Treatment of malaria in children.SB Bavdekar, UB Nadkarni, CT Deshmukh
Department of Pediatrics, Seth G S Medical College & KEM Hospital, Parel, Mumbai.
Keywords: Age Factors, Antimalarials, classification,pharmacology,therapeutic use,Child, Drug Resistance, Human, Malaria, drug therapy,parasitology,Patient Selection,
Malaria is acknowledged to be by far the most important tropical parasitic disease, causing great suffering and loss of life. More than two billion people, nearly 40% of the world's population are at risk. The major load of morbidity and mortality due to malaria is borne by young children before they have developed certain degree of immunity to the disease. The treatment of malaria has to keep pace with the evolution of resistance acquired by malarial parasites. Plasmodium falciparum, which is responsible for causing severe forms of the disease, is also adept at developing resistance to drugs thereby decreasing their efficacy in treatment over a period of lime.
Chloroquine: Chloroquine, a 4-aminoquinolone drug, has been the mainstay of therapy for over 25 years. However. widespread resistance of falciparum to this drug has been a major factor limiting its usefulness. For sensitive forms it is an effective schizonticidal drug and is also effective against mature gametocytes of Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. It probably acts by forming a complex with ferriproloporphyrin IX (FP IX) formed during digestion of haemoglobin. The complex of chloroquine and FP IX does not allow the parasite to sequester FP IX, which is a membranolytic agent potentially toxic to the parasite . The mechanism by which parasites develop resistance to chloroquine is not known but is probably related to lack of FP IX production or efficient sequestration of FP IX even in presence of chloroquine .
Chloroquine resistance was first detected almost simultaneously in Colombia and Thailand in 1961. Following this the resistance has spread to almost all areas where P. falciparum is seen. The only exceptions being areas of Arabia and South America. Most strains of P. vivax, P. malariae and P. ovale have remained sensitive to chloroquine even after years of exposure. Though, vivax malaria resistant to treatment and prophylaxis with chloroquine was reported , such resistant strains seem to be restricted to Papua New Guinea. Indonesia and lvian Jaya (Indonesian New Guinea). The resistance to chloroquine has been graded as R I R II and R III depending upon positivity of smear on day 2 and on the basis of presence of recrudescence and a major effort is being made to identity drugs, which could reverse chloroquine resistance. However, initial studies carried out to induce reversal of chloroquine resistance by use of verapamil, desipramine or amitriptyline have not met with any success .
Despite these limitations, chloroquine remains the drug of choice in treatment of sensitive P. falciparum malaria and in treatment of P. vivax. P. malariae and P. ovale malaria because it provides symptomatic relief and reduces morbidity and mortality even in endemic areas where the resistance is predominantly R I or R II in addition, the drug can be administered orally, intramuscularly or intravenously and can be given safely to children and pregnant women.
Quinine: Quinine is a chinchona alkaloid which is a rapidly acting bloods schizonticidal drug. It is also effective against gametocytes of P. vivax, P. malariae ajid P. ovale. It acts by producing changes in parasite membranes and in hemozoin of food vacuoles. Quinine is available for oral as well as intravenous administration. it should never be given subcutaneously as this leads to skin necrosis. When intravenous route is required, quinine should always be given by rate controlled infusion, never by bolus intravenous injection. Hypoglycemia due to hyperinsulinemia is the most frequent adverse effect followed by cardiovascular and neurologic toxicity. The commonest ECG abnormality found with quinine is prolongation of QT interval but it causes dysrrhythmia and hypotension on rare occasions. Mild side effects are more common and these include nausea, tinnitus, restlessness and blurring of vision.
Resistance to quinine was reported from Brazil as early as 1910 but fortunately, this did not spread. P. falciparum strains with reduced sensitivity have been reported from Thailand but the major limitations of using quinine are its comparatively low therapeutic safety index, inability to monitor some of its side effects like tinnitus, blurring of vision and nausea in young children and need to watch for hypoglycemia and cardiotoxicity. Thus, many prefer to use quinine in patients of severe Falciparum malaria under intensive care monitoring.
Quinine, nevertheless, is the drug of choice in treatment of chloroquine resistant severe Falciparum malaria. It is also used for the treatment of malarial attack which has “broken through” chloroquine prophylaxis. To reduce its toxicity and improve compliance it is at times given in combination with another schizonticidal drug like tetracycline or sulfadoxine-pyrimethamine combination. However, tetracyclines cannot be administered to children under the age of 8 years and pregnant women.
Quinidine, the dextrorotatory diasterioisomer of quinine is at least as effective as quinine and is used in the treatment of severe or resistant falciparum malaria when quinine is not available. It is administered as an intravenous infusion.
Sulfadoxine-Pyrimethamine combination: This combination of antimetabolites of foliate pathway has been successful operational anti-malarial drug in areas with highly developed resistance to chloroquine. Besides this, the commonest use of this drug is for standby self-treatment. However resistance to this combination has now been reported from South- East Asia and Africa. The oral preparation of this combination is widely used though a preparation for intramuscular administration in children is available and has been studied in Brazil, Mali, Mozambique and Thailand . Preliminary reports indicate that it clears parastemia as quickly as chloroquine does The most dreaded side-effects of the combination are skin and mucous membrane lesions, some of which can be extensive and fatal.
Primaquine: Primaquine is highly effective against gametocytes and against hypnozoites of relapsing malarias but has hardly any schizonticidal activity. It is therefore used to prevent relapses in case of relapsing malaria. The common side-effects include anorexia nausea and epigastric pain and severe adverse effects such as anaemia, leukopaenia and methaemoglobinaemia occur infrequently. The haemolytic action of primaquine is increased in subjects with a genetic deficiency of enzyme glucose-6-phospate dehydrogenase (G6PD). It is, therefore advisable to determine G6PD status before administering primaquine as it can induce severe hemolysis in individuals with Asian variant of G6PD deficiency. It should never be administered during pregnancy since all fetuses are relatively G6PD deficient.
An analogue of primaquine, WR238605 is undergoing phase 1 clinical trial. Quantitative studies of the gametocytocidal properties indicate that this causal prophylactic and radical curative drug is 7 to 9 times more potent than primaquine in its gametocidal properties. It is hoped that this drug may find unprecedented applications in malaria control.
Tetracycline: It is a slow blood schizontocide and is therefore never used alone for therapy but tagged on to a rapidly schizonticidal drug like quinine- In any case the drug has limited applicability in Paediatrics as it is contraindicated before the age of 8 years.
Mefloquine: Mefloquine is a potent, long acting blood schizontocide, which may have some sporonticidal activity. Its mechanism of action has not been clearly defined. The postulated mechanisms include formation of a drug-heme complex that is toxic to the parasite and change in PH of parasite food vacuoles making digestion of haemoglobin difficult.
Mefloquine is available only as an oral preparation as its parenteral formulation is extremely irritant to peripheral vasculature. Its intra-gastric administration in seriously ill patients resulted in erratic blood levels. Common side-effects include nausea, vomiting, diarrheal, abdominal pain and loss of appetite. Other adverse effects include dizziness, rash, pruritus, urticaria and bradycardia. Neuro-psychiatric side effects of mefloquine have been a cause of concern.
Despite its limitations as non-availability of parenteral preparation obviating its use in cases of severe malaria and its side effects, mefloquine is an extremely useful drug. It is given as a single dose of 15 mg/kg thereby ensuring compliance. The gastrointestinal side-effects can be minimised by dividing the total dose into two. Studies in children in 1980s using mefloqine have consistently shown response rates in excess of 90%19. Studies in Malawi and Thailand have shown that vomiting following its administration can be decreased, by giving it in a crushed tablet form. Mefloquine has proved effective in the treatment of chloroquine-sensitive and chloroquine- resistant falciparurn malaria. It is also effective against parasites resistant to sulfadoxine-pyrimethamine combination and to quinine. Though most strains of P vivax remain sensitive to chloroquine, mefloquine has been successfully used in treating P vivax malaria.
However, reports of mefloquine failure have started emerging,,,). Various strategies have been suggested to limit and delay the emergence of this resistance. A triple combination of mefloquine, sulfadoxine and pyrimethamine was used to obtain a 100% response rate in P. falciparum malaria cases in Zambia and China,. WHO, however does not favour this combination as it caused an increased incidence of skin reactions. Looareesuwan et al have reported better response rates with mefloquine-qinghaosu combination than with mefloquine alone. Sowunmi and coworkers used a higher dose of mefloquine (25m9/kg) in children to obtain 100% cure rate. One of the important strategies is to limit the use of this vital drug to conditions when it is essential and not to use it for prophylaxis or treatment when other drugs like chloroquine or quinine or sulfonamide-pyrimethamine combination is likely to be effective.
Halofantrine: Halofantrine is a 9-phenanthrene-methanol antimalarial agent, which is an effective schizonticidal drug. it probably acts by formation of a complex with FPIX that is toxic to the parasite. Inhibition of proton pump at the host-parasite interface has also been hypothesised as an alternate mode of action . Halofantrine is available only for oral administration and its absorption is enhanced when given after food. Many studies have shown that when given in the dose of 8 mg/kg 6 hourly for 3 doses. It is effective in treating chloroquine-sensitive as well as chloroquine resistant P. falciparum malaria,,,. If it is given as a single dose of 16 mg/kg, it leads to a high recrudescence rate in semi-immune children. Hence, it is advised that divided doses be adhered to and the course be repeated after a week. Though, a majority of patients treated with halofantrine have had falciparum malaria, a sufficient number of patients with vivax malaria have been evaluated to confirm its efficacy against P vivax. The side-effects of this drug are usually mild and include diarrheal, abdominal pain, pruritus and skin rashes. Isolated cases of neuromuscular spasms, mouth ulcers, convulsions and raised transaminases have been reported. Children tolerate this drug well. The greatest attention is now being directed at its cardiac effects. It has been associated with prolongation of Qtc interval and ventricular arrhythmias. These effects are more common in populations with pre-existing prolongation of QTc interval and in patients with thiamine deficiency. Though isolated reports of in-vitro resistance of strains of P. falciparum to halofantrine have appeared from Thailand, Malaysia, Congo, Senegal and Cameroon, the susceptibility of plasmodia to halofantrine can be considered to be good. It is necessary to preserve the longevity of the drug and, therefore, it should be used only in cases of chloroquine-resistant or multi-drug resistant plasmodial infections.
Artemisinin and its derivatives: Artemisinin is the antimalarial principal isolated by Chinese scientists in 1972 from Artemisia annua, a medicinal plant from which is derived the traditional medicine qinghaosu. Artemisinin and related compounds are the most rapidly acting antimalarial drugs. The preparations which are being used include artemether (for intramuscular injection) and artesunate (for intramuscular, intravenous or oral administration).
Parenteral preparations have been used to treat severe falciparum malaria successfully while oral derivatives have been used to treat uncomplicated multi-drug resistant malaria. The cure rates have approached 90% but with chances of recrudescences ranging Upto 50%. As stated earlier, a study in Thailand using a combination of artemisinin and mefloquine showed that the combination resulted in more efficient clearing of parasitemia than when the agents were used alone. Most of the literature on these compounds is in Chinese and is being translated into English. Pre-clinical trials have been completed in the U. S. and phase I safety, tolerance and pharmacokinetic studies have been completed in Netherlands. A vast majority of studies using these compounds have been carried out in adults. Studies in children are underway in Nigeria, Malawi and Gambia and preliminary results suggest that artemether clears peripheral P. falciparum parasitemia more rapidly than quinine in children with severe malaria.
On the basis of early experiences it has been recommended that the use of these drugs can be restricted to cases of severe malaria and multi-drug resistant malaria to prevent or delay emergence of resistance. It has been suggested that oral artemisinin derivatives be administered in combination with mefloquine-even where mefloquine resistance is emerging for a minimum of three successive days. If for any reason it has to be used alone, artemisinin be given for a minimum of 5 successive days.
As soon as a patient presents with manifestations suggestive of malaria, stained thick and thin blood films be examined immediately by a competent person. The smears should be utilised to diagnose the type of plasmodial infection and also for determining parasite index. Plasmodium falciparum infection is always a potentially serious infection in non-immune or partially immune children in some cases parasitemia may be scanty or undetectable and the appearance of parasites may be altered by chemoprophylaxis or therapy received by the patient. A therapeutic trial is entirely justified on grounds of clinical suspicion . The type of antimalarial drug used depends on many factors such as the type of plasmodial infection detected or suspected, resistance pattern of the parasite in the given area, chemoprophylactic or chemotherapeutic agents received by the patient and of course the presence of clinical or laboratory evidence of severe falciparum infection. Some of the features of severe falciparum malaria are listed in [Table - 1]. WHO suggests that the treatment to be given may have to be altered depending upon the type of health-care facility. Oral anti malarial drugs can be used in patients without manifestations of severe infection. These drugs are listed in [Table - 2].
Severe falciparurn malaria is a medical emergency and should be ideally managed in a tertiary care centre as the patient requires intensive monitoring, prompt treatment and at times, management of organ failure. A suspicion of severe falciparum malaria is of the utmost importance. Attempts should be made to confirm the diagnosis but, failing that, clinical suspicion should prompt antimalarial therapy even it parasites are not found in the blood film.
Immediate investigations should include thick and thin blood smears, hematocrit finger prick blood glucose and lumbar puncture. Estimation of while cell and platelet counts, serum electrolytes, urea and creatinine are also important. Shock needs to be treated with adequate volume of appropriate fluids. Electrolytes and acid-base imbalance, if any, should be corrected. 10-25% dextrose solution should be used to correct hypoglycaemia. To have any- impact on mortality chemotherapy must be started as quickly as possible using a rapidly schizonticidal drug to which the parasite is likely to be sensitive [Table - 2]. Vomiting and inability to swallow oral drugs make parenteral therapy advisable in severely affected patients, atleast in the initial stages. In-addition, only intravenous administration ensures bio-availability of the drug under all clinical conditions including shock, diarrheal, gastro-intestinal Malabsorption and bleeding. Quinine is the drug of choice in patients with chloroquine-resistant falciparurn malaria and in infection that has "broken through" chloroquine chemoprophylaxis. Decreasing sensitivity to quinine has been detected in certain areas, where alternatives include mefloquine, halofantrine and artemisnin. Chloroquine remains useful in those dwindling areas of the world in which P. falciparum is still sensitive to this drug, as it is less toxic than quinine.
Good nursing care is vital. Temperature, pulse, respiration and blood pressure must be monitored regularly, at least 4-6 hourly intervals for a minimum of first 48 hours. A careful record of fluid intake and output must be maintained. An unconscious patient should receive meticulous nursing care including maintenance of a clear airway and periodic change of position.
Fever needs to be treated with antipyretics and tepid sponging. Severe anaemia is corrected by packed cell transfusion. Renal failure and pulmonary edema are rare complications of severe malaria in children. Renal failure may require peritoneal dialysis while pulmonary edema is managed with upright posture, fluid restriction, diuretics, vasoactive drugs and mechanical ventilation. Exchange transfusion has been used to treat hyperparasitemia of more than 10%. The procedure can correct anaemia without precipitating circulatory overload, restore clotting factors and may remove toxic metabolites, circulating mediators and toxins. It should, however, be carried out only it pathogen-free blood is available, the patient is severely ill as well as hyperparasitemic and the clinical facilities are adequate.
The commonest manifestation of severe malaria in children is cerebral malaria. Such patients should, in addition to antimalarial therapy and meticulous nursing care. receive phenobarbital sodium in the dose of 10-15 mg/kg on admission to prevent seizures. Corticosteroids are contra-indicated. Invert sugar, mannitol and urea hardly have any role and it may be better to avoid them as they have the potential of producing electrolyte imbalance and circulatory overload. Gordeuk et a1 have shown that desferrioxamine hastens the clearance of parasitemia and enhances recovery from deep coma in cerebral malaria. They postulate that desferrioxamine chelales iron which is an essential nutrient for the growth of P falciparum and also inhibits peroxidant damage to central nervous system.
Malaria, being a formidable foe to the well-being of children, is given the utmost importance. The world community has tried to focus on various strategies to control malaria. Committing the political leadership to the task of malaria control, environmental manipulation, use of chemical agents and other measures of vector control and research into malarial vaccines are some of these strategies. But, the only weapons, which can reduce morbidity and mortality from malaria, in the short-term, are, anti-malarial drugs. As the parasites have the proven ability to develop resistance, these drugs have to be used judiciously to maximise the benefits at the same time preserving the longevity of the newer anti-malarial agents.
[Table - 1], [Table - 2], [Table - 3]