disease.

40. d.) Artemisinin & its derivatives. • their use was restricted to the management of severe malaria • were used as 3rd line drugs in CQ failure, SP failure orally. • Monotherapy was given over 5-7 days and compliance was ensured.

41. PRIMAQUINE • It was the only drug in clinical use that destroyed hypnozoites of both P vivax and P ovale, and so was used for the radical cure of the relapsing malarias. It is also gametocidal against all 4 species of human plasmodia and was used to render patients noninfectious. • Contraindicated in G6PD deficiency. • Other drugs used- • proguanil, tetracycline, quinidine and erythromycin. • e.) Combination therapy used include • Artemisinin+ SP • Artemisinin+ mefloquine • SP+ Chloroquine • SP+ Quinine

42. DRUGS FOR SEVERE MALARIA • A. Quinine[IV or IM] • 20mg/kg in 4.3% dextrose in 0.18 normal saline over 4 hours. Then, 12 hours after the start of the loading dose, give 10mg\kg over 4 hours every 12 hours until the patient can tolerate orally. • Change to Quinine tablets 10mg\kg every 8hours to complete 7 days of treatment or give a single dose of SP. • SUMMARY • DAY 1- 30-40mg\kg • DAY 2- 30mg\kg • DAY 3- 15mg\kg • IM sites- anterior thighs.

43. B. Artemisinin derivatives • As an alternative to quinine in the treatment of severe malaria. • Dosage • Artesunate: 2.4mg\kg IV bolus, repeat 1.2mg\kg after 12 hours and then 1.2mg\kg daily for 6 days. The daily dose was changed to oral if the patient is able to swallow. • Artemether: 3.2mg\kg loading IM, followed by 1.6mg\kg daily for 6days. The daily dose was changed to oral if the patient is able to swallow.

44. THEREASON FOR A CHANGE TO NEW TREATMENT MODALITIES

45. If our previous modalities of treatment were as effective as it used to be, today we will not be talking about the need for change to a different modality of treatment. Recent estimates of the global malaria burden have shown increasing levels of malaria morbidity and mortality, reflecting the deteriorating malaria situation in Africa. • Taking note of the very high morbidity and mortality rate as well as the huge economic burden malaria has caused Africa, African leaders met in yr 2000 at Abuja to declare and rededicate themselves to reducing the burden of malaria in Africa by at least half by year 2010 through “ROLL BACK MALARIA” PROGRAMME.

46. Key among the factors contributing to the increasing malaria mortality and morbidity is the widespread resistance of Plasmodium falciparum to inexpensive monotherapies, such as. sulfadoxine–pyrimethamine (SP), amodiaquine, and chloroquine, which still remains the cheapest and most affordable drug. Drug resistance has been implicated in the spread of malaria to new areas and re-emergence of malaria in areas where the disease had been eradicated. P falciparum still remains the commonest cause of malaria in Nigeria.

47. DRUG RESISTANCE • Drug resistance in malaria is the ability of the parasite strain to survive or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance of the subject. This definition was later modified to specify that the drug in question must “gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action

48. A distinction must be made between a failure to clear malarial parasitaemia and true antimalarial drug resistance. While drug resistance can cause treatment failure, not all treatment failure is due to drug resistance. • Causes of Treatment failure include • Incorrect Dosing • Poor Compliance to duration of dosing Regimen • Poor Drug Quality • Drug interaction • Poor absorption • Presumptive treatment for malaria • Misdiagnosis • non absorption of the right dose e.g. in frequent vomiting • Handling and storage of the drugs

49. Mechanisms of antimalarial resistance • In general, resistance appears to occur through spontaneous mutations that confer reduced sensitivity to a given drug or class of drugs. For some drugs, only a single point mutation is required to confer resistance, while for other drugs, multiple mutations appear to be required. Provided the mutations are not deleterious to the survival or reproduction of the parasite, drug pressure will remove susceptible parasites while resistant parasites survive.

50. Chloroquine Resistance • Chloroquine resistance has been reported from all falciparum endemic areas with the exception of Central America and the Caribbean. In Africa, Chloroquine resistance was first detected in Tanzania, in the late 1970s and has since spread and intensified across the continent. • .