Malaria > Malaria

INTRODUCTION

As per the latest WHO information, over 40% of population of over 2075 million people in the world in more than 100 countries are exposed to the risk of malaria and 500 million of them suffer from malaria each year and one million die in Africa alone each year. In India incidence of malaria is 2.2 million each year since 1984 with 293 deaths during 1993. According to National Malaria Eradication programme 1997 the national average of incidence of falciparum malaria has risen to 34.5%. Incidence of cerebral malaria due to P. falciparum infection has been reported in 2 to 55% cases in different series of studies. It is a potentially fatal complication and carries a mortality of around 20% and its incidence seems to be increasing probably due to resistance to antimalarial medicines.
The affordable and widely available antimalarial chloroquine that was in the past the mainstay of malaria control is now ineffective in most falciparum malaria endemic areas. It is a form of an acute malaria caused by asexual form of parasite Plasmodium falciparum accompanied by Cerebral manifestations, like acute diffuse symmetrical encephalopathy characterised clinically by stupor, light to deep coma with other neurological symptoms. Prompt recognition and treatment can save the patient.

Pregnancy, lack of previous exposure to parasite and immuno-suppression seem to be the predisposing factors. According to a recent study it has come to light that there is a great genetic diversity in Plasmodium falciparum. A total of 71 clinical isolates were analysed. The malaria hyper endemic region (Orissa) not only showed the maximum number of variant forms of each gene but also the maximum number of cases with mixed alleles compared with the non-hyper endemic regions (Madhya Pradesh and Rajasthan).

CAUSES OF MALARIA
Human malaria is caused by infection of red blood cells with one of the four different species of the protozoan parasite Plasmodium: Plasmodium falciparum, P. vivax, P. ovale and P. malariae. Occasional infections with monkey malaria parasites, such as P.knowlesi, also occur. In India there is a higher prevalence of P.vivax and P.falciparum.

TRANSMISSION OF MALARIA
The malaria parasite is transmitted by various species of Anopheles mosquitoes, which bite mainly between sunset and sunrise.

NATURE OF THE DISEASE
Malaria is an acute febrile illness with incubation period of 7 days or longer.  The most severe form is caused by P. falciparum, in which variable clinical features include fever, chills, headache, muscular aching and weakness, vomiting, cough, diarrhoea and abdominal pain; other symptoms related to organ failure may supervene, such as: acute renal failure, generalized convulsions, circulatory collapse, followed by coma and death

LIFE CYCLE OF PLASMODIUM
Click here to see the life cycle of Plasmodium

MALARIA SYMPTOMS DIAGNOSIS
The most important element in the clinical diagnosis of malaria in both endemic and non endemic areas is to have a high index of suspicion. Clinical diagnosis supplemented by the detection of parasites in the blood forms the mainstay of diagnosing malaria. 

In areas where the risk of malaria is low, clinical diagnosis of uncomplicated malaria should be based on the degree of exposure to malaria and a history of fever in the previous 3 days with no features of other severe diseases.

In areas where the risk of malaria is high, clinical diagnosis should be based on a history of fever in the previous 24 hrs. and or the presence of anaemia, for which pallor of the palms seems to be the most reliable sign in young children.

In areas of high malaria transmission the most common cause of fever in children under 5 years of age is usually malaria. Here it is advisable to start antimalarial treatment for children with fever or a history of fever and no other obvious cause.

The diagnosis of malaria rests on the demonstration of asexual form of the parasite in peripheral blood smears stained preferably with Giemsa. Both thin and thick blood smears should be made with great care on clean slides. The thin smear should be air dried rapidly, fixed in anhydrous methanol, and stained. The red cells in the tail of the film should be examined under oil immersion microscopy. The level of parasitaemia is expressed as the number of parasitised erythrocytes per 1000 red blood cells, and this figure is then converted to the number per microlitre of blood.

The thick smear should be dried thoroughly and stained (also with Giemsa) without alcohol fixation. Since many layers of erythrocytes overlie one another and are lysed during the staining procedure, the thick film concentrates the parasites up to 40 times that of the thin smear, thereby increasing the sensitivity of diagnosis. Both parasites and white blood cells are counted, and the number of parasites per unit volume is calculated from the total leucocyte count. A minimum of 200 white cells should be counted. Interpretation of thick films requires experience because artifacts are common. Phagocytosed malaria pigments may be visible inside peripheral blood monocytes or polymorphonuclear leucocytes and may provide a clue to recent infection if malaria parasites are not seen. Occasionally, parasites and pigment are evident in bone marrow aspirates or smears obtained from fluid expressed after intradermal puncture, but not on peripheral blood smears.

Fluorescent Dyes
Staining of the parasites with the fluorescent dye acridine orange allows a more rapid diagnosis when levels of parasitaemia are low. Compared with microscopy, this technique is less accurate for species identification and for quantification of parasitaemia.

Microhaematocrit Centrifugation
Using this method with the CBC tube is a more sensitive method of detection of malaria infection. However, microhaematocrit centrifugation does not allow identification of the species of plasmodium. To determine the species, a peripheral blood smear must be examined.

Polymerase Chain Reaction (PCR)
This is a very specific and sensitive test for determination of the species of plasmodium present in an infected individuals blood. PCR is also very effective at detecting the plasmodium species present with parasitaemia as low as 10 parasites/ml of blood.

Parasight F (Dipstick Test)
This test is useful in detecting P.falciparum infection only. It is based on antibody recognition of the HRP-2 antigen of P.falciparum and has been found to be as specific as microscopy studies, in most cases. It is often able to detect P.falciparum in parasitaemias that are below the threshold of reliable microscopic species identification. The dipstick test is not as effective when parasite levels are below 100 parasites/ml of blood and rarely will be negative in those with high parasitaemias. For these reasons, Parasight F test results should always be confirmed with a second type of screening test.

The relation between the level of parasitaemia and the prognosis is complex; in general, patients with parasitaemia levels in excess of 105 per microlitre (~2 percent) are more likely to die. However, non-immune patients may die with relatively low parasite densities, and partially immune persons may tolerate relatively high levels with minor symptoms.
At any level of parasitaemia, a predominance of more mature parasites (i.e., >20 percent of parasites with visible pigment) or circulating P. falciparum schizonts (meronts) carries a poor prognosis.

Differential
Causes of fever with which malaria is particularly liable to be confused include upper respiratory infections, infections such as influenza, dengue and sandfly fevers and tuberculosis. Occasionally kala-azar, trypanosomiasis or bacterial endocarditis may be confused with it, as may be fever that can accompany neoplastic disease including Hodgkin’s disease. In jaundiced patients, infectious hepatitis (see below) or diseases of the biliary tract may be considered.
Meningitis should not cause difficulty, for signs of meningeal irritation are very rare in malaria in which, moreover, the cerebrospinal fluid is almost invariably normal. Any fever may, of course, give rise to convulsions in young children.
From all these conditions, malaria can usually be distinguished readily by blood film examination.

Other Clinical features
Rigors with aching limbs, headache and vomiting should always suggest a diagnosis of malaria. Vomiting is usually most marked as the temperature rises; when it falls there is a feeling of relief and vomiting usually ceases until the next paroxysm takes place. Febrile herpes is very common in malaria.

Confusion with delirium occurs in severe P. falciparum infections but is very rare in the other malarias. This confusion, which may simulate acute alcoholic intoxication, from which it must be differentiated, is sometimes referred to as the acute brain syndrome.

The commonest gastro-intestinal symptom in malaria is tenderness of the liver and, in P. falciparum infections; jaundice - usually mild - may be added to this. Fever in the presence of jaundice suggests malaria rather than infectious hepatitis, in which the fever has usually resolved by the time jaundice develops. Jaundice with intermittent fever and vomiting caused by P. falciparum constitutes the syndrome which used to be known as and is still sometimes referred to as bilious remittent fever.

Diarrhoea is rarely caused by malaria but can result from necrosis and damage to the intestinal wall in severe P. falciparum infections. Diarrhoea in the presence of fever is likely therefore to result from some infections such as typhoid, paratyphoid, cholera or dysentery but a blood film to exclude malaria should always be taken even when one of the other infections seems to be the probable cause of the fever.

A laboratory finding that may be of some value in malaria is slight leucopoenia with a relative increase in large mononuclear cells, contrasting with bacterial infections in which a polymorphonuclear leucocytosis develops. In the malaria patient, pigment in urine is usually increased.

TREATMENT OBJECTIVES

Uncomplicated malaria:
The objective of treating uncomplicated malaria is to cure the infection.  A secondary but equally important objective of treatment is to prevent the emergence and spread of resistance to antimalarials.  Tolerability, the adverse effect profile and the speed of therapeutic response are also important considerations.

Severe malaria:
The primary objective of antimalarial treatment in severe malaria is to prevent death. Prevention of recrudescence and avoidance of minor adverse effects are secondary. In the treatment of severe malaria in pregnancy, saving the life of the mother is the primary objective.

Treatment of uncomplicated vivax malaria
For chloroquine-sensitive vivax malaria the conventional dose of 25 mg base / kg bw is well tolerated and effective. The practical dose generally followed is 10 mg base /kg bw on first and second day followed by 5 mg base / kg bw on third day.

In chloroquine resistant areas

Quinine salt 10 mg/kg bw 8 hourly for 7 days or

Artesunate oral 2 mg /kg bw at 0, 12 and 24 hours followed by 2 mg /kg bw once daily to a total of 7 days.

Other artemisinin derivatives like artemether, artemotil ( α-β arteether) produce rapid clearance of parasitaemia and rapid resolution of symptoms.  Artemisinin derivatives when given alone, a 7-day course of treatment is required; but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective.

Treatment of uncomplicated falciparum malaria
Uncomplicated malaria is defined as symptomatic malaria without signs of severity or evidence of vital organ dysfunction. Acute falciparum malaria ranges from mild to severe malaria.  Young children and non-immune adults with malaria may deteriorate rapidly. Any patient whom the attending physician suspects of having severe malaria should be treated as such initially because the risks of under-treating severe malaria considerably exceed those of giving parenteral treatment to a patient who does not need it.

WHO now recommends Antimalarial combination therapy for the treatment of falciparum malaria, to reduce the treatment costs and treatment failure (recrudescence)

Artemisinin-based combination therapy (ACT)
Artemisinin and its derivatives (artesunate, artemether, artemotil (arteether), dihydro-artemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10,000 in each asexual cycle.  Artemisinin and its derivatives are eliminated rapidly  

In a 3 day ACT regimen, the artemisinin component is present in the body during only two asexual parasite life cycles. This exposure to 3 days of artemisinin treatment reduces the number of parasites in the body by a factor of approximately one hundred million. However, complete clearance of parasites is dependent on the partner medicine being effective and persisting at parasiticidal concentrations until all the infecting parasites have been killed. This calls for a partner drug which is eliminated slowly.

The artemisinin compounds are active against all four species of malaria parasites that infect humans and are generally well tolerated.

The following ACTs are currently recommended:

Artesunate + Sulphadoxine-Pyrimethamine
The total recommended treatment is 4 mg / kg bw of artesunate given once a day for 3 days and a single administration of sulphadoxine-pyrimethamine (25/1.25 mg base/kg bw) on day 1.

Artesunate + Mefloquine
The total recommended treatment is 4 mg / kg bw of artesunate given once a day for 3 days and 25 mg base / kg bw of mefloquine usually split over 2 or 3 days.

Artesunate + Amodiaquine
The total recommended treatment is 4 mg / kg bw of artesunate and 10 mg base / kg bw of amodiaquine given once a day for 3 days

Artemether-Lumefantrine
Co-formulated tablets: Each containing 20 mg of artemether and 120 mg of lumefentrine. The total recommended treatment is a 6-dose regimen of artemether-lumefentrine given twice a day for 3 days.

Treatment of severe Falciparum Malaria
The main treatment objective is to prevent the patient from dying. Secondary objectives are prevention of recrudescence, transmission or emergence of resistance and prevention of complications and disabilities.

The mortality of untreated severe malaria is thought to be close to 100%. Death from severe malaria often occurs within hours of admission to hospital or clinic, and so it is essential that full therapeutic concentrations of antimalarial are achieved as soon as possible.

Clinical assessment
Severe malaria is a medical emergency. The airway should be secured in unconscious patients and breathing and circulation assessed. The patient should be weighed so that antimalarials and fluids can be given on body weight basis.

An intravenous cannula should be inserted and immediate measurements of blood glucose, haemoglobin, parasitaemia and in adults, renal function should be taken.

A detailed clinical examination should be done especially for the level of consciousness and coma. The Glasgow coma scale is suitable.

Antimalarial treatment
To avoid life threatening complications it is essential that antimalarial treatment in full doses is given as soon as possible in severe malaria.  Two classes of drugs are currently available for the parenteral treatment of severe malaria: the cinchona alkaloids – Quinine and the artemisinin derivatives (artesunate, artemether and arteether (artemotil) )

QUININE
Has an unparalleled record of saving innumerable serious patients of malaria and has withstood the treacherous falciparum malaria with negligible drug resistance.
 
Pharmacokinetic modeling studies suggest that a loading dose of quinine of twice the maintenance dose (i.e. 20 mg salt / kg bw) reduces the time to reach therapeutic plasma concentrations.  After the first day of treatment, the total daily maintenance dose of quinine is 30 mg salt /kg bw usually divided into three equal doses at 8 hr intervals.

ARTEMISININ DERIVATIVES
Although various artemisinin derivatives have been used in the treatment of severe malaria including artemether, artemisinin (rectal), artemotil (arteether) and artesunate, the pharmacokinetic properties of artesunate are superior to those of others. Since artesunate is water soluble it can be given either by intravenous or intramuscular injection (besides oral formulations for follow up treatment).

The dosing of artemisinin derivatives has been largely empirical. The doses now recommended are those arrived at after large scale studies. The recent change in dose is the higher maintenance dose of parenteral artesunate at 2.4 mg / kg bw based on pharmacokinetic and pharmacodynamic studies and extrapolation from studies with oral artesunate.

Artesunate by iv or im is to be administered as follows:
2.4 mg /kg bw at 0, 12 and 24 hrs then once daily to complete 7 days treatment.

Expert opinion is that the previously recommended maintenance dose of 1.2 mg / kg bw may have been insufficient in some patients. Studies have also suggested that the MIC for artesunate is achieved by a minimum daily dose of 2 mg / kg bw and any dose below that may not be sufficient. 

FOLLOW-ON TREATMENT
Following initial parenteral treatment, once the patient can tolerate oral therapy, it is essential to continue and complete treatment with an effective oral antimalarial.  Current practice is to continue the same drug orally as given parenterally  to complete a full 7 days of treatment.