Malaria Mosquito Borne Infectious Disease Biology Essay

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Malaria is a mosquito-borne infectious disease of humans and other animals caused by parasites of the genus plasmodium. It begins with a bite from an infected female mosquito (more than 30 anopheline species), which introduces the parasite via its saliva into the circulatory system, and ultimately to the liver where they mature and reproduce. The disease causes symptoms that typically include fever, chills and headache, which in severe cases can progress to coma or death. Malaria is widespread in tropical and subtropical regions in a broad band around the equator, including much of Sub Saharan Africa, asia and the Americas.

There are five species of parasites of the genus Plasmodium that affect humans and of which only 3 species are found in India. These are Plasmodium malariae (Laveran, 1881), Plasmodium vivax (Grassi and Feletti, 1890), Plasmodium falciparum (Welch, 1897), Plasmodium ovale (Stephens, 1922) and Plasmodium knowlesi (Robert Knowels, 1932). Malaria due to P. falciparum is the most deadly, and it predominates in Africa. P. vivax is less dangerous but more widespread, and the other species are found much less frequently. P. knowlesi is the fifth major human malaria parasite (following the division of plasmodium ovale into 2 species). This is an emerging infection that was reported for the first time in humans in 1965 and it accounts for up to 70% of malaria cases in certain areas in South East Asia where it is mostly found.

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HISTORY

Malaria has great impact on social and economic development of humans. Malaria was linked with poisonous vapours of swamps or stagnant water and named by the Italians in the 18th century as Malaria (from the Italian mala "bad" and aria "air"). In the fifth century B.C., the greek physician Hippocrates described the clinical manifestations and some of the complications of Malaria. The first major breakthrough in understanding the etiology of the disease was in 1880, when Laveran, a French army surgeon in Algeria, described exflagellated gametocytes of Plasmodium falciparum in a fresh blood film from a patient with Malaria. It was only in 1897, that Ronald Ross, a British army surgeon in India, conclusively established the major features of the life cycle of plasmodia by a careful series of experiments in naturally infected sparrows.

During the 20th Century, progress was made in vector control technology and in 1955 potent synthetic compound called DDT was found and along with other residual insecticides, the World Health Organization (WHO) launched a worldwide program of malaria eradication. This ambitious program was hindered by the development of DDT resistance among vector and chloroquine resistance in some strains of Plasmodium falciparum. Soon it was accepted by the world that "Malaria" was here to stay and subsequently in 1978, the World health assembly changed its focus from eradication to control.

EPIDEMIOLOGY OF MALARIA

Global Scenario

Based on documented cases, the WHO estimates that there were 216 million cases of malaria in 2010 resulting in 655,000 deaths. This is equivalent to roughly 2000 deaths every day. A 2012 study estimated the number of documented and undocumented deaths in 2010 as 1.24 million. An estimated 3.3 billion people were at risk of Malaria in 2010, although of all geographical regions, populations living in Sub-Saharan Africa have the highest risk of acquiring Malaria; in 2010, 81% of cases and 91% of deaths are estimated to have occurred in the WHO African region.

The majority of cases (65%) occur in children under 15 years of age. Pregnant women are also especially vulnerable: about 125 million pregnant women are at risk of infection each year. In Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly. There are about 10,000 malaria cases per year in Western Europe, and 1300-1500 in the United States. Both the global incidence of disease and resulting mortality has declined in recent years. According to the WHO, deaths attributable to malaria in 2010 were reduced by over a third from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies.

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in Sub-Saharan Africa where 85-90% of malaria fatalities occur. As of 2010, about 106 countries have endemic malaria. Every year, 125 million international travelers visit these countries, and more than 30,000 contract the disease. The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other. Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters in which mosquito larvae readily mature, providing them with the environment they need for continuous breeding.

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Regional Scenario

Out of the 11 countries of SEAR, 10 are malaria endemic. Maldives has no endogenous transmission since 1984. SEAR accounts for 30% of global morbidity and 8% of global mortality due to malaria. An estimated 82.8% of the total population is at risk and about 2.5 million cases are reported annually in the region. India contributes to more than three-fourths of the total cases in the South East Asian Region. Since 2004, there has been an increasing number of reports of the incidence of P. knowlesi among humans in various countries in South East Asia, including Malaysia, Thailand, Singapore, the Philippines, Vietnam, Myanmar and Indonesia.

Country Scenario

Malaria transmission occurs in almost all areas of India except areas above 1800 meters sea level. Country's 95% population lives in malaria risk prone areas and 80% of malaria reported in the country is confined to areas consisting 20% of population i.e. residing in tribal, hilly, difficult and inaccessible areas. Directorate of National Vector Borne Disease Control Programme (NVBDCP) has framed technical guidelines/ policies and provides most of the resources for the programme.

The case load, around 2 million cases annually in the late nineties, has shown a declining trend since 2002. At low levels of surveillance, the Slide Positivity Rate (SPR) may be a better indicator. The SPR has shown gradual decline from 3.32 in 1995 to 1.41 in 2010 (3). The reported Pf cases declined from 1.14 million in 1995 to 0.77 million cases in 2010. However, the Pf % has gradually increased from 39% in 1995 to 52.12% in 2010. Number of reported deaths has been leveling around 1000 per year.

Currently, 80.5% of the population of India lives in malaria risk areas. Since 1970s, in India, areas with an API above 2 cases per 1000 population per year have been classified as high risk and thereby eligible for vector control. The current situation of Malaria in India is shown in Fig 6.1.

Malaria in India is unevenly distributed with a risk of increase in cases in epidemic forms every 7-10 yrs depending on the immune status of the population, breeding potential of the mosquitoes and the rainfall pattern. In North-East states efficient malaria transmission is maintained during most months of the year. Intermediate level of stability is maintained in the plains of India in the forests and forest fringes, predominantly tribal settlements in 8 states (AP, Gujarat, Jharkhand, MP, Chattisgarh, Maharashtra, Orissa and Rajasthan).

The largest number of cases in the country is reported in Orissa, followed by Chhattisgarh, West Bengal, Karnataka, Jharkhand, Madhya Pradesh, Uttar Pradesh, Assam, Gujarat and Rajasthan. The largest numbers of deaths are reported in Orissa, followed by West Bengal, Assam, Maharashtra, Meghalaya, Mizoram, Karnataka, Jharkhand and Madhya Pradesh Fig 6.2.

Annually about 100 million fever cases are being screened by blood smears. There are 3.12 lakh Drug Distribution Centers, 1.17 lakh Fever Treatment Depots and 13 thousand Malaria Clinics functioning in the country.

IMPORTANT TIMELINE

1947: At the time of independence, malaria was responsible for an estimated 75 million cases and 0.8 million deaths annually.

1953: National Malaria Control Programme was launched.

1958: With its overwhelming success, GOI launched National Malaria Eradication Programme.

1965-66: Due to concerted implementation of strategies, particularly spraying with DDT, the number of annual cases was successfully brought down to 100,000 and deaths were eliminated.

1971: Since the resurgence of malaria in early 1970s, urban malaria has been recognised as an important problem contributing to overall malaria morbidity in the country. To assist the states in control of malaria in urban areas, Urban Malaria Scheme (UMS) was launched in 1971. The scheme is being implemented in 131 towns in the country. Urban malaria poses problems because of haphazard expansion of urban areas. The urban malaria vector, An. stephensi breeds in stored water and domestic containers. Construction activities and aggregation of labour provide ideal opportunities for vector to breed and transmit malaria in urban areas.

1976: However, in the following years, the Programme faced various technical obstacles as well as financial and administrative constraints, which led to countrywide increase in malaria incidence to 6.47 million cases.

1977: Modified Plan of Operation (MPO) under NMEP was launched as a contingency plan to effectively control malaria by preventing deaths, reducing morbidity so as to improve the health status of the people. With the adoption of the MPO strategy, the total malaria cases decreased significantly. Presently, about 2 million cases are being reported in the country annually, about half of which are P. falciparum cases.

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1982: The National Anti-malaria Drug Policy was drafted in 1982 to combat the increasing level of resistance to chloroquine detected in Pf.

1997: The name of the programme was changed to National Anti Malaria Programme. Enhanced Malaria Control Project (EMCP) was launched in April 1997 with the assistance of the World Bank. This is directly benefiting the six crore Tribal Population of the eight peninsular states covering 100 districts and 19 urban areas.

2003: National Vector Borne Diseases Control Programme was envisaged as an umbrella programme for prevention and control of Malaria and other vector borne diseases such as Filariasis, Dengue, Japanese Encephalitis and Kala-azar.

2008: the global malaria action plan (GMAP) was launched by the roll back malaria partnership (RBM) as a blueprint for the control, elimination and eventual eradication of malaria, setting as its objective the reduction of the number of preventable malaria deaths worldwide to near zero by 2015.

2010: The year 2010 was an important milestone on the way to achievement of internationally agreed goals and targets for malaria Control. It was the date set by the World Health Assembly in 2005 to ensure reduction of the malaria burden by at least 50% compared to the levels in 2000. The aim was to make indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINS) available to all people at risk of malaria, and for all public health facilities to be able to provide reliable diagnosis and effective treatment for malaria.

2011: In the light of progress made by 2010, RBM updated the GMAP targets in June 2011. Maintaining an overall vision of a "malaria-free world", the targets are now to: (i) reduce global malaria deaths to near zero by end-2015, (ii) reduce global malaria cases by 75% from 2000 levels by end-2015, and (iii) eliminate malaria by end-2015 in 10 new countries since 2008, including in the WHO European Region. These targets will be met by: achieving and sustaining universal access to and utilization of preventive measures; achieving universal access to case management in the public and private sectors and in the areas where public health facilities are able to provide a parasitological test for all suspected malaria cases, near zero malaria deaths is defined as no more than 1 confirmed malaria death per 100,000 population at risk.

SOCIOECONOMIC IMPACT

Malaria affects everyday life of the afflicted persons and is one of the major causes of loss of income and absenteeism in schools. It is thus, directly linked with socio-economic development and referred to as both a disease of poverty and a cause of poverty. Economists believe that malaria is responsible for a growth penalty of up to 1.3 percent per year in some African countries. When compounded over the years, this penalty leads to substantial differences in GDP between countries with and without malaria and severely restrains the economic growth.

The direct costs of malaria include a combination of personal and public expenditures on both prevention and treatment of the disease. The indirect costs of malaria include lost productivity or income associated with illness or premature death. Although difficult to express in financial terms, another indirect cost of malaria is the human suffering caused by the disease.

J. A. Sinton estimated a loss of Rs.7, 500 million per year to the Indian economy on account of malaria in 1935. The Indian Institute of Management - Ahmedabad calculated that each rupee spent on the malaria programme since 1953-54 has brought in a benefit of Rs.9.27 to the nation. According to an estimate by MRC-ICMR, Delhi, in 1994, every rupee invested in malaria control produces a direct return of Rs. 22.10. The calculations do not include the hidden but large savings on account of the labour days, which is many times higher than that of the direct savings of an individual. In terms of Disability Adjusted Life Years (DALYs), malaria in India contributes to 1.86 million years. Among the females, DALYs lost were 0.786 million as against 1.074 million in the males. The maximum DALYs lost (53.25%) were in the middle productive ages from 15 to 44 years followed by children <14 years of age (27.68%) and rest 19% in >45 years of age.

Transmission dynamics of malaria

A large number of factors related to "Agent", "Host", 'Vector' and "Environment" have a role in determining the transmission dynamics.

Host factors

Age : All ages are equally affected. Children are usually effective carriers of gametocytes. In areas with high falciparum transmission, newborns will be protected during the first few months of life due to maternal antibodies transferred to them through the placenta.

Gender : Gender does not affect the incidence or severity of malaria infection and disease per se, but because they are often related to frequency of exposure (via occupation, social behaviour, and migration).

Innate Immunity : Some persons residing in highly malarious areas do not acquire infection. This may be due to innate immunity of the individual. Such immunity is mainly due to antibodies and T-lymphocytes specific for Plasmodium, which result in reduced illness despite infection.

Blood group : There are other factors, which determine immunity against malaria. Genetic characteristics of the erythrocytes and presence of haemoglobinopathies usually confer some sort of protection against infection with malaria parasite. Individuals lacking in Duffy blood group antigen are refractory to P.vivax infection. This points to the fact that Duffy coating on the RBC wall may modify receptors in respect of P.vivax merozoites. Haemoglobin HbS sickle cell trait and Haemoglobin C have a protective effect against P.falciparum.

Economic Status : Economic status is inversely related to incidence of malaria mainly because of poor housing. Ill ventilated and poorly lighted houses provide ideal resting places for mosquitoes.

Migration : Large scale migration of population from one part of the country for sowing, transplanting and harvesting of crops results in spread of malaria. Tropical aggregation of labour is associated with malaria. The labour migrating from malarious to non-malarious areas bring immune and non-immune population together coupled with local and imported parasite reservoir at the site of temporary camps. Focal outbreaks can be explosive in such situations. They also bring different strains of malaria parasite to the project site including drug resistant strains.

Environmental factors

Weather: There are seasonal variations in mosquito density, resting, feeding and biting habits, longevity and flight capabilities. Malaria is therefore, seasonal in most parts of the country. In most of the states the maximum transmission is during the period July to November.

Temperature and Humidity : Optimal conditions for malaria transmission occur when the temperature is between 20°C and 30°C and the mean relative humidity is at least 60%. Sporogony does not occur at temperatures below 16°C or at temperatures higher than 33°C. Water temperatures regulate the duration of the aquatic breeding cycle of the mosquito vector. A high relative humidity increases mosquito longevity and therefore increases the probability that an infected mosquito will survive long enough to become infective. The forest cover of an area keeps humidity levels at high level resulting in long survival of all vector mosquitoes.

Altitude : Transmission decreases with increasing altitude and as a rule and it stops above the heights of 2000 m.

Man made malaria : Construction of roads, railways, irrigation works, dams and barrages, deforestation and other engineering projects have resulted in creation of mosquito breeding place in many new areas. The proximity of human habitation to breeding sites directly influences vector - human contact and, therefore, transmission. Agriculture and irrigation have an intricate role in malaria transmission. In areas where irrigation channels are not properly maintained, high vector mosquito density is observed. Temporary hutments in agriculture fields result in increased exposure to mosquitoes. Wells, overhead tanks, ornamental tanks, roof gutters, water storage containers, construction sites, room coolers, valve chambers etc. are important breeding places for A.stephensi. Use of disposable cups, bottles and other items, which can collect water, increase the risks of mosquito breeding. The slums within the town and its periphery are the worst affected areas because of lack of water management and appropriate anti-larval operations.

Agent factors

Genus : The disease is caused by the haemoparasites of genus Plasmodium, family Plasmodiidae, suborder Haemosporidiidae, order Coccidia.

Life cycle : The life cycle of the plasmodium occurs in two stages, the sexual cycle (sporogony) in the mosquitoes and asexual cycle (schizogony) in the human host. Within the vertebrate host, schizogony is found both within erythrocytes (erythrocytic schizogony) and in other tissues (exo - erythrocytic schizogony). The development of asexual cycle in man, its duration and course of infection are determined by the genetic composition of the malaria parasite.

Sporozoites (microscopic, motile forms of malarial parasite) are released into blood of the human host from the saliva of infected female mosquito when it bites him/ her. Within minutes, these attach to and invade liver cells by binding to hepatocyte receptor for the serum proteins thrombospondin and properdin. The sporozoites multiply in the hepatocytes and get released in batches from them in form of merozoites, which are the asexual, haploid forms.

The human red blood cells contain sialic acid residues on the glycophorin molecules attached to their surface. The plasmodium merozoites attach to these sialic acid residues by a parasite lectin like molecule. In the RBCs, the parasites grow in a membrane bound digestive vacuole, hydrolyzing hemoglobin through secreting enzymes. This stage is called the trophozoite and contains a single chromatin mass. The next stage is the schizont (erythrocytic schizont) with multiple chromatin masses, each of which develops into a fresh merozoite. The schizont forms after about 48 hr of intra-erythrocytic life (72 hr for P. malariae) and is characterized by consumption of almost all the hemoglobin and occupation of most of the RBC cavity.

The RBC ruptures and a new batch of merozoite is released from it, which infects other RBCs. This cycle repeats itself till the host immune mechanisms come into play. Some schizonts mature into sexual forms called the gametocytes that infect the mosquitoes when they take their blood meal.

During the hepatic phase, a proportion of sporozoites do not devide but remain dormant for a period ranging from 3 weeks to a year longer before reproduction. These dormant forms are called hypnozoites and are the cause of relapses that occur in P. vivax and P. ovale.

After being ingested in the blood meal of the biting female mosquito, the male and female gametocytes form a zygote in the insect's gut wass. The resulting oocyst expands by asexual division until it bursts to release a myriad of motile sporozoites, which then migrate in the hemolymph to the salivary gland of the mosquito to await inoculation into other human at the next feeding episode.

Parasite load : The parasite load and the gametocyte production are influenced by development of immunity in human host. The difference in parasitaemia levels observed in P.vivax and P.falcipatum are attributed to the fact that P.vivax tends to invade younger RBCs while the P.falciparum invades all RBCs irrespective of their age.

Reservoir : The source of infection is a malaria case with adequate number of mature viable gametocytes circulating in the blood. It has been estimated that in order to infect a mosquito, the blood of a human carrier must contain at least 12 gametocytes per mm3 and the number of female gametocytes must be more than the male gametocytes. The human case of malaria becomes infective to mosquito when mature, viable gametocytes develop in the blood of the patient in sufficient density.

Bionomics of malaria vectors

There are many species of anopheline mosquitoes in India but only 6 are regarded as primary vectors and another 3 or 4 as secondary or local vectors. The following characteristics of vector mosquitoes play an important role in the epidemiology of malaria.

Breeding Habits : The breeding habits of mosquitoes show a lot of variation. Hence, vector mosquitoes tend to be confined to certain geographical areas only. Anopheles sundaicus prefers to breed in brackish waters. The main urban vector Anopheles stephensi commonly breeds in wells, cisterns and over head tanks. Tanks, pools, burrow pits and ditches are the preferred breeding spots for Anopheles annularis and Anopheles philippinensis while Anopheles dirus is usually found breeding in forest pools, streams and slit trenches. A.culicifacies is the major vector of rural malaria. It breeds in different ground water collections. During the rainy season, breeding places are numerous. Hence the density is at its peak in the rainy season. The other major vectors are A.minimus and A.fluviatilis. They breed in running channels with clear water. Therefore the densities reach the peak after the monsoon season when streams and channels have slow moving clear water.

Density : For effective transmission of malaria in a locality, the mosquito vector must attain and maintain a certain density. This is called critical density and it varies from one mosquito to another and also under different environmental conditions. Anopheles culicifacies needs a very high density for transmission of malaria.

Longevity : A mosquito, after an infective blood meal, must live for at least 10 days to complete the development of malaria parasites.

Tropism : Some mosquitoes like Anopheles fluviatilis, Anopheles minimus prefer human blood and are called anthropophilic. Others like Anopheles culicifacies preferably feed on animal blood and are called zoophilic. When the densities are high or when the man cattle ratio is higher, they feed on humans too. This preferential feeding habit is called tropism. It has obvious bearing on the transmission of malaria.

Biting and resting behaviour : Some vector mosquitoes bite at or soon after dusk, others either during late night or early hours of the morning. However, some species may be active at two different periods during the same night. Control strategies should consider such habits of mosquitoes. Use of impregnated bed nets would definitely be more effective when there are late biters in that area. A female mosquito rests either indoors (endophilic) or outdoors (exophilic) after a blood meal for maturation of its eggs. The common resting places are either human dwellings, cattle sheds or mixed dwellings.

Flight Range : The distribution and dispersal of vector species depend upon their flight range. This is important for tracing the source and planning control measures. Some have a short flight range e.g. Anopheles dirus, Anopheles annularis and Anopheles fluviatilis. The species with flight range upto Two km distance are Anopheles culicifacies and Anopheles stephensi. Anopheles sundaicus may fly upto 8 or 10 km.

MODE OF TRANSMISSION

The most prevalent mode of Transmission of malaria is through the bite of the infected Female anopheles mosquito. The mosquito is infective only if the sporozoites are present in its salivary glands. However, malaria can also be transmitted by intravenous or intramuscular Injection of infected blood or plasma in an otherwise healthy person. The parasite can stay alive for nearly two weeks at - 4°c in bottled blood. Rarely transmission can also occur from Infected mother to the newborn.

Malaria SURVEILLANCE

Malaria surveillance connotes the maintenance of an on-going watch/ vigil over the status of malaria in a group or community. The main purpose of surveillance is to detect changes in trends or distribution in malaria in order to initiate investigative or control measures.

1. Fortnightly Domiciliary visits

The active case detection is carried out by multipurpose health workers (male) under primary health care system by conducting active case detection every fortnight by making domiciliary visits. Technical justification for a fortnightly blood smear collection is based on transmission dynamics of malaria. The incubation interval in case of P.vivax is approximately 22 days while for P.falciparum it is 35 days. Thus, surveillance cycle of less than one incubation interval will catch most of the secondary cases before the commencement of next cycle.

2. Fever Treatment Depots (FTDs)

Fever Treatment Depots are established in remote villages. The FTD holder is given training for one or two days at the PHC in the collection of blood smears, administration of presumptive treatment, impregnation of bed nets, promotion of larvivorous fish, etc.

3. Passive Case Detection (PCD)

All Allopathic, Ayurvedic, Homeopathic, Siddha medicine dispensaries in the health sector are identified and involved in passive case detection. All the fever cases attending the hospital should be screened for malaria and given presumptive treatment.

4. Rapid Fever Survey

In case of an epidemic outbreak, every house of the village in the suspected epidemic zone is visited and all fever cases are screened by taking blood smears.

5. Mass survey

As an alternative to Rapid Fever Survey, if possible mass survey of the entire population may be carried out in the suspected epidemic zone. Here all the population irrespective of age, sex or fever status is screened by taking blood smear.

6. Drug Distribution Centre (DDC)

If it is not possible to have FTD, the medical officer should establish DDC. The functions of DDCs are the same as those of FTDs, except that the DDCs do not take blood slides but administer drugs to fever cases.

7. Annual blood smears examination rate and its validity

All fever cases occurring in the community are examined for malaria parasite, and then the total malaria parasite load is examined. The monthly blood examination rate (MBER) norms are 0.8 percent during non-transmission season and 1.2 to 1.8 percent during transmission season were laid down in the Indian Malaria Eradication Programme.

ABER = No. of blood smears collected during the year x 100

Population covered under surveillance

MBER = No. of blood smears collected during the month x 100

Population covered under surveillance

ABER/ MBER is an index of operational efficacy of the programme. The Annual Parasite Incidence (API) depends upon the ABER. A sufficient number of blood slides should be systematically obtained and examined for malaria parasite to work out accurate API.

8. Slide Positivity Rate (SPR)

The Slide Positivity Rate among the blood smears collected through both active and passive surveillance gives more accurate information on distribution of malaria infection in the community over a period of time. Trends in SPR can be utilized for predicting epidemic situations in the area. If monthly SPR exceeds by 2 ½ times of the standard deviation observed in SPR of the preceding 3 years or preceding 3 months of the same year, an epidemic build up in the area can be suspected.

SPR : No. of blood smears found positive for malaria parasite X 100

No. of blood smears examined

9. Annual Parasite Incidence (API)

This parameter measures the incidence of malaria. It is calculated as:

API = No. blood smears found positive for malaria parasite x 1000

Total population under surveillance

API can be utilized for assessing the malaria endemicity in the area and impact of control operations. The level of API determines whether spray should be taken up in any area. In only those areas with API more than 2, regular rounds of spray would be planned. API calcualtes incidence of malaria and based on this, areas are divided into high & low risk zones.

10. P. falciparum Percentage

This is calculated as:

P.f % = No. blood smears found positive for P.falciparum x 100

     No. blood smears found positive for malaria parasite

Pf % is required to find out prevalence of P.falciparum infection, which can cause severe manifestations of malaria including death.

PATHOPHYSIOLOGY

P.vivax, P. ovale and P. malariae cause low level parasitemia, mild anaemia and in rare instances, splenic rupture and nephritic syndrome. P. Falciparum on the other hand usually cause high levels of parasitemis, severe anaemia, cerebral symptoms, renal failure, pulmonary edema and even death. Pathophysiology of malaria results from destruction of erythrocytes, the liberation of parasite and erythrocyte (Cytokines, Nitric Oxide etc) material into the circulation, and the host reaction to these events. P. falciparum malaria differs from the other human species of malaria parasite because infected erythrocytes also sequester in the microcirculation of vital organs, interfering with micro circulatory flow and host tissue metabolism, which results in severe organ damage.

The P. falciparum's greater pathogenicity is due to the following reasons:

(a) It is able to infect red cells of any age and maturity, leading to high parasite burden and profound anaemia. (compared to that caused by other species which infect only the young or very old RBCs)

(b) P. falciparum causes infected RBCs to clump together (forming rosettes) and to stick to the vascular endothelium (sequestration) blocking the blood flow. Ischemia due to poor perfusion causes the manifestations of cerebral malaria, which is the main cause of mortality especially in children.

(c) P. falciparum stimulates production of high levels of cytokines like TNF, INF gamma and IL-1. This is induced further by GP-1 linked proteins and merozoite surface antigens released from infected RBCs. These cytokines suppress production of new RBCs, increase fever, stimulate nitric acid production which in turn causes tissue damage and induce expression of endothelial receptors for P. falciparum erythrocyte membrane protein 1 (PfEMP1; it forms knobs in RBC membrane and binds to ligands like CD36, VCAM-1, ICAM-1 and E-selectin, on endothelial lining).

CLINICAL FEATURES

The clinical features of malaria result from the periodic release of merozoite release from the RBCs and subsequent cytokine activation. The showers of merozoite occur with definite periodicity: every 48 hours in falciparum, vivaz and ovale and every 72 hours in malariae. This accounts for the classical intermittent fever in malaria. However, this periodicity may not follow a strict pattern in all clinical settings.

Uncomplicated Malaria : The classical (but rarely observed) malaria attack lasts 6 - 10 hours. It consists of three typical stages. In the Cold Stage, Hot Stage and Sweating Stage. Classically, the attacks occur every second day with the "tertian" parasites (Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale) and every third day with the "quartan" parasite (Plasmodium malariae, Plasmodium knowlesi). More commonly, the patient presents with a combination of symptoms of fever, chills, sweats, headaches, nausea, vomiting, body aches and general malaise. Physical findings may include elevated temperature, perspiration, weakness, enlarged spleen, etc.

Severe Malaria : Severe malaria occurs when Plasmodium falciparum infections are complicated by serious organ failures or abnormalities in the patient's blood or metabolism. The manifestations of severe malaria include cerebral malaria, with abnormal behaviour, impairment of consciousness, seizures, coma, or other neurologic abnormalities, severe anaemia due to hemolysis, hemoglobinuria, pulmonary edema or Acute Respiratory Distress Syndrome (ARDS).

Relapse : In cases of Plasmodium vivax and Plasmodium ovale infections, recurrent attacks could be due to re - activation of hypnozoites in the liver. This can occur any time after 30 to180 days of the primary attack. Such long - term relapses commonly occur in patients who have either not taken primaquine or taken incomplete treatment.

Recrudescence : In Plasmodium falciparum and Plasmodium malariae infections, the parasites can remain in the blood for months or even years and cause recurrent symptoms from time to time.

DIAGNOSIS

Peripheral smear examination for malarial parasite is the gold - standard in confirming the diagnosis of malaria. Thick smears are used to detect infection and to estimate parasite concentration. Thin film examination is the gold standard in diagnosis of malarial species.

The other tests include QBC Test, Para Sight F test, OptiMal Assay, the Immuno Chromatographic Test (ICT Malaria P.f. test), Polymerase Chain Reaction, detection of antibodies by Radio Immuno Assay, Immunofluorescence or Enzyme Immuno Assay.

Immunochromatographic Tests for Malaria Antigens

Immunochromatographic tests are based on the capture of the parasite antigens from the peripheral blood using either monoclonal or polyclonal antibodies against the parasite antigen targets. The various parasite antigen targets are

1. Histidine-rich protein 2 (HRP2) of P. falciparum (PfHRP2): It is a water soluble protein produced by the asexual stages and gametocytes of P. falciparum, expressed on the red cell membrane surface, and shown to remain in the blood for at least 28 days after the initiation of antimalarial therapy.

2. Pan-malarial Plasmodium aldolase. It is an enzyme of the parasitic glycolytic pathway expressed by the blood stages of P. falciparum as well as the non-falciparum malaria parasites.

3. Parasite specific lactate dehydrogenase (pLDH). It is a soluble glycolytic enzyme produced by the asexual and sexual stages of the live parasites and it is present in and released from the parasite infected erythrocytes. It has been found in all human malaria species, and different isomers of pLDH for each of the species exist.

The Rapid Malaria Tests: The RDTs have been developed in different test formats like the dipstick, strip, card, pad, well, or cassette. The test procedure varies between the test kits. In general, the blood specimen (2 to 50µL) is either finger-prick blood specimen, anticoagulated blood, or plasma, and it is mixed with a buffer solution. The pLDH test is formatted to detect a parasitemia of >100 to 200 parasites/µL and some of the PfHRP2 tests are said to detect asexual parasitemia of >40 parasites/µL.

TREATMENT

WHO recommends that all malaria endemic countries should have their own national anti - malaria drug policy. India's first national anti - malaria drug policy was drafted in 1982. The main treatment guidelines based on national anti - malaria drug policy are as follows :

1. Microscopically positive P. falciparum/ P vivax cases :

â- Plasmodium falciparum cases should be treated with chloroquine for three days and Primaquine for first day only.

â- Plasmodium vivax cases should be treated with chloroquine for three days and Primaquine for 14 days.

2. Clinical malaria: When diagnosis by microscopy or Rapid Diagnostic Kits (RDK) is not possible, cases showing signs and symptoms of malaria without any other obvious causes should be considered as "clinical malaria" and treated with only chloroquine in low risk area while in high risk area give additional Primaquine on the first day.

3. Chloroquine resistant areas : Plasmodium falciparum is treated with artesunate along with sulphadoxine/sulphalene + pyrimethamine.

4. Severe and complicated malaria : Mainly of Plasmodium falciparum, parenteral artemisinin or quinine is the drug of choice, irrespective of chloroquine resistance status of the area.

VACCINES AGAINST MALARIA

Development of malaria vaccine s is proceeding along three lines. (a) Sporozoite vaccines - directed against the stage of parasite which is injected into humans when a mosquito bites. (b) Merozoite vaccines - also called the blood-stage vaccines, these are directed against the asexual forms which are responsible for symptomatic manifestations in malaria. These are expected to to mimic naturally acquired immunity to malaria. Thus the recipients might continue to have occasional malarial infection but severity and duration of illness would be low and mortality reduced. (c) Transmission-blocking vaccines - prevent development of sexual stages of malara parasite in human host or mosquito vector. These might not have a benefit for individual patient, but would reduce the level of transmission within the community by rendering mosquitoes non-infective.

Of the several candidate vaccines under research, the RTS,S/ASO1E is the most promising one. This anti CS (circum sporozoite) vaccine is the only candidate to have entered the phase 3 clinical trials and is believed to be at least 5-10 years ahead of other potential vaccines. The final results of these vaccine trials are expected to arrive in 2014.

CONCLUSION

Malaria is well-known for its debilitating, demoralizing and impoverishing consequences and, therefore, estimation of its true burden and control is central to addressing these issues with the final aim of lifting the human resource above poverty line. The poor may find it hard to deal with persistent malaria problem, as coping with it is economically disastrous for the communities living on the edge. A good investment in malaria control not only makes public health sense but also economic sense in the present era of economic liberalization and surge in India.