MALARIA

1. INTRODUCTION  2. PREVALENCE  3. ETIOLOGY 4. LIFE CYCLE  5. PATHOGENESIS  6. TRANSMISSION  7. CLINICAL FEATURES  8. DIAGNOSIS 9. MANAGEMENT OF UNCOMPLICATED MALARIA Aims of malaria treatment Referral to a specialist / hospital General management of uncomplicated malaria Treatment of uncomplicated malaria Treatment of non-falciparum uncomplicated malaria Treatment of uncomplicated falciparum malaria Treatment of mixed infections Treatment based on clinical criteria without laboratory confirmation 10. ALGORITHM FOR THE DIAGNOSIS AND TREATMENT OF MALARIA 11. MANAGEMENT OF SEVERE MALARIA 12. SEVERE MALARIA CAUSED BY PLASMODIUM VIVAX  13. MANAGEMENT OF SPECIFIC COMPLICATIONS 14. CHEMOPROPHYLAXIS 15. SUMMARY 16. REFERENCES

INTRODUCTION

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.

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PREVALENCE

Global Scenario Malaria is a potentially fatal threat to almost half of the world's population. According to World Malaria Report 2008 , in 2006, there were an estimated 247 million malaria cases among 3.3 billion people at risk, causing nearly a million deaths, mostly of children below 5 years of age. i n 2008, 109 countries were endemic for malaria, 45 within the WHO African region. Fig. 1: Estimated incidence of malaria per 1000 population, 2006 Indian Scenario According to World Malaria Report 2008, India had an estimated 10.6 million malaria cases in 2006 that accounted for approximately 60% of cases in the WHO South-East Asia Region. Most affected Indian states are Uttar Pradesh, Bihar, Karnataka, Orissa, Rajasthan, Madhya Pradesh and Pondicherry . In the year 2006, of the 15,000 deaths attributed to malaria, 4,900 were among children less than 5 year of age.

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ETIOLOGY

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. Species can usually be distinguished by morphology on a blood smear. 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. falciparuminfection. 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 odd 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

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LIFE CYCLE

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. 2: 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. 2. 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. B. Erythrocytic cycle: After initial replication in the liver, the parasites undergo asexual multiplication in the erythrocytes (Fig. 2 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. 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. 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. 2 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 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.

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PATHOGENESIS

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. 3: Schematic representation of resetting 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 developingP.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.

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TRANSMISSION

Fig. 5: 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.

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CLINICAL FEATURES

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

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DIAGNOSIS

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. 6: Ookinetes of P. vivax in a thick blood smear. Fig. 7: 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. 8: 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. 9: 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).

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MANAGEMENT OF UNCOMPLICATED MALARIA

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. How to recognize the danger signs? Ask: Is the patient unable to drink? Has the patient had convulsions? Does the patient vomit repeatedly? How much urine does the patient pass? Very little? None at all? Is it dark? Look: Is the patient abnormally sleepy, difficult to wake, or confused? Does the patient have anaemia? Does the patient have severe dehydration? (Look for sudden weight loss, loose skin, sunken eyes, dry mouth.) Is the patient unable to stand or sit? If the answer to any of these questions is yes, the patient has severe febrile disease, probably severe malaria. The patient's life is in danger. Urgent treatment is needed at a clinic or hospital to save the patient's life. Give the first dose of antimalarial treatment. Then, refer the patient to the nearest clinic or hospital. Write a referral note to go with the patient; include details of what has been observed and what treatment has been given and when. 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 1. 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.  Glucose-6-phosphate dehydrogenase (G6PD) should be measured in all patients before giving 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: Guidelines for diagnosis and Treatment of malaria in India 2009. 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: Guidelines for diagnosis and Treatment of malaria in India 2009. 2. 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 (2006 Guidelines) are as follows: Artemether/Lumefantrine Artesunate + Amodiaquine Artesunate + Sulfadoxine -Pyrimethamine Artesunate + Mefloquine •  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 guidelines for diagnosis and treatment of malaria, recommend single dose of primaquine on first day in patients infected with P . falciparum (Table 9) . Table 5. Dosing schedule for artemether-lumefantrine   No. of tablets at approximate timing of dosinga 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 – 4) 3 3 3 3 3 3 > 34 (> 14) 4 4 4 4 4 4 aThe 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 2006. 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 2006. 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 2006. 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 2006. Table 9: Primaquine for P. falciparum (single dose on first day) Age in years Dosage (in mg) < 1 Nil 1–4 7.5 5–8 15 9–14 30 15 and above 45 Reference: Guidelines for diagnosis and Treatment of malaria in India 2009. 3. Treatment of mixed infections Mixed infections with P. falciparum should be treated as falciparum malaria. 4.  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.

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ALGORITHM FOR THE DIAGNOSIS AND TREATMENT OF MALARIA

Reference: Guidelines for diagnosis and Treatment of malaria in India 2009.

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MANAGEMENT OF SEVERE MALARIA

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. Table 10: Antimalarial drugs for the treatment of severe falciparum malaria Artesunate: 2.4 mg/kg i.v . or intramuscular ( i.m .), given on admission (time=0), then at 12 hours and 24 hours, and, then, once a day (care should be taken to dilute the artesunate powder in the 5% sodium bi-carbonate provided in the pack). Quinine: 20 mg quinine salt/kg on admission ( i.v . infusion in 5% dextrose/dextrose saline over a period of 4 hours) followed by a maintenance dose of 10 mg/kg, 8-hourly; infusion rate should not exceed 5 mg/kg per hour. Loading dose of 20 mg/kg should not be given if the patient has already received quinine. NEVER GIVE A BOLUS INJECTION OF QUININE. If parenteral quinine therapy needs to be continued beyond 48 hours, the dose should be reduced to 7 mg/kg, 8-hourly. Artemether: 3.2 mg/kg i.m . given on admission; then, 1.6 mg/kg per day. α β Arteether: 150 mg i.m. daily for 3 days in adults only (not recommended for children). Reference: Guidelines for Diagnosis and Treatment of malaria in India 2009 Once the patient can take oral therapy, further follow-up treatment should be as below: •  Patients receiving parenteral quinine should be treated with oral quinine 10 mg/kg three times a day to complete a course of 7 days, along with doxycycline 3 mg/kg per day for 7 days. Note: Doxycycline is contraindicated in pregnant women, and children below 8 years of age; instead, clindamycin 10 mg/kg body weight, 12-hourly for 7 days, should be used. •  Patients receiving artemisinin derivatives should get the full course of oral ACT. However, ACT containing mefloquine should be avoided in cerebral malaria due to neuropsychiatric complications.

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SEVERE MALARIA CAUSED BY PLASMODIUM VIVAX

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.

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MANAGEMENT OF SPECIFIC COMPLICATIONS

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 asStreptococcus 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.

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CHEMOPROPHYLAXIS

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.

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SUMMARY

Malaria is one of the most important infectious diseases in the world, leading to considerable morbidity and mortality. 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.