Recommendations and IAP Plan of Action

Background

Malaria is a major public health problem of developing countries. Approximately, 2.48 million malaria cases are reported annually from South Asia of which 75% cases are contributed by India alone(1). The magnitude of the problem is further enhanced by P. falciparum resistance to standard antimalarial drugs particularly chloroquine. Important contributing factors of drug resistance are population movement, infrastructure defi-ciency, deforestation, unplanned development, drug pressure and haphazard use of drugs. It has been found drug pressure is the singlemost important factor in the development of resistance following presumptive antimalarial treatment. Malaria which was a rural problem of the past has now emerged in different forms namely, urban and forest malaria. These new addition is becoming an increased burden to our country. Indian Academy of Pediatrics has set up a National Task Force to form a uniform guideline on diagnosis and management of malaria which can be followed by all members of IAP in general. The list of the members who took part in the workshop is given in Annexure I.

Diagnosis of malaria in our country is mainly based on symptoms due to lack of proper infrastructure. As per national antimalarial drug policy all fever cases, both in high and low risk areas, without any other obvious causes are to be treated with antimalarials(2). Even in Integrated Management of Childhood Illness (IMCI) strategy all fever cases are given antimalarials(3). This indiscriminate use of antimalarial is constantly increasing the overall drug pressure. The greatest decrease in antimalarial drug use could be achieved through improving the diagnosis of malaria atleast at the places where diagnostic facilities are available. With the development of rapid antigen tests which are cost effective and does not require expertise considerable reduction of unnecessary treatment is possible.

To reduce the increasing drug resistance, in all cases of fever 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.

Light microscopy of well stained thick and thin films by a skilled microscopist has remained the "gold standard" for malaria diagnosis. Thick films are nearly 10 times more sensitive for diagnosis of malaria as larger amount of blood are there in a given area as compared to thin films(4). Species identification is better with thin films as morphology of the parasite and RBC are well preserved.

1.1a. Collection of blood Sample

Timing of 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 fever(5). Collection should be before administration of antimalarials which causes detection of parasites difficult due to its morphologic alteration.

Smears should be prepared soon after collection which enables better adherence of films to the slide and cause minimal distortion of parasites and red cells. In blood collected with anticoagulants films should be prepared within 2 hours for best results(4).

1.1b. Examination of blood film

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.

1.1c. Advantage of microscopy

These are immunochromatographic test (ICT) to detect plasmodium specific antigens in blood sample. Test employ monoclonal antibodies directed against targeted parasite antigens.

Histidine rich protein II (HRP-II) is actively secreted by asexual stages and young gametocytes of P falciparum but not by mature gametocytes(12).

A metabolic enzyme Parasite lactate dehydrogenase (pLDH)(13) is produced by all four species of plasmodia, both asexual and sexual (gametocytes) stages provided they are viable(14). Following successful treatment the enzyme is rapidly cleared from the blood and the test become negative within days of treatment. Monoclonal antibodies produced against this antigen are of three groups. One specific for Plasmodium 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 malarie but unable to separate them individually. Commercially available kit can detect falciparum, vivax and other malaria but cannot differentiate ovale and malarie malaria.

1.2b. Performance characteristic of RDTs

Performance of these kits are evaluated extensively in both endemic and non endemic regions but with newer kits (which detect both falciparum and vivax), the assessment of performance are few that too with small sample size. Instruction guidelines provided by the manufacturer should be followed. Care should be taken to maintain temperature and humidity as recommended. Faulty technique may give false results.

The sensitivity to detect P. falciparum HRP-II with parasite density above 100 parasite per µl of blood is above 90%(15). With low level of parasitemia e.g., with 10 parasites per µl of blood the sensitivity decreases to 74.6% and with 10-100 parasites per µl of blood it is 81.3%(16). pLDH kit to detect falciparum and vivax malaria has a sensitivity comparable to that of HRP-II(17) but number of studies are much less to comment for its superiority over older HRP-II tests. Some investigations have shown specificity of these test are also above 90%.

HRP-II tests can remain positive for 7-14 days following successful malaria treatment even when blood doesn't show parasitemia by microscopy(18). On the other hand as pLDH is produced by only viable parasite so the tests detecting this antigen becomes negative within 3-5 days of treatment(17).

Of all the malaria diagnostic tests RDTs are easiest to perform.

In comparism to high transmission areas, malaria in our country occurs less frequently, in all age groups and almost always symptomatic. Drug resistance including multidrug resistance has started developing in our country so laboratory confirmation of malaria is an essential component of disease management. Expert microscopic diagnosis is available in central levels of health care system like metro cities but it is often unreliable or unavailable in remote areas with poor health facilities. So RDTs will be useful in the following situations in our country:

RDTs permit on the spot confirmation of malaria even at the peripheral health care system, by unskilled health workers with minimal training. Rational use of RDTs as a complement to microscopy might offer following benefits :

Other diagnostic methods namely microscopy using fluorochromes and on centrifused blood specimens, molecular probes, polymerase chain reaction (PCR) and serology are available. Unfortunately, they are not suitable for routine disease management and do not have wide field application. Their use is currently for only research and epidemiological purpose.

Treatment of malaria may be presumptive, curative and radical.

A case of fever treated for malaria without parasitological diagnosis with an aim to prevent mortality and morbidity due to delay in treatment.

Treatment given after diagnosis but without 8 aminoquinolines because of contraindication.

Therapy after parasitological confirmation to eliminate all the forms of parasite from all possible host tissues.

Malaria in children has some unique features. Young children below 5 years whose passive immunity wanes and as yet to develop sufficient immunity 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.

The main aim of antimalarial treatment in children, which is also the basis of National Antimalarial Program, is to prevent morbidity and death 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%(21). Extrapolating from these data it is evident that the use of presumptive treatment of malaria has the potential for facilitating resistance by greatly increasing the number of patients who are treated unnecessarily.

Hence, all efforts should be given to treat malaria after diagnosis by microscopic examination, rapid diagnostic tests or both as facilities and circumstances dictate. In situation where such facilities are not available one should make atleast clinical diagnosis of malaria following clinical algorithmic approach.

Further, a complete and successful antimalarial therapy is possible only when the parasite species are known. In case of clinically suspected malaria at times the first smear examination may be negative but it is prudent of avoid the diagnosis of "blood smear negative malaria". In these cases repeated blood smear at 12 to 24 hours interval(19) and RDTs are suggested and all other causes of fever are to be excluded.

One of the major problem in the successful treatment of malaria is the development of resistance of P. falciparum to first line drug chloroquine (CQ) in certain areas of our country. Malaria is prevalent in all parts below 5000 feet mean sea level. Before initiating treatment it is desirable to have some idea about the pattern of resistance in our country.

Transmission of malaria is usually low in most parts of India but intense transmission is seen in North Eastern States and large areas of Orissa, Chattisgarh, Jharkhand and Madhya Pradesh. Year 2004 reveals largest number of cases in our country reported from Orissa followed by Gujarat, Chattisgarh, West Bengal, Jharkhand, Karnataka, Uttar Pradesh and Rajasthan(22).

To combat drug resistant malaria, the NVBDCP recommends the use of combination therapy i.e., artesunate plus sulfadoxine/pyrimethamine (SP) for P. falciparum cases in chloroquine resistant areas.

P. falciparum resistant to chloroquine and sulfadoxine/pyrimethamine are prevalent in the neighboring countries of Bangladesh, Bhutan, Myanmar and Nepal. North Eastern part of our country share international border with the above mentioned countries and reports resistance to sulfadoxine/pyrimethamine at various level in district of seven North Eastern States(23).

Though few reports of emergence of chloroquine resistance P. vivax are there but the drug still retains its effectivity against P. vivax infection in our country.

Treatment regimes are to be tailored specifically according to the resistance pattern of the region under consideration (Tables Ia, Ib, Ic).

Drug sensitivity

Recommended treatment

Multidrug resistant
P.  falciparum
i.e., both to CQ and SP

Quinine, 10 mg salt/kg/dose3  times daily for 7-10 days.
In case of cinchonism, 
Quinine, 10 mg salt/kg/dose 3 times daily for 3-5 days
+
Tetracycline (if age >8 yrs) 4 mg/kg/dose 4 times daily for 7-10 days
OR
Doxycycline (if age >8 yrs) 3 mg/kg/day 2 times daily for 7-10 days
OR
Clindamycin 20mg/kg/day divided 3 times daily × 7-10 days
A single dose of primaquine above 1 year age (0.75mg/kg) 
is given for gametocytocidal action.

3.1. Standardized test system for the assessment of in vivo drug response in P. falciparum malaria were developed by WHO following reports of chloroquine resistance(19).

Parasites are sensitive if clearance of asexual parasitemia by day 6 from the initiation of treatment, without subsequent recrudescence until day 28 (Day 0 = first day of treatment).

Grade I resistance (RI): If clearance of asexual parasitemia for at least 2 consecutive days, latest on day 6, after the initiation of treatment, followed by recrudescence within day 28.

Grade II resistance (RII) : If there is marked reduction of asexual parasitemia to less than 25% of the pretreatment count within 48 hours of the initiation of treatment, but no subsequent disappearance of asexual parasitemia (positive on day 6 after the initiation of treatment).

Grade III resistance (RIII): If there is modest reduction (not less than 25%), no change, or an increase in asexual parasitemia, during the first 48 hours following the implementation of the treatment and no subsequent clearance of asexual parasites.

This system is not practicable in day to day practice due to the need of daily blood examination for 28 days.

Subsequently, WHO developed a new system of monitoring with follow up for 14 days where both clinical and parasitological assessment was done(25). Parasitological assessment should include detection of malaria parasite, species determination and parasite density measurement. Patient should also be assessed clinically with examination of body temperature.

Microscopy should be done at day 0, before initiation of treatment, on day 3, 7 and 14 if not indicated more frequently. Parasite count on day 0 is taken 100% for that particular child.

Early treatment failure: The patient will be classified as early treatment failure (ETF) under the following situations :

Late treatment failure: Patient will exhibit late treatment failure (LTF)(25) under following situations:

So from practical point of view the therapeutic response is taken as adequate if the patient is afebrile without parasitemia from day 3 onwards. In day to day practice where repeated blood examination is not possible resistance should be suspected in spite of full treatment and no history of vomiting or diarrhea, if patient does not respond within 72 hours parasitologically(2). If the patient shows therapeutic failure then he/she should be given alternative therapy as guided in the treatment section.

Danger signs of malaria :

(i) Not able to drink or breast feed

(ii) Vomiting everything.

(iii) Recent history of convulsion

(iv) Lethargic or unconscious state

(v) Unable to sit or stand up

According to IAP recommendations, if by day 3 of the treatment, there is no clinical improvement, a blood smear is to be repeated. In case it is positive and the level of asexual parasitemia is more than or equal to 25% of the pretreatment value, revise treatment. If less than 25%, follow the patient till 28 days. Continuation of fever till day 5 or reappearance thereafter, but within 28 days, repeat blood smear. If positive, irrespective of the percentage of parasitemia, revise treatment.

Definition of severe falciparum malaria: One or more of the criteria written in Table III in the presence of asexual parasitemia define severe falciparum malaria.

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 inject-able 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 medical facility available preferably in a intensive care setting. Confirmation of the diagnosis is preferable but one should not delay the treatment if it needs more than one hour(26). Further, in cases of strong clinical suspicion prompt antimalarial therapy is needed even if parasite are not found in the initial blood examination.

Severe malaria in children differs to certain extent from adults. Progression to cerebral malaria can be very rapid, but again, recovery is also rapid. Most common complications in children are cerebral malaria, severe anemia, respiratory distress (acidosis) and hypo-glycemia. Fortunately, common complications in adults like pulmonary edema and jaundice are rare in children. The definition of severe malaria was proposed by working groups convened by WHO in 1990(27) and modified in the year 2000(28) (Tables II and III). In case of high degree of suspicion physician should not withhold treatment even if the patient do not clearly qualify into any one of the categories.

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.

Ideally, antimalarial drug should be given initially by intravenous infusion, which should be replaced by oral administration as soon as condition permits.

Drug

Dosage(26)

Artesunate

2.4 mg/kg IV (loading dose), followed by 1.2 mg/kg at 12 and 24 hours, then 1.2 mg/kg
daily for 6 days. If the patient is able to swallow, then the daily dose can be given orally.
OR
Artemether 3.2 mg/kg (loading dose) IM, followed by 1.6 mg/kg daily for 6 days. If the 
patient is able to swallow, then the daily dose can be given orally.

After weighing the patient antimalarials should be given according to the body weight. If parenteral injection is not possible, referral is likely to be delayed and artemisinin is not available as suppository form consider crushed antimalarial to be given by nasogastric tube. But it has the risk of causing vomiting and may produce inadequate drug levels in the blood.

According to the National Anti Malaria Programme (NAMP), drug policy in all cases of severe malaria is either IV quinine or parentral artemisinin derivatives to be given irrespective of chloroquine resistance status(2). A single dose of primaquine (0.75 mg/kg) is to be given for gametocytocidal action irrespective of the drug given.

Artemisinin are the most rapidly acting of all known antimalarial drugs, they often produce a 10,000 fold reduction of parasites per asexual cycle. They have the broadest time window of antimalarial effects from ring forms to early schizonts. Thus, they can stop para- site maturation, particularly from the less pathogenic circulating ring stages to the more pathogenic cytoadherent stages(19).

Artemisinin also has an excellent safety profile and the cost of therapy as compared to quinine is almost similar. There are no reports of resistance to artemisinin at present but declining sensitivity to quinine has been reported from some South East Asian countries like Thailand.

All these theoretical advantages are not reflected in few randomized control trials available. However, most trials are conducted with artemether administered intramuscularly, which has questionable reliability of absorp-tion in severe malaria. More comperative studies with artesunate which can be given intravenously and which does not have the pharmocokinetic disadvantage of artemether are needed for its recommendation.

However, artemisinin should be used when rate controlled intravenous infusion of quinine is not possible, patients have contraindications to quinine use and evidence of inadequate response or resistance to quinine noted. Simultaneous use of quinine and artemisinin is not indicated as it may be harmful and there is no added advantage. In limited studies available artisunate has been found to be better than artemether.

Of the various complications of falciparum malaria the common and important ones in children are as follows:

5.1a. 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, hypoglycemia). 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.

5.1b. Severe anemia

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

5.1c. Lactic acidosis

Deep breathing with indrawing of lower chest wall without any localizing chest signs suggest lactic acidosis. It usually accompanies cerebral malaria, anemia or dehydration. Correct hypovolemia, treat anemia and prevent seizures. Monitor acid base status, blood glucose and urea and electrolyte level.

5.1d. Hypoglycemia

It is common in children below 3 years specially with hyperparasitemia 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 every 4 to 6 hours. If facilities to monitor blood glucose is not available assume hypoglycemia in symptomatic patient and treat accordingly. Correct hypoglycemia with IV dextrose (25% dextrose 2 to 4 mL/kg by bolus) and it should be followed by slow infusion of 5% dextrose containing fluid to prevent recurrence.

5.1e. Hyperpyrexia

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

5.1f . Hyperparasitemia

Specially seen in nonimmune children associated with severe disease. Consider exchange transfusion/cytapheresis if greater than 20% of RBCs are parasitised.

5.1g. Circulatory collapse (Algid malaria)

In case of circulatory collapse suspect gram negative septicemia, send blood for culture before starting antibiotics. Resuscitate with judicious use of fluids.

Usually seen is nonimmune children which should be treated with vitamin K, blood or blood products as required.

List of participants of the Workshop organized by IAP Task Force on Guidelines for Diagnosis and Management of Malaria in Children.

Chairperson: Raju C. Shah;
Convenor:     Ritabrata Kundu;
Members:     Amitava Nandy,
                   Deepak Ugra,
                   Nigam P. Narain,
                   Nitin K Shah,
                   Nupur Ganguly,
                   Panna Choudhury,
                   Shivananda,
                   Tapan Kr. Ghosh.