Malaria is a major public health problem, accounting for sizeable morbidity, mortality and economic loss. Malaria, which predominantly occurs in tropical areas, is a potentially life-threatening disease caused by infection with Plasmodium protozoa transmitted by an infective female Anopheles mosquito vector. Individuals with malaria may present with fever and a wide range of symptoms. Malaria is curable if effective treatment is started early. Delay in treatment may lead to serious consequences, including death. Prompt and effective treatment is also important for controlling the transmission of malaria.

top

Global Scenario
Malaria is one of the main infectious diseases in the world. In 2008, there were an estimated 243 million cases of malaria worldwide. The vast majority of cases (85%) were in the African region, followed by the Southeast Asia (10%) and Eastern Mediterranean regions (4%). Of the total number of malaria cases, 93% were due to Plasmodium falciparum (P. falciparum) .

Malaria accounted for an estimated 863,000 deaths in 2008, of which 89% were in the African region, followed by the Eastern Mediterranean (6%) and the Southeast Asia regions (5%). The estimated number of deaths in children less than 5 years of age was 85% of the total number of deaths due to malaria.

Southeast Asia region: In 2008, 2.4 million laboratory-confirmed malaria cases and 2408 deaths were reported whereas the estimates were about 24 million cases and 40,000 deaths, respectively . Four countries accounted for 97% of the estimated cases in the region ( Bangladesh , 10%; India , 55%; Indonesia , 15% and Myanmar , 17%).

Indian Scenario
Malaria is one of the major public health problems of the country. In 2009, around 1.5 million malaria cases were reported by the National Vector Borne Disease Control Programme (NVBDCP), of which 40–50% were due to P. falciparum. Malaria accounted for 1123 deaths in 2009.

The largest numbers of cases in the country were reported by Orissa, followed by Jharkhand, Chhattisgarh, West Bengal, Assam, Madhya Pradesh, Meghalaya, Uttar Pradesh, Gujarat , Karnataka and Rajasthan.

top

The 4 Plasmodium species known to cause malaria include Plasmodium falciparum (P.falciparum) , Plasmodium vivax (P. vivax), Plasmodium ovale (P. ovale) and Plasmodium malariae (P. malariae). A fifth species, Plasmodium knowlesi (P. knowlesi), has recently been identified as a clinically significant pathogen in humans. In some cases, individuals with malaria are infected with multiple Plasmodium species. Each Plasmodium species has a defined area of endemicity, although geographic overlap is common. In India , infection with P. vivax and P. falciparum is common.

P .vivax: If this kind of infection goes untreated, it usually lasts for 2-3 months with diminishing frequency and intensity of paroxysms. Of patients infected with P. vivax, 50% experience a relapse in a few weeks to 5 years after the initial illness. Splenic rupture may be associated with P. vivax infection secondary to splenomegaly resulting from RBC sequestration.  P. vivax infects only immature RBCs, leading to limited parasitemia.  However, in recent years, severe malaria caused by P. vivax has been noted.

P. ovale: These infections are similar to P. vivax infections, although they are usually less severe. P. ovale infection often resolves without treatment. Similar to P. vivax , P. ovale infects only immature RBCs and parasitemia is usually less than that seen in P. falciparum .

P. malariae: Those infected with this species of Plasmodium remain asymptomatic for a much longer period of time than those infected with P. vivax or P. ovale . Recrudescence is common in those infected with P. malariae . It often is associated with a nephrotic syndrome, possibly resulting from deposition of antibody-antigen complex upon the glomeruli.

P. knowlesi : P. knowlesi was originally described as a malarial parasite of long-tailed macaque monkeys. Cases infected with P. knowlesi have been documented in Malaysian Borneo, Thailand , Myanmar , Singapore , and in the Philippines , and other neighboring countries. Patients infected with this, or other simian species, should be treated as seriously as those infected with falciparum malaria, as P. knowlesi may cause fatal disease.

P. falciparum: The most malignant form of malaria is caused by this species. Infection with P. falciparum is not limited to RBCs of a particular age and, hence, represents the highest level of parasitemia among the 5 Plasmodium species infecting humans. This species also causes vascular obstruction due to its ability to adhere to endothelial cell walls. This property leads to most complications of P. falciparum infection. P. falciparum can cause cerebral malaria, pulmonary edema, rapidly developing anemia, renal problems and Blackwater fever.

Table 1: Characteristics of Plasmodium Species Infecting Humans  

	Finding for indicated Species
Characteristic	P. falciparum	P. vivax	P. ovale	P. malariae
Duration of intrahepatic phase (days)	5.5	8	9	15
Number of merozoites released per infected hepatocyte	30,000	10,000	15,000	15,000
Duration of erythrocytic cycle (hours)	48	48	50	72
Red cell preference	Younger cells (but can invade cells of all ages)	Reticulocytes and cells up to 2 weeks old	Reticulocytes	Older cells
Morphology	Usually only ring forms, banana-shaped gametocytes	Irregularly shaped large rings and trophozoites; enlarged erythrocytes; Schuffner's dots	Infected erythrocytes, enlarged and oval with tufted ends; Schuffner's dots	Band or rectangular forms of trophozoites common
Pigment color	Black	Yellow-brown	Dark brown	Brown-black
Ability to cause relapses	No	Yes	Yes	No

The malaria parasite life cycle involves two hosts, humans and mosquito. While the exo-erythrocytic cycle and erythrocytic cycle takes place in humans, the sporogonic cycle occurs in the mosquito.

Fig. 1: Life cycle of malaria parasite
Adapted from: www.dpd.cdc.gov

A. Exo-erythrocytic cycle: The parasite multiplication in the liver is known as exo-erythrocytic cycle (Fig.1: Step 1- 4)

1. Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal.

2. These microscopic motile forms of the malarial parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells.

3. These mature into schizonts and begin a period of asexual reproduction.

4. By this amplification process, a single sporozoite eventually may produce from 10,000 to > 30,000 daughter merozoites. The swollen infected liver cell envetually bursts, discharging motile merozoites into the bloodstream.

In P. vivax and P.ovale infections, a proportion of the intrahepatic forms do not divide immediately but remain dormant for a period ranging from 3 weeks to a year longer before reproduction begins. These dormant forms or hypnozoites are the cause of the relapses that characterize infection with these two species.

B. Erythrocytic cycle: After initial replication in the liver, the parasites undergo asexual multiplication in the erythrocytes (Fig. 1: Step 5-7).

5. Merozoites invade the red blood cells (RBCs) and multiply six to twentyfold every 48 – 72 h. When the parasites reach densities of ~50 m L of blood, the symptomatic stage of the infection begins.

After entry into the bloodstream, merozoites rapidly invade erythrocytes and become trophozoites. Attachment is mediated via a specific erythrocyte surface receptor. In the case of P. vivax , this receptor is related to the Duffy blood-group antigen Fy a or Fy b . Most West Africans and people with origins in that region carry the Duffy-negative FyFy phenotype and are therefore resistant to P.vivax malaria.

During the early stage of intraerythrocytic development, the small “ring forms” of the four parasitic species appear similar under light microscopy. As the trophozoites enlarge, species-specific characteristics become evident, pigment becomes visible, and the parasite assumes an irregular or ameboid shape. By the end of the 48-h intraerythrocytic life cycle (72 h for P. malariae ), the parasite has consumed nearly all the hemoglobin and grown to occupy most of the RBC. It is now called a schizont .

6. Multiple nuclear divisions taken place, and then the RBC ruptures to release 6-30 daugher merozoites, each potentially capable of invading a new RBC and repeating the cycle. The disease in human beings is caused by the direct effects of RBC invasion and destruction by the asexual parasite and the host's reaction.

7. After a series of asexual cycles ( P. falciparum ) or immediately after release from the liver ( P. vivax, P. ovale, P. malariae ), some of the parasites develop into morphologically distinct, longer-lived sexual forms (gametocytes) that can transmit malaria.

C. Sporogonic cycle: The parasite multiplication in the mosquito is known as sporogonic cycle (Fig. 1: Step 7-11).

8. The gametocytes, male (microgametocytes) and female (macrogametocytes) are ingested by an Anopheles mosquito during a blood meal.

9. The male and female gametocyte mature into gametes and unite to form a zygote in the insect's midgut.

10. This zygote matures into an ookinete, which penetrates and encysts in the mosquito's gut wall.

11. The resulting oocyst expands by asexual division until it bursts to liberate motile sporozoites, which then migrate in the hemolymph to the salivary gland of the mosquito to await inoculation into another human at the next feeding.

The clinical symptoms and signs of malaria are caused by the asexual forms of the parasite, which invade and destroy RBCs, localize in tissues and organs by binding to endothelial cells ( cytoadherence ), and induce the release of many pro-inflammatory cytokines (e.g. tumour necrosis factor a , TNF a ).

Fig. 2: Schematic representation of rosetting and cytoadherence leading to vessel obstruction. Parasites inside red blood cells are depicted as black circle. Arrow shows an infected red blood cell involved in both cytoadherence and resetting.

The initiating step in pathogenesis is invasion of RBCs by merozoites. Invasion is highly specific, ordered and sequential. Inside the cell, the ring form of

P. falciparum matures via the trophozoite to the schizont stage. The schizont-infected RBC binds specifically to the endothelial cells in post-capillary venules in organs such as the brain. Cytoadherence is the major factor responsible for the absence of mature forms of P. falciparum from the peripheral circulation ( sequestration ). (The other forms of human malaria are not thought to sequester). Sequestering parasites presumably cause microvascular obstruction, though the role and extent of this obstruction remains unclear.

Fig. 4: Section of brain showing blood vessels blocked with developing P.falciparum parasites (see arrows).

Cytoadherence may also localize the effect of putative parasite ‘toxins', which leads to endothelial cell activation and/or damage as a result of cytokine release.

The mature parasite can also ‘ rosette' , a process in which RBCs containing the more mature stages bind uninfected RBCs to their surface. The mechanisms by which resetting lead to disease remain parasites that rosette have been associated with severe disease. Malaria-infected RBCs are also relatively non-deformable.

An important feature of malaria is the explosive increase in cytokines (notably TNF a ) during febrile episodes, coinciding with rupture of schizont-infected RBCs and suggesting toxin release.

The parasites derive their energy solely from glucose, and they metabolize it 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis. The plasmodia also cause lysis of infected and uninfected RBCs, suppression of hematopoiesis, and increased clearance of RBCs by the spleen, which leads to anemia as well as splenomegaly. Over time, malaria infection may also cause thrombocytopenia.

The morbidity and mortality caused by P. falciparum is increased greatly over that caused by other Plasmodium species because of the increased parasitemia of P. falciparum and its ability to cytoadhere.

top

Fig. 3: Anopheles mosquito
The malaria parasite typically is transmitted to humans by mosquitoes belonging to the genus Anopheles . In rare cases, malaria can also be transmitted through blood transfusion, organ transplant, or the shared use of needles or syringes contaminated with blood. Malaria also may be transmitted from a mother to her fetus before or during delivery ("congenital" malaria).

Note: When P. vivax and P. ovale are transmitted via blood, no latent hypnozoite phase occurs and treatment with primaquine is not necessary, as it is the sporozoites that form hypnozoites in infected hepatocytes.

top

The most common presentation of malaria is high fever. The incubation period is variable; the average is 10-14 days, but it may be as short as 7 days under optimal conditions or, in exceptional cases, upto 20 years in P. malariae infection. Symptoms occur within 6 weeks of the traveler leaving an endemic area in more than 90% of P. falciparum infections, and within one year in P.vivax infection. There may be a relatively short prodormal period of tiredness and aching.

The classical paroxysm begins abruptly within an intitial “cold stage', with dramatic rigors during which the patient has a temperature of more than 40 o C, may be restless and excitable and may vomit or convulse, and finally a sweating stage, when the fever abates and the patient may fall asleep. This paroxysm may last 6-10 hours, and is followed by a prolonged asymptomatic period followed by further rigors in untreated patients. There may be accompanying headache, cough, myalgia (flu like symptoms), diarrhoea and mild jaundice. In falciparum malaria, severe manifestations may intervene and can be rapidly fatal.

In adults, severe malaria is characterized by multiorgan damage, including renal failure. This is uncommon in children with severe malaria, who usually present with prostration, respiratory distress, severe anaemia, and/or cerebral malaria.

Table 2. Characteristics of severe malaria

top

Malaria must be excluded in all febrile patients living in, or returning from, an endemic country, regardless of whether they have been taking antimalarial drugs. It may be difficult to distinguish from other febrile illnesses as symptoms are non-specific. Malaria seldom, if ever, causes lymphadenopathy, pharyngitis or a rash; another explanation must be considered in patients with these features.

Clinical diagnosis of malaria is difficult, and misdiagnosis is frequent when laboratory conformation is not available or is disregarded by doctors anxious to identify a treatable cause of illness. Microscopy remains an important tool for diagnosis, but laboratory diagnosis in clinics without microscopy has now become possible through the development of rapid diagnostic tests.

Diagnostic tests

1. Microscopic demonstration of the parasite in blood smear
The diagnosis of malaria rests on the microscopic demonstration of asexual forms of the parasite in stained peripheral-blood smears.

 A definitive diagnosis of malaria is made by prompt microscopic examination of thick and thin blood films. Thick films contain many layers of RBCs, which lyse when stained, and are useful for screening. A thin film is a monolayer that is fixed before staining so that the RBCs do not lyse; it is useful for quantifying infection and for determining the species of Plasmodium . Examination of the blood film allows accurate speciation of the parasite and determination of parasite density. Occasionally, the initial blood film is negative, particulary when chemoprophylaxis has been taken, and the film should be repeated when the clinical suspicion is high. In general, films taken daily for 3 days (off antimalarial drugs) are an appropriate screen, though this may have to be prolonged when symptoms persist.

Fig. 4: Ookinetes of P. vivax in a thick blood smear.

Fig. 5: Red blood cells infected with P. falciparum

2. Rapid diagnostic tests (RDTs)
Rapid diagnostic tests are based on detection of circulating parasite antigens. These tests are especially useful in areas where facilities or expertise for microscopic examination of blood smear are not available. Kits for these tests are expensive. Similar to blood smears, these rapid tests may provide false-negative results in patients with very low parasitemia and should be repeated if results are initially negative and the diagnosis remains unknown. Available RDTs are as follows:

•  PfHRP2 dipstick or card test: This antigen capture test uses a monoclonal antibody to the histidine –rich protein 2 ( PfHRP2) of

P. falciparum . This is a useful test requiring minimal expertise, but it is not quantitative and can detect the presence of P. falciparum only. It remains positive for weeks after infection.

Fig. 6: PfHRP2 dipstick test

•  Plasmodium LDH dipstick or card test: It is a rapid test detecting parasite-specific lactate dehydrogenase (LDH). Monoclonal antibodies capture the parasite antigens and read out as coloured bands. One band is genus specific (all malarias) and the other is specific for P. falciparum. It may miss low-level parasitemia with P. vivax, P. ovale and P malariae , and does not speciate these organisms. It is not quantitative.

Fig. 7: Plasmodium LDH dipstick test

3. Other test

•  Polymerase chain reaction analysis: It is useful in accurate species diagnosis, mixed infections and the detection of low-level parasitemia. However, cost, time required and the need for specialized equipment make it impractical.

Laboratory Findings in malaria

• Normochromic, normocytic anemia is usual.
• The leukocyte count is generally normal, although it may be raised in very severe infections. There is slight monocytosis, lymphopenia, and eosinopenia, with reactive lymphocytosis and eosinophilia in the weeks after the acute infection.
• The erythrocyte sedimentation rate, plasma viscosity, and levels of C-reactive protein and other acute-phase proteins are high.
• The platelet count is usually reduced to 10 5 /µL.
• Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin times and by more severe thrombocytopenia.
• Levels of antithrombin III are reduced even in mild infection.
• In uncomplicated malaria, plasma concentrations of electrolytes, blood urea nitrogen (BUN), and creatinine are usually normal.
• Findings in severe malaria may include metabolic acidosis, with low plasma concentrations of glucose, sodium, bicarbonate, calcium, phosphate, and albumin together with elevations in lactate, BUN, creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin.
• Hypergammaglobunemia is usual in immune and semi-immune subjects.
• Urinalysis generally gives normal results.
• In adults and children with cerebral malaria, the mean opening pressure at lumbar puncture is ~160 mm of cerebrospinal fluid (CSF); usually the CSF is normal or has a slightly elevated total protein level [< 1.0 g/L (< 100 mg/dL)] and cell count (< 20/ m L).

top

Once a definitive diagnosis of malaria is made, treatment with specific antimalarial drugs and supportive measures are initiated. Speciating the parasite is critical in patients with malaria. Infection with P. falciparum may be more severe than infection with other Plasmodium species. In addition, chloroquine resistant P. falciparum is found in many areas.

Aims of malaria treatment

• Complete cure
• Prevention of progression of uncomplicated malaria to severe disease
• Prevention of deaths
• Interruption of transmission
• Minimizing the risk of selection and the spread of drug-resistant parasites

Referral to a specialist / hospital
Once diagnosis of malaria is confirmed, appropriate antimalarial treatment should be initiated immediately. While uncomplicated malaria can be managed at home, severe malaria needs special care at a hospital. Danger signs of severe malaria should be looked for and if any of these are noted, the patient should be referred to a specialist/hospital.

Symptoms and signs of severe malaria

• changes in behaviour (convulsions; unconsciousness; drowsiness; confusion; inability to walk, sit, speak, or recognize relatives);
• repeated vomiting, inability to retain oral medication, inability to eat or drink;
• passage of small quantities of urine or no urine, or passage of dark urine;
• severe diarrhoea ;
• unexplained heavy bleeding from nose, gums or other sites ;
• high fever (above 39° C);
• severe dehydration (loose skin and sunken eyes);
• anemia; and
• jaundice
• respiratory distress
• shock

General management of uncomplicated malaria

• Avoid starting treatment on an empty stomach. The first dose should be given under observation. The dose should be repeated if vomiting occurs within 30 minutes.
• The patient should report back if there is no improvement after 48 hours or if the situation deteriorates.
• The patient should also be examined for concomitant illnesses.

Treatment of uncomplicated malaria

 •  Treatment of non-falciparum uncomplicated malaria
Malaria caused by P.vivax , P. ovale or P.malariae requires a standard course of treatment with chloroquine, which usually leads to abatement of the fever.  When there is doubt about the infecting species, patients should be treated, as for falciparum malaria.

In P. vivax and P. ovale malaria, primaquine is given to eradicate the exerythrocytic forms (hypnozoites) responsible for relapses.  Patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency should not be given primaquine, because of the danger of drug-induced haemolysis in G6PD-deficient individuals.  Primaquine is not given to pregnant women and infants.

Chloroquine and primaquine resistance has now been documented in vivax malaria; may require quinine and / or prolonged treatment with primaquine.

Table 3: Chloroquine for P.vivax and P. falciparum cases in areas considered to be chloroquine-sensitive

Age in years	Number of tablets *
	Day 1 (10 mg/kg)	Day 2 (10 mg/kg)	Day 3 (5 mg/kg)
<1	½	½	¼
1–4	1	1	½
5–8	2	2	1
9–14	3	3	1½
15 and above	4	4	2

*Each tablet contains 150 mg base

Reference: National Drug Policy on Malaria 2010, Directorate of National Vector Borne Disease Control Programme.

Table 4: Primaquine for P. vivax (daily dosage for 14 days)

Age in years	Daily dosage (in mg)
<1	Nil
1–4	2.5
5–8	5.0
9–14	10.0
15 and above	15.0

Reference: National Drug Policy on Malaria 2010, Directorate of National Vector Borne Disease Control Programme.

•  Treatment of uncomplicated falciparum malaria
In the setting of rapid decline in many countries of the efficacy of the commonly used inexpensive monotherapies, such as chloroquine and sulphadoxine-pyrimethamine and due to the spread of drug resistance, the World Health Organization (WHO) now recommends use of artemisinin combination therapies (ACTs ) for the treatment of uncomplicated P. falciparum malaria.

• ACT consists of an artemisinin derivative combined with a long-acting antimalarial drug to try and reduce the risk of further resistance developing.
• Artemisinin derivatives must never be administered as monotherapy for uncomplicated malaria. These rapidly acting drugs, if used alone, can lead to the development of parasite resistance.
• ACTs should be given only to confirmed P. falciparum cases found positive by microscopy or RDT.
• According to the current World Health Organization (WHO) guidelines, ACTs can be given in the second and third trimester of pregnancy. The recommended treatment in the first trimester of pregnancy is quinine.
• WHO-recommended ACT Combinations (2010 Guidelines) are as follows:
  • Artemether/Lumefantrine
  • Artesunate + Amodiaquine
  • Artesunate + Sulfadoxine -Pyrimethamine
  • Artesunate + Mefloquine
  • Dihydroartemisinin + Piperaquine

•  Unique properties and mode of action of the artemisinin component combined with long acting antimalarial drug, offers the following advantages:

• Rapid and substantial reduction of the parasite biomass.
• Rapid resolution of clinical symptoms.
• Effective action against multidrug-resistant P. falciparum.
• Reduction of gametocyte carriage, which may reduce transmission of resistant alleles (in areas with low or moderate malaria transmission).
• Few reported adverse clinical effects.

•  Indian National Drug Policy on Malaria 2010 recommends single dose of primaquine on second day in patients infected with P . falciparum (Table 9).

Table 5. Dosing schedule for artemether/lumefantrine  

			No. of tablets at approximate timing of dosing a
Body weight in kg		(age in years)	0h	8h	24h	36h	48h		60h
5-14	(< 3)		1	1	1	1		1	1
15 – 24	( ≥ 3-8)		2	2	2	2		2	2
25 – 34	( ≥ 9 – 14)		3	3	3	3		3	3
> 34	(> 14)		4	4	4	4		4	4

a The regimen can be expressed more simply for ease of use at the programme level as follows: the second dose on the first day should be given any time between 8 h and 12 h after the first dose. Dosage on the second and third days is twice a day (morning and evening).

Reference: WHO guidelines for the treatment of malaria 2010.

Table 6: Dosing schedule for artesunate + amodiaquine  

Age	Dose in mg (No. of tablets)
	Artesunate (50 mg)			Amodiaquine (153 mg)
	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3
5 -11 months	25 (1/2)	25	25	76 (1/2)	76	76
≥ 1-6 years	50 (1)	50	50	153 (1)	153	153
≥ 7-13 years	100(2)	100	100	306 (2)	306	306
>13 years	200 (4)	200	200	612 (3)	612	612

Reference : WHO guidelines for the treatment of malaria 2010.

Table 7: Dosing schedule for artesunate + sulfadoxine-pyremethamine

Age	Dose in mg (No. of tablets)
	Artesunate (50 mg)			sulfadoxine-pyremethamine (500/25)
	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3
5 – 11 months	25 (1/2)	25	25	250/12.5 (1/2)	-	-
≥ 1- 6 years	50 (1)	50	50	500/25 (1)	-	-
≥ 7-13 years	100 (2)	100	100	1000/50 (2)	-	-
> 13 years	200 (4)	200	200	1500/75 (3)	-	-

Reference : WHO guidelines for the treatment of malaria 2010.

Table 8: Dosing schedule for artesunate + mefloquine  

Age	Dose in mg (No. of tablets)
	Artesunate (50 mg)			Mefloquine (250 mg)
	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3
5 – 11 months	25 (1/2)	25	25	-	125 (1/2)	-
≥ 1- 6 years	50 (1)	50	50	-	250(1)	-
≥ 7-13 years	100 (2)	100	100	-	500 (2)	250 (1)
> 13 years	200 (4)	200	200	-	1000 (4)	500 (2)

Reference : WHO guidelines for the treatment of malaria 2010.

Table 9: Primaquine for P. falciparum (single dose on second day of treatment)

Age in years	Dosage (in mg)
< 1	Nil
1–4	7.5
5–8	15
9–14	30
15 and above	45

Reference: National Drug Policy on Malaria 2010, Directorate of National Vector Borne Disease Control Programme.

•  Treatment of mixed infections

Mixed infections with P. falciparum should be treated as falciparum malaria.

•  Treatment based on clinical criteria without laboratory confirmation

All efforts should be made to diagnose malaria either by microscopy or RDT. However, special circumstances should be addressed as mentioned below:

•  Line of treatment, if RDT is negative and a microscopy result cannot be obtained within 24 hours

If RDT for only P. falciparum is used, negative cases showing signs and symptoms of malaria without any other obvious cause for fever should be considered as “clinical malaria” and be treated with chloroquine in the full therapeutic dose of 25 mg/kg body weight over 3 days. If a slide result is obtained later, the treatment should be adjusted according to species.

•  Line of treatment, if neither RDT nor microscopy is available

“Clinical malaria” cases should be treated with chloroquine in the full therapeutic dose.

top

Click here to view Algorithm

top

The great majority of severe malaria disease is due to P. falciparum , but increasing evidence shows that P. vivax might also present with severe disease.

• Severe malaria is an emergency and treatment should be given promptly.
• The diagnosis must be confirmed microscopically and intravenous access should be established as soon as possible. 
• Patients with severe malaria should be transferred to the highest possible level of clinical care (e.g. high-dependency unit, ICU). 
• Glucose and when possible, lactate and arterial blood gases should be measured. 
• Meticulous attention must be paid to fluid balance, because both dehydration and overhydration can occur. 
• Convulsions should be treated with intravenous diazepam and attention given to hypoglycaemia and hyponatraemia.  There is no clear evidence for routine use of prophylactic anticonvulsants.
• Blood should be taken for cross-matching and coagulation studies. 
• Parenteral artemisinin derivatives or quinine should be used, irrespective of chloroquine sensitivity.
• In the first trimester of pregnancy, parenteral quinine is the drug of choice. However, if quinine is not available, artemisinin derivatives may be given to save the life of the mother. In the second and third trimester, parenteral artemisinin derivatives are preferred.
• Care must be taken giving quinine to the elderly.  In these patients, a baseline ECG should be obtained, carefully observing the rhythm and QTc interval, and a cardiac monitor should be slowed in the event of marked prolongation of the QTc interval. 
• Recent evidence in childhood malaria has shown that blood transfusion may be beneficial in patients with respiratory distress and metabolic acidosis.
• Patients must be assessed individually.  Useful parameters during treatment include twice-daily parasite counts, regular pH and blood gas measurements and, when appropriate, measurement of glucose, lactate, C-reactive protein and renal function.
• Careful monitoring of blood glucose is essential during intravenous quinine treatment. 
• Elective mechanical ventilation should be considered where facilities are available, particularly in patients with severe acidosis, clear evidence of raised intracranial pressure or respiratory failure.
• Intravenous (I.V.) preparations should be preferred over intramuscular (I.M.) preparations.

Antimalarial drugs for the treatment of severe falciparum malaria

Artesunate: 2.4 mg/kg body weight i.v. or i.m. given on admission (time = 0 h); then at 12 h and 24 h and then once a day.

Artemether : 3.2 mg/kg body weight i.m. given on admission and then 1.6 mg/kg body weight per day.

Arteether: 150 mg i.m. daily for 3 days in adults only (not recommended for children).

Note: The parenteral treatment in severe malaria cases should be given for minimum of 24 hours once started (irrespective of the patient's ability to tolerate oral medication earlier than 24 hours). After parenteral artemisinin therapy, patients should receive a full course of oral ACT for 3 days (as described under treatment of uncomplicated falciparum malaria).

However, ACT containing mefloquine should be avoided in cerebral malaria due to neuropsychiatric complications.

Quinine Initial therapy with parenteral Quinine: 20 mg/kg * body weight on admission (IV infusion or divided IM Injection) followed by maintenance dose of 10 mg/kg body weight 8 hourly. The infusion rate should not exceed 5 mg salt/kg body weight per hour. * Loading dose of Quinine i.e. 20 mg /kg body weight on admission may not be given if the patient has already received quinine or if the clinician feels inappropriate. Note: The parenteral treatment in severe malaria cases should be given for minimum of 24 hours once started (irrespective of the patient's ability to tolerate oral medication earlier than 24 hours). Oral therapy after parenteral Quinine : Those patients who received parenteral Quinine therapy should receive oral quinine 10 mg/kg body weight 3 times a day for 7 days (including the days when parenteral Quinine was administered) plus Doxycycline 3 mg/kg body weight once a day or Clindamycin 10 mg/kg body weight 12-hourly for 7 days (Doxycycline is contraindicated in pregnant women and children under 8 years of age).

top

In recent years, increased attention has been drawn to severe malaria caused by P. vivax. Some cases have been reported in India , and there is reason to fear that this problem will become more common in the coming years. Severe malaria caused by P. vivax should be treated like severe P. falciparum malaria.

top

Cerebral malaria : The mainstay of treatment of cerebral malaria is antimalarial drugs.  A number of adjuvant therapies (e.g. corticosteroids, heparin) have been tried, but have not been shown to be effective.  An osmotic agent such as mannitol may be tried in patients with suspected raised intracranial pressure.

Hypoglycaemia : A ll patients with cerebral malaria should be monitored and treated for hypoglycaemia on admission and during quinine infusion.

Acute renal failure: This may require dialysis or haemofiltration.  Non-oliguric renal failure may be managed conservatively.

Acidosis leading to respiratory distress : Fluid replacement is essential.  Aspirin should be avoided.  Sodium bicarbonate has not been shown to be beneficial.  Transfusion has been shown to improve severe acidosis in anaemic young children.  Early haemodiafiltration and/or ventilation may be used.  The inotrope adrenaline should be avoided unless absolutely necessary.

Anaemia: Anaemia is mainly caused by rupture of infected cells and haemolysis.  Haemoglobin should be monitored, but transfusion should be reserved for patients in whom haemoglobin declines to below about 7.0 g/dl.

Bacterial superinfection:   Bacterial superinfection with an organism such as Streptococcus pneumoniae or Salmonella spp. is common in malaria.  Broad-spectrum antimicrobial antimicrobial drugs should be given as appropriate.

Jaundice : mild jaundice may be common and is mainly caused by haemolysis.  Deeper jaundice may result from major liver involvement, but may be caused by viral hepatitis.

Hyperparasitaemia : Complicated hyperparasitaemia may be treated with exchange transfusion.  Use of this treatment is controversial, but it should be considered when safe blood is available, in all patients in whom parasitaemia exceeds 30%, and in situations in which the parasitaemia is lower but:

• There are manifestations of severe, complicated malaria.
• There are medical complications (e.g. diabetes, ischaemic heart disease).
• The patient is elderly.
• The patient is pregnant.

top

Chemoprophylaxis is recommended for travellers, migrant labourers and military personnel exposed to malaria in highly endemic areas. Use of personal protection measures like insecticide-treated bed nets should be encouraged for pregnant women and other vulnerable populations. Recommendations based on Guidelines for Diagnosis and Treatment of malaria in India 2009 are as follows:  

• For short-term chemoprophylaxis (less than 6 weeks)

Doxycycline: 100 mg daily in adults and 1.5 mg/kg for children more than 8 years old. The drug should be started 2 days before travel and continued for 4 weeks after leaving the malarious area.
Note: Doxycycline is contraindicated in pregnant women, and children less than 8 years old.  

• For long-term chemoprophylaxis (more than 6 weeks)

Mefloquine: 5 mg/kg body weight (up to 250 mg) weekly and should be administered 2 weeks before travel, during stay, and continued for 4 weeks after leaving the area.
Note: Mefloquine is contraindicated in cases with a history of convulsions, neuropsychiatric problems and cardiac conditions.

top

Malaria is one of the major human killers worldwide. It is endemic in most parts of India and other tropical countries. Increasing resistance has been encountered to the commonly used antimalarial drugs in several parts of the world. This has aggravated the problem of malaria. Artemisinins hold great promise in the treatment of malaria, especially falciparum malaria. WHO recommends the judicious use of combination therapy with artemisinins in order to retard resistance and prolong utility of these vital drugs in our antimalarial armamentarium.

top

1. Guidelines for Diagnosis and Treatment of Malaria in India , 2009.
2. http://emedicine.medscape.com/article/221134. Last accessed on 07-08-09.
3. http://nvbdcp.gov.in/Doc/Malaria-situation-may2010.pdf. Last accessed on 11.08.2010.
4. Harrison textbook of medicine, 17th edition, 2008.
5. Medicine 2005; 33 (8): 39-43.
6. N. Engl. J. Med 2008; 358 (17): 1829-1836.
7. National Drug Policy on Malaria 2010, Directorate of National Vector Borne Disease Control Programme.
8. The journal of clinical investigation 2008; 118(4): 1266-1274.
9. WHO - World malaria report 2009.
10. WHO guidelines for the treatment of malaria 2006.
11. WHO guidelines for the treatment of malaria 2010.

top