Antimalarial Drug Prescribing Practice In Pediatrics In A University Teaching Hospital.

1.1 BACKGROUND OF THE STUDY

Malaria is a global public health problem and remains one of the major killers in many parts of the world, especially in the endemic countries. In Europe malaria was particularly present in the Mediterranean basin and Eastern regions, including the European Russia.  From the mid nineteenth Century forward the process of regression of malaria started in North-Western European countries, as England and Holland, where the improvement of the health services in urban and rural areas progressed rapidly and resulted in a better control of the anopheline mosquitoes population. Throughout the first half of the 20th Century, malaria in Europe underwent a continual reduction, thanks to a combination of improved economic situation and control measures regularly implemented. In 1955 the WHO launched the Global Malaria Eradication program, a worldwide campaign for the eradication of malaria based on the use of DDT and other insecticides with residual activity applied inside the housing against vector Anopheles mosquitoes and on the use of antimalarial drugs for the elimination of plasmodia in humans. The campaign brought, toward the end of the 1960s, the eradication of malaria in all developed countries where malaria was endemic (Mediterranean countries, many regions of the tropics, etc.) and produced the interruption of malaria transmission in most areas of the tropical Asia and Latin America like in Brazil the number of cases decreased from 6 million to 37,000 (Majori, 2012)

By the mid-20th century, malaria was eliminated as a major health problem in many parts of the world. For instance at the end of world war II a massive malaria control program based on DDT (Dichloro Diphenyl Trichloroethane) spraying was carried out in Italy (Wikipedia,2014).  Malaria also was eliminated in the United States of America by the use of DDT in the National Malaria Eradication Program from 1947-1952.   Complete eradication of A.gambiae from northeast Brazil and thus from the New world was achieved in 1940 by meticulous application of Paris Green to breeding places and Pyrethrum spray-killing to adult resting places (Parmakelis et al, 2008). But then at the close of the 20th Century, malaria remained endemic in more than 100 countries throughout the tropical and subtropical zones, including large areas of central and south America, Hispanics (Haiti and the Dominican Republic), Africa, the middle East, the Indian subcontinent, southeast Asia and Oceania.

In 1969, the WHO abandoned the strategy of the eradication and replaced it with control strategy in order to reduce the morbidity and mortality. In 1992, WHO drew up a new strategy with emphasis on early diagnosis and immediate treatment in the context of programs managed by the basic health care system.  Many countries such as Thailand, China, Brazil, Solomon Islands, Philippines, Vietnam, obtained good results in terms of control. Even though the estimated incidence of malaria globally has reduced by 17% since 2000 and malaria-specific mortality rate by 26%, (Majori, 2012), for many others, and especially for those in sub-Saharan Africa, the malaria situation is still critical. There were an estimated 216 million episodes of malaria and 655,000 malaria deaths in 2010, of which 91% were in Sub-Saharan Africa. 

In Africa, an estimated 300-500 million cases of malaria occur each year resulting in approximately one million deaths. In many parts of sub-Saharan Africa, it is still the largest contributor to the burden of disease and premature death (WHO, 1996; Dillip et al, 2009), constituting the highest percentage (91%) of the 881,000 people who die of malaria every year, while children under 5 years of age make up 85% (EDCTP, 2011). To be precise, more than half of all estimated malaria cases occur in just five African countries: Nigeria, Democratic Republic of Congo, Ethiopia, United Republic of Tanzania and Kenya (WHO, 2008). In fact among death due to malaria occurring in Africa more than 90% are in under-five children that results in brain damage (Maslove, 2009). Children suffer mostly from malaria and in absolute terms malaria kills 3000 children below 5 years old daily, constitutes 25% of child mortality in Africa and 25-30% in Nigeria (Adesanmi, 2011). In young children, malaria can progress from a mild to severe case within 24 hours after the onset of symptoms. Prompt diagnosis and timely malaria treatment within 24 hours after onset of first symptoms can reduce illness progression to severe stages and, therefore, decrease mortality (Getahun, 2010).

During the past decades, numerous large-scale initiatives have been undertaken with the goal of reducing or eradicating the burden of malaria in the developing world. To mention but a few of such projects: the organization ‘Malaria no more’ set a public goal of eliminating malaria from Africa by 2015. The Global Fund to Fight AIDS, Tuberculosis and Malaria has distributed 230 million insecticide treated nets intended to stop mosquito-borne transmission of malaria.  President’s Malaria Initiatives (PMI), PATH malaria Vaccine Initiative, Harvard Malaria Initiative etc.  However, the ambitious goals set by these programmes for reducing the burden of malaria in the near future appear unlikely to be met (Attaran, 2004). And even though effective treatment exists, it must be administered promptly and timely by trained personnel in order to be effective, thus, most malaria deaths can be prevented when clinical cases are promptly diagnosed and effectively treated. Major factors affecting the outcome of the diseases are health-seeking behaviour and socio-economic status, which determine access to health services (WHO, 1996 (b); Getahun et al, 2010) that is why most deaths occur at the community level, outside health institutions. 

Nigeria is one of the areas of high stable transmission, morbidity and mortality are highest in young children especially 6 months and above, in whom acquired protective immunity is insufficient to protect against severe disease. Those with high peripheral parasitaemia (>4-5% infected erythrocytes) are at increased risk of severe malaria and death (Crawley et al, 2010). Until recently, in areas of high malaria transmission like Nigeria, malaria treatment has been mainly on clinical diagnosis because malaria was considered one of the commonest causes of fever with a high mortality rate. Now it has been made obvious that causes of fever can range from non serious viral infections to serious life threatening conditions, thus making it impossible to base the diagnosis of malaria solely on the clinical presentation. Improper diagnosis poses the risk of overtreatment with anti-malarial drugs and under treatment of non-malarial causes of fever. Therefore for optimal treatment and to save lives, an accurate diagnosis is essential (FMOH, 2011).  In line with WHO recommendation of diagnosis in all age groups before administration of appropriate treatment for malaria, Nigeria has provided guidelines on parasite-based diagnosis which is imperative to achieve targeted treatment and accurate estimation of true malaria cases (FMOH, 2011). This entails making use of proper laboratory tools to confirm the presence of the malaria parasite in the patient.

Growing resistance to conventional anti-malarial drugs and the associated resurgence in infection rates and malaria-related morbidity and mortality, particularly in sub-Saharan Africa (Bassat et al, 2011), has led to a paradigm shift in treatment strategies. Since 2004, the World Health Organization (WHO) recommends treatment with artemisinin-based combination therapy (ACT) (WHO, 2010), and ACT has been adopted as first-line treatment for uncomplicated Plasmodium falciparum malaria in virtually all African countries. The WHO had published guidelines in 2005- edited in 2010- to provide global evidence-based recommendation on the treatment of malaria. It contains information on the treatment of uncomplicated malaria and severe malaria. In the 2005 edition, the WHO recommended presumptive treatment of malaria using ACTs where the availability and use of laboratories are limited. However, recently in the 2010 edition the guideline places emphasis on testing for malaria with RDTs or microscopy before treating while reaffirming the use of ACTs. Following the indications of the WHO, Nigeria changed the first-line therapy for uncomplicated Plasmodium falciparum malaria from Chloroquine to artemisinin-based combination therapy (ACT) in 2005 (Ajayi, 2009). This combination reduces the risk of development of further resistance (Sinclair, 2009). The rationale for using ACT is based on the concept that the artemisinin will substantially and rapidly reduce even multidrug-resistant P. falciparum  parasitaemia, leaving the residual parasite to be killed by high concentrations of the partner drug. In this way, the probability of the development of de novo resistance is greatly reduced (Sirima et al, 2009).  ACT also reduces gametocyte carriage and infectivity. Artemether-lumefantrine (AL), the first fixed-dose ACT to be prequalified  by the WHO, has consistently shown PCR-corrected cure rates > 95%  against this species, with prompt resolution of parasitaemia and fever,  rapid gametocyte clearance and good tolerance in populations of adults  and children even when administered unsupervised (Bassat et al, 2011).

Malaria is a preventable, treatable and curable infection. Several Non-governmental organizations in collaboration with the government have made drugs and other interventions for its prevention and treatment widely available. Many of these are easy to apply and are affordable and accessible, yet Nigeria continues to suffer under the severe disease and economic burden brought upon it by malaria.

1.2 STATEMENT OF THE PROBLEM

The degree of morbidity and mortality due to malaria infection is highest in young children especially between 6 months and five years. This is because the acquired protective immunity in this group is usually insufficient to protect against severe disease, mostly in areas of high stable transmission.  Malaria, as a killer disease, accounts for 60% of outpatient visits and 30% of hospitalizations among children under five years of age in Nigeria (US Embassy, 2011). It is estimated that about 50% of the population in Nigeria experience at least one episode yearly while the under-five children have up to 2-4 attacks of malaria annually (FMOH, 2005). 

Key to reducing the morbidity and mortality from malaria is the prompt delivery of effective drug treatment to sick children. In fact, more than 50% of deaths from severe childhood illnesses including malaria occur within 24 hr of hospital admission (Crawley, 2010). Early identification and treatment of children at highest risk of death are therefore of great importance. Increased resistance of the parasite to the existing antimalarial drugs militates against the proper treatment of this infection. The WHO had therefore recommended some treatment guidelines to combat multidrug resistance and to prevent its further development. It is a well known fact that antimalarial drug resistance accounts for the failure to control malaria in many areas of the tropical world and the consequent increasing global mortality. In fact the growing risk of resistance against many effective antimalarial drugs is one threat to the international ambition to eliminate malaria death by 2015 (EDCTP, 2011).

In view of this panorama, it is necessary to study the antimalarial drug prescribing practice in pediatrics in a teaching hospital in order to determine the quality of the treatments given and whether they comply with the recommended treatment guidelines. 

1.3 SIGNIFICANCE OF THE STUDY

Without the knowledge of how drugs are being prescribed and used, it is difficult to initiate a discussion on rational drug use or to suggest measures to improve prescribing habits. Information on the past performance of prescribers is the linchpin of any auditing system, thus facilitating the rational use of drugs in the population. The success of the National Treatment Policy depends a lot on the adherence of health care providers to its guidelines. The importance of this research cannot be over emphasized because the information generated will help in assessing the rationality of the antimalarial therapy used especially in children under five, one of the vulnerable groups affected by malarial infection. Therefore, this research was carried out to identify- if any- associated problems with the drug use. Thus the goals of the treatment guidelines which are; reduction of morbidity and mortality, and encouragement of rational drug use to prevent or delay the development of antimalarial drug resistance will be achieved.

1.4 MALARIA: A GENERAL OVERVIEW

The name Malaria derived from ‘mal’ ‘aria’ (bad air in medieval Italian). This was because the ancient Romans thought that the disease came from the horrible fumes from the swamps. The history of malaria stretches from its prehistoric origin as a zoonotic disease. Its prevention and treatment have been targeted in science and medicine for hundreds of years. Precise statistics do not exist because many cases occur in rural areas where people do not have access to hospitals or other health care facilities. As a consequence, the majority of the cases were undocumented. Malaria, a widespread and potentially lethal infectious disease, has afflicted people for much of human history, and has affected settlement patterns (Carter, 2002). It is common in tropical and subtropical regions because rainfall, warm temperatures, and stagnant waters provide an environment ideal for mosquito larvae. 

Malaria is a mosquito-borne infectious disease of humans and other animals caused by the parasitic protozoan (a type of unicellular microorganism) of the genus Plasmodium. Plasmodium is a large genus of the parasitic protozoa. The parasite always has two hosts in its life cycle: a mosquito vector and a vertebrate vector. There are five identified species of this parasite causing human malaria, namely, Plasmodium falciparum, P. vivax, P. ovale,  P. malariae and P.knowlesi (Crawley, 2010). The principal mode of spread of malaria is through the bites from infected female anopheles mosquito. Anopheles came from the Greek word meaning ‘useless’, a genus of mosquito first described and named by J.W Meigen in 1818 (Wikipedia). About 460 species are recognized; while over 100 can transmit human malaria, only 30-40 commonly transmit parasites of the genus plasmodium, which cause malaria in human in endemic areas. Anopheles gambiae is one of the best known, because of its predominant role in the transmission of the most dangerous malaria parasite species to humans- Plasmodium falciparum. Anopheles mosquitoes breed in water and each species has its own breeding preference. Transmission is more intense in places where mosquito lifespan is longer (parasite has time to complete its development inside the mosquito) and where anthropophilic mosquitoes prevail.  Forty-one of the Anopheles species are defined by experts “Dominant Vector Species” (DVS). DVS are the most important malarial vector worldwide, providing the majority of human malaria cases. Characteristics of dominant vector species are their propensity for humans feeding, longevity, abundance and elevate vectorial capacity.

Africa has the most effective and efficient DVS of human malaria, the Anopheles gambiae complex.  There are 4 principal species belonging to An. gambiae complex: An. gambiae, An. arabiensis, An. merus and An. melas. 

Environmental factors play an important role in vector distribution and malaria biodiversity. Climate seasonality, rainfall patterns, temperature, humidity, presence of vegetation and surface water all are directly related to the malaria transmission cycle. In addition, human activities such as agriculture, irrigation, deforestation, urbanization, population movements, dam/road constructions and wars are also connected to transmission levels and malaria epidemiology (Autino, 2012).

Other uncommon modes of transmission are from blood transfusion and mother to child transmission. The severity and course of a clinical attack depends on the species and strain of the infecting plasmodium parasite, as well as, the age, the genetic constitution, malaria-specific immunity and nutritional status of the child and previous exposure to antimalarial drugs.

Life Cycle of Malaria Parasite

In the life cycle of plasmodium, a female mosquito of the genus Anopheles (the definitive host) transmits a motile infective asexual forms or sporozoites into the human host (the secondary host) during a blood meal, thus acting as a transmission vector. The sporozoites travel through the blood vessels and invade the liver (parenchymal hepatocytes) to begin an asexual multiplication stage called exoerythrocytic schizogony (tissue schizogony) and become hepatic vegetative forms or schizonts. Hepatic phase of parasite development (hepatic schizogony) lasts on average between 5 (Plasmodium falciparum) and 15 days (Plasmodium malariae).  In case of Plasmodium vivax and Plasmodium ovale infections, a proportion of parasites may remain dormant in hepatocytes as hypnozoites for several months up to 5 years. From the clinical point of view, the hepatic schizogony is asymptomatic, as only a few numbers of liver cells is infected. (Gilles, 1993; Bartoloni, 2012)

The schizonts rupture to release thousands of the daughter cells or merozoites, which are then released into the blood to infect erythrocytes or red blood cells (RBC) (Anandan, 2005). The merozoites develop into the characteristic ring or trophozoite forms in RBC and then go through another asexual reproductive stage called erythrocytic schizogony (blood schizogony) to produce more merozoites. When the infected RBC ruptures, the merozoites invade new blood cells and repeat the erythrocyte cycle. In 1 or 2 weeks, a subpopulation of merozoites differentiates into the sexual forms, resulting in male and female gametocytes.  If the gametocytes in the host blood are ingested by a female Anopheles mosquito during a blood meal, the male and the female gametocytes fuse to form a fertilized, motile zygote, the ookinete in the mosquito midgut. The ookinetes develop into new sporozoites that migrate to the insect’s salivary glands, ready to infect a new vertebrate host, thus, complete the cycle. Erythrocytic forms never reinvade the liver without developing into sporozoites in the vector, and therefore, malaria infections from transfusion never result in the exoerythrocytic or “liver” form (Anandan, 2005). Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar, and thus do not transmit the disease. The female Anopheles of mosquito prefers to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal (Arrow et al, 2004).  

1.5.1 EPIDEMIOLOGY OF MALARIA

In Epidemiology, an infection is said to be endemic (Greek “in”, within and “demos”, people) in a population when that infection is maintained in the population without the need for external inputs. For example, chicken pox is endemic (steady state) in the UK, but malaria is not. Even though, every year there are a few cases of malaria acquired in the UK, but these do not lead to sustained transmission in the population due to the lack of a suitable vector (mosquitoes of the genus Anopheles).

In malariometry, the term endemicity is used to indicate disease prevalence and areas with the same level of endemicity often have similar characteristics of disease distribution. This guides malaria experts in the design, implementation, monitor, control and prevention activities. Malaria endemicity is a very complex issue, influenced by many factors ranging from factors related to the man-host interactions (agricultural activities, nocturnal activities, migration movements, wars, limited resources), to the parasite ( different species, sporogonic cycle length, drug susceptibility), to the vector (density, larvae breeding sites, temperature, receptivity, feeding pattern, longevity, insecticide susceptibility) and to the environment (physical-biological-socio-economic). Moreover, malaria incidence may fluctuate according to seasonality. Different methods to classify malaria endemicity in a population exist. They include:

i) proportion of individuals in a population with a palpable enlargement of spleen (spleen rate [SR]), 

ii) proportion of individuals in a population with a laboratory-confirmed parasite infection (parasite rate [PR]),

iii) number of infective bites per person (entomological inoculation rate [EIR]), 

iv) number of microscopically confirmed malaria cases detected during one year per unit population (annual parasite incidence [API]). 

Proportion of individuals with splenomegaly (SR) in a given population was the first method used to assess malaria endemicity during a malariometric survey in 1848 in India, where spleen dimension was assessed in selected population age groups (Autino, 2012). Thus, malariometry attention was focused on clinical manifestations of malaria. On the basis of splenomegaly prevalence rates in children from 2 to 9 years old, 4 different endemicity areas can be distinguished: 

• holo-endemic areas, where proportion of people with splenomegaly is above 75%;

• hyperendemic areas, where splenomegaly prevalence is between 51 and 75%;

• meso-endemic areas, with prevalence between 50 and 11%; 

• hypo-endemic areas, where prevalence is below11% (Hay SI et al, 2008), 

Parasite rate (PR) assesses the proportion of individuals with microscopically confirmed presence of asexual parasites in peripheral blood. Its short coming is the fact that it is a technique that requires expert laboratory technicians and is affected by malaria seasonal variation.

Spleen and parasite rate are actually less used, whereas entomological inoculation rate (EIR) and annual parasite incidence (API) are utilized to prepare epidemiologic malaria maps that show malaria distribution in the world. Where data are unavailable, a model is required to predict malaria endemicity. 

Many recent studies investigated a predictive framework known as model-based geostatistics (MBG) to assess malaria endemicity and the prevalence of other vector-borne and intermediate host borne diseases.

Maps showing the global distribution of P.falciparum and P. vivax have recently been published by Malaria Atlas Project. These maps provide a geographical framework for monitoring malaria incidence and evaluation of impact on malaria control worldwide. P. falciparum malaria endemicity has been mapped considering national malaria reports, medical intelligence and biological rules of transmission, such as temperature and aridity, important for Anopheles vectors spreading. In 2007, the world was stratified into three spatial representations:

i) areas without P. falciparum malaria risk, 

ii) unstable risk areas (P. falciparum annual parasite incidence [PfAPI]: < 0.1 per 1.000 people per annum [pa]) and 

iii) stable risk areas (PfAPI > 0.1 per 1.000 people.

Stable - unstable classification is another way to determine malaria endemicity.  Malaria stability can be defined on the ground of the number of mosquitoes’ lifetime bites in the human host. This vector-based index differentiated stable and unstable malaria. Vector-based classification is less used because of entomological-based metrics complexity, ethical concerns related to exposing human beings to malaria infection and measurement error issues.

The global area at risk of stable P. falciparum malaria was quantified in 29.7 million km2, distributed into Africa (18.2 million km2, 61.1%), Americas (6.0 million km2, 20.3%) and Central and South East Asia regions (5.5 million km2, 18.6%). 

Of the 2.37 billion people exposed to P. falciparum transmission worldwide, 0.98 billion live in unstable risk areas, whereas 1.383 billion live in stable risk areas, distributed into Africa (0.657 billion, 47.5%), Americas (0.041 billion, 2.9%) and Central and South East Asia (0.686 billion, 49.6%). Children are the most represented category, accounting for 32% of the population at risk in Americas and in Central and South East Asia. In Africa this percentage rises up to 43% (Autino, 2012). 

In areas of high malaria transmission (stable transmission areas), repeated malaria infections provide inhabitants with partial immunity. In contrast,

Unstable malaria areas are characterized by outbreaks and irregular epidemics among people with low immunity. In stable and unstable areas, pregnant women and children under 5 years old are at greatest risk of the most severe clinical symptoms of malaria. This is because a woman's immunity is temporarily depressed during pregnancy, while the immune system of small children is not fully developed (Ricci, 2012)

In high-transmission settings, infected but asymptomatic persons constitute an important part of the infectious reservoir. Even though treated cases (mainly children) have higher densities of gametocytes, and infectivity is positively related to gametocyte density, children constitute only a proportion of the infective reservoir (Uzochukwu et al, 2010).   

Different malaria endemic areas have different epidemiological situations and also the feasible targets may differ.

More than 40% of the world’s population—approximately 3 billion people—are exposed to malaria in 108 endemic countries. Estimates from WHO for 2008 suggested that 243 million cases (95% CI 190–311 million) of malaria (around 90% caused by P falciparum) resulted in 863 000 deaths (708 000–1 003 000), of which more than 80% occurred in children younger than 5 years of age in sub-Saharan Africa (Crawley et al, 2010). 

Although the exact geographic distribution of the various species is not well documented, the distribution and prevalence of the five different Plasmodium species vary throughout the world. 

It is reported that Plasmodium vivax is more prevalent in India, Pakistan, Bangladesh, Sri Lanka, and Central America, whereas P. falciparum is predominant in Africa, Haiti, Dominican Republic, the Amazon region of South America, and New Guinea. Both P. falciparum and P. vivax are prevalent in all of Southeast Asia, South America, Middle East, North Africa, Ethiopia, Somalia, and Sudan (Price, 2009). Plasmodium vivax and plasmodium falciparum are the species which are responsible for malaria in Pakistan (Jalal et al, 2006). Most of the infections with P. ovale occur in Africa, and the distribution of P. malariae is considered worldwide

Plasmodium falciparum

Plasmodium falciparum is responsible for most malaria-related deaths worldwide and is the predominant Plasmodium species in sub-Saharan Africa. Transmission intensity and population at risk vary substantially between and within countries (Guerra, 2008).

Of the 2·4 billion people at risk of falciparum malaria, 70% live in areas of unstable or low endemic risk. Almost all populations at medium and high levels of risk live in sub-Saharan Africa, where the burden of disease, death, and disability from falciparum malaria is high. In areas of high stable transmission, morbidity and mortality are highest in young children in whom acquired protective immunity is insu?cient to protect against severe disease. Areas of low or unstable transmission are subject to malaria epidemics, and people of all ages are at risk of severe disease. Of the 2.37 billion people are at risk of P. falciparum transmission worldwide, 26% located in the African Region and 62% in South East Asian and Western Pacific regions. It is the most prevalent specie in Africa.  Between 1998 and 2006, blood samples were collected from nine different African countries and analyzed by PCR for the presence of each of the four human malaria parasites. Out of 2.588 samples, 1.737 were positive for Plasmodium species and 1.711 (98.5%) were positive for P. falciparum considering both mono and mixed infection (Autino et al, 2012).

Plasmodium Vivax

P vivax is the most prevalent of the five human malaria parasites outside Africa (Price, 2009; Crawley, 2010).  It is also common and often presents as a co-infection with P. falciparum in a single illness (Sinclair et al, 2009). It is mostly absent from central and west Africa because a high proportion of the population have the Duffy-negative phenotype, which prevents erythrocyte invasion by the parasite (Crawley, 2010).

P vivax coexists with other Plasmodium species and mixed infections are common. Because transmission rates are low in most regions where P vivax is prevalent, a?ected populations do not achieve high levels of immunity (or premunition) to this parasite and people of all ages are at risk of infection, although children are more often ill.  P. vivax is transmitted in 95 tropical, subtropical and temperate countries. People living at risk of P. vivax malaria infection are 2.85 billion, 91% living in Central and South East Asia region, 5.5% in America and 3.4% in Africa. As many as 57.1% of people exposed to P. vivax infection lives in unstable malaria areas.

Often termed benign malaria, there is increasing evidence that P vivax is responsible for substantial morbidity and mortality, especially in infants. Control is not straightforward because it is difficult to achieve radical cure by elimination of dormant liver stages (hypnozoites). The parasite is more easily transmissible than is P falciparum because the sexual forms (gametocytes) are produced earlier in the life cycle, often before treatment.

In Central and South America P. vivax is the predominant species accounting for 71-81% of all malaria cases, followed by P.  falciparum.  Most of the malaria cases occur in Brazil; the others are distributed in 20 other countries of Central and South America (Autino, 2012).  In Asia, P. vivax and P. falciparum are the predominant species.

Plasmodium ovale

The diagnosis of P. ovale malaria is difficult and it makes the assessment of the real burden and distribution difficult. P ovale is rare outside Africa. In a recent multicenter study, blood samples were collected from the indigenous population of nine African countries and malaria parasites were searched by PCR method. Of 1.737 samples, 67 were positive for P. ovale: 12 single infections, 51 mixed with P. falciparum and 4 triple infections with P. falciparum and P. malariae.  P. ovale infection is in Asia.  It is present in Papua, Indonesia and in Thailand, while it is very rare in Philippines, where it has been reported only in the island of Palawan (Autino, 2012).

Plasmodium malariae

Infection with P malariae occurs in most malaria-endemic areas, but is much less common than is infection with P falciparum or P vivax.  

P. malariae is spread in sub-Saharan Africa, in Southeast Asia, in Indonesia, in many islands in western Pacific and in areas of the Amazon Basin of South America. Its distribution overlaps with that of P. falciparum (Collins et al, 2007; Autino, 2012).  In a recent study, blood samples were collected from the indigenous population of nine African countries and malaria parasites were searched by PCR method. Plasmodium malariae was found in 147 of the 1.737 positive blood samples, 14 as mono-infections, 129 as mixed infections with P. falciparum and 4 as triple infections with P. ovale and P. falciparum. In Nigeria, between November 2001 and October 2002, a total of 350 pregnant women attending the ante-natal clinics were randomly recruited and blood samples were collected. Of 350 blood samples, 96 (27.4%) were positive for malaria parasite and 11 (11.5%) were P. malariae positive as tested by microscopy (Iriemenam et al, 2011).  

Plasmodium knowlesi

P knowlesi, a zoonosis found throughout southeast Asia, is often misidentified as P malariae, although the clinical course is more severe and fatalities have been described (Crawley, 2010). It has been known since the 1930s in Asian Macaque monkeys and as experimentally capable of infecting humans. In 1965, a natural human infection was reported in a U.S soldier returning from the Pahang jungle of the Malaysian Peninsula (Antinoris et al, 2013).

Forest areas are the reservoirs of P. knowlesi. An analysis of stored blood films identified cases of Plasmodium knowlesi infection occurring since 1996 in Sarawak region, Malaysian Borneo (Autino et al, 2012).

Malaria remains one of the most common imported infections in the United Kingdom (UK). Between 1500 and 2000 malaria cases are reported each year in the UK, although informal reviews of reporting suggest that this may represent about half of all cases that occur. Approximately three-quarters of reported infections are due to Plasmodium falciparum and there were between 10 and 20 deaths annually. Children under 16 years account for 14% of cases. Two-thirds of cases occur in people of African or South Asia ethnic origin and over half of the cases occur in those who had been visiting friends and family in endemic areas. Most patients with falciparum malaria acquire infection in Africa, West Africa being the commonest geographical source.  In Cameroon, hospital statistics reveal that 35 - 45% of deaths are from the severe forms of malaria, with children <5 years and pregnant women carrying the greatest burden (Chiabi et al, 2009).

Most Plasmodium vivax infections are acquired in South Asia (Lallo et al, 2007). The World Health Organization (WHO) estimated the number of reported cases from Indonesia were 2.5 million in 2006 (Tjitra et al, 2012).

Malaria is the predominant cause of febrile illness and a major public health problem in Solomon Islands (SI). In 2009, there were 40,136 reported malaria cases in the country, with an annual incidence rate of 77/1,000 population, of which Plasmodium falciparum accounted for 72% and Plasmodium vivax 28%. There were 13 deaths due to malaria in 2009 (Wijesinghe et al, 2011).

Millions of U.S. travelers venture to endemic countries annually (Abanyie et al, 2011). An average of 1,500 cases and five deaths due to malaria occur annually in the U.S. These numbers include U.S. travellers to endemic countries as well as foreign visitors diagnosed and treated in the U.S (Abanyie et al, 2011).

1.5.2 CLASSIFICATION OF MALARIA INFECTION

Malaria is classified into either “severe” or “uncomplicated” by the World Health Organisation (WHO).

Severe Malaria

Malaria is deemed severe when any of the following criteria are present;

• Decreased consciousness

• Significant weakness such that the person is unable to walk

• Inability to feed.

• Two or more convulsions

• Low blood pressure; systolic or diastolic (< 70mmHg in adult & 50mmHg in children

• Breathing problems

• Circulatory shock

• Kidney failure or hemoglobin in the urine

• Bleeding problems or hemoglobin less than 50g/L (5g/dl)

• Pulmonary oedema

• Blood glucose less than 2.2mmol/L (40mg/dl)

• Acidosis or lactate levels of greater than 5mmol/L

• A parasite level in the blood of greater than 100,000 per microlitre(µL) in low-intensity transmission areas or 250,000 per µL in high-intensity transmission areas.

Severe malaria is usually caused by P.falciparum (often referred to as falciparum malaria). There are serious complications of malaria. Among these is the development of respiratory distress, which occurs up to 25% of adults and 40% of children with severe P.falciparum malaria while it occurs in 29% of pregnant women. Possible causes include respiratory compensation of metabolic acidosis, non cardiogenic pulmonary oedema, concomitant pneumonia and severe anemia (Taylor, 2012).  The clinical manifestations of malaria are dependent on the previous immune status of the host. In areas where endemicity of P. falciparum malaria is stable, severe malaria most commonly occurs in children up to 5 years of age, while is less common in older children and adults because of the acquisition of partial immunity. In areas of lower endemicity, the age distribution of severe malaria is less well defined and may also occur in adult semi-immune persons. 

Specific population at increased risk of developing severe malaria includes the following: 

• Non immune pregnant women in second and third trimester. They are particularly susceptible to develop pulmonary oedema and hypoglycemia. 

• People with immunosuppression related to HIV show an impaired immune control of malaria. There is an increasing risk of illness, increased parasitemia and severe malaria. Therapeutic responses to antimalarial treatment are impaired so treatment failure rates are increased. 

• Transplant recipients. Malaria in this group can be caused by graft-borne or blood borne infection or reactivation of previous infection due to immunosuppression and is usually severe, owing to the impaired immune response.

• Presence of the sickle cell trait confers some protection against malaria; however, for those with homozygous sickle-cell disease, malaria is regarded as a significant cause of morbidity and mortality, producing further haemolysis against the background of that due to sickle-cell disease itself.

• Subjects who have no spleen or whose splenic function is severely impaired are at particular risk of severe malaria. Malarial parasitaemia in asplenic individuals may rise rapidly to very high levels. Post-splenectomy episode of P. falciparum malaria has been reported in immigrants.

• Other groups at increased risk for developing severe malaria are malnourished children, elderly and those with comorbidities.

Cerebral Malaria

Cerebral malaria is defined by WHO as unrousable coma in a patient with P.falciparum parasitaemia in who other causes of encephalopathy have been excluded. This is a severe P.falciparum malaria presenting with neurological symptoms, including coma (with a Glasgow coma scale less than 11 or a Blantyre coma scale greater than 3 or with a coma that lasts longer than 30 minutes after a seizure (WHO, 2010). It involves encephalopathy and retinal whitening.  Cerebral malaria is one of the leading causes of neurological disabilities in African children (Idro et al, 2010). Individuals with cerebral malaria frequently exhibit neurological symptoms including abnormal posturing, nystagmus (a condition of involuntary eye movement), conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma (Bartoloni et al, 2012).

Uncomplicated Malaria

Uncomplicated Malaria is defined as symptomatic malaria without signs of severity or evidence (Clinical or laboratory) of vital organ dysfunction. The signs and symptoms of uncomplicated malaria are nonspecific. Malaria is, therefore suspected clinically mostly on the basis of fever or a history of fever (WHO, 2010). About two days before the onset of fever, one may experience prodromal symptoms, such as malaise, anorexia, lassitude, dizziness, with a desire to stretch limbs and yawn, headache, backache in the lumbar and sacroiliac region, myalgias, nausea, vomiting and a sense of chillness. The fever is usually irregular at first and the temperature rises with shivering and mild chills. After some days fever tends to become periodic depending on the synchronized schizogony. The paroxysm presents three stages: a cold stage, characterized by a sudden onset with a feeling of extreme coldness. The subject may shiver and his or her teeth may chatter in virtue of an intense peripheral vasoconstriction phenomenon. This lasts for about 10-30 minutes and only occasionally up to 90 minutes, the temperature rises gradually to a peak (usually between 39° C and 41°C).  Eventually the shivering ceases, and then comes the hot stage characterized by hot and dry skin with the face flushed. The last stage termed the sweating stage begins with sudden profuse sweating, appearing first at the temples, and rapidly becoming generalized and copious. The temperature falls rapidly and the subject feels well, although extremely tired, and usually falls asleep. This stage lasts 2 to 3 hours. 

At the physical examination, splenomegaly may be present during the acute attack but is more commonly observed after the second week of the attack. The liver may also be enlarged and palpable. 

Laboratory findings may reveal some degree of anaemia and reticulocytosis due to lysis of parasitized and unparasitized red blood cells. Thrombocytopenia is common and sometimes mild leucopenia is present. On examining the blood films, representatives of all developmental forms of the asexual parasite, from the early ring to mature schizont, may be observed, while gametocytes are usually present after a period of about a week. The density of parasitemia seldom exceeds 2% of the erythrocytes. Although the subject may not appear very ill, serious complications may develop at any stage. In non-immune people P. falciparum malaria may progress very rapidly to severe malaria unless appropriate treatment is started. If the acute attack is rapidly diagnosed and adequately treated, the prognosis of falciparum malaria is good, even if complications may still occur. The response to treatment is usually rapid with resolution of fever and most symptoms within 3 days.

 Recrudescence which is the renewal of clinical manifestation and/or parasitemia, due to persistent erythrocytic forms, may occur.

1.5.3 PATHOPHYSIOLOGY OF MALARIA INFECTION 

Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase) and one that involves red blood cells or erythrocytes (erythrocytic phase). Within the red blood cells, the parasites multiply further again asexually, periodically breaking out of their host cells to invade fresh red blood cells. Several of such amplification cycles occur. Thus classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells (Bledsoe, 2005).

The characteristic malarial paroxysms of chills and fever in patients usually coincide with the periodic release of merozoites and other pyrogens in the blood. In P. falciparum infections, this periodicity may not always be apparent. However, intervals of 48 hours between paroxysms are reported for Plasmodium vivax, Plasmodium ovale, and P. falciparum (tertian periodicity), and 72 hours for Plasmodium malariae (quartan periodicity). Unlike infections caused by P. falciparum and P. malariae, infections with P. vivax and P. ovale have a latent form of the exoerythrocytic phase that can persist in the host liver for months to years. This latent form can produce relapses of the erythrocytic infection. Relapse is when symptoms reappear after the parasites have been eliminated from blood but persists as dormant hypnozoites in liver cells. Relapse commonly occurs between 8-24 weeks and is often with P.vivax and P.ovale infections (Nadjm et al, 2012).  At the time of schizont rupture, the release of malaria parasites and erythrocytic material into the circulation induce the pathophysiology process of malaria and the onset of symptoms. The activation of the cytokine cascade is responsible for many of the symptoms and signs of malaria (Bartoloni, 2012). 

The interval from time of infection until parasites become detectable in the blood is termed prepatent period. 

The incubation period is defined as the interval between infection and the onset of symptoms. The duration of incubation period is influenced by several factors such as the species of infecting parasites, the way of parasite transmission, the degree of previous immune status of the host, the chemoprophylactic use of antimalarial drugs, and probably the density of parasite inocula. Incubation period ranges from 9 to 30 days with P. falciparum infections, tending to present the shortest, and P. malariae the more prolonged times. In most of P. falciparum and P. vivax malaria, the incubation period is approximately two weeks. In blood-induced infections, the incubation period is usually shorter with symptoms developing within 10 days of transfusion for P. falciparum, 16 days for P. vivax, and 40 days or longer for P. malariae (Bartoloni, 2012).  As far as the degree of previous protection possessed by the infected subject is concerned, it is known that effective immunity prolongs incubation period and reduces level of parasitemia and clinical manifestations. Low asymptomatic parasitemia may persist in migrants from endemic areas long after their arrival in the host country. Pregnancy and co-infection with HIV have been associated with late presentation of malaria caused by P. falciparumin immigrants. Prolonged incubation period may also be caused by the use of antimalarial drugs that, although ineffective, may impact on the parasite multiplication rate.

Liver dysfunction as a result of malaria is uncommon and usually only occurs in those other liver conditions such as viral hepatitis or chronic liver disease. The syndrome is sometimes called malaria hepatitis (Bhalla, 2006). While it has been considered a rare occurrence, malarial hepatopathy has seen an increase, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a greater likelihood of complications and death (Bhalla, 2006).   

1.5.4 MALARIA PREVENTION ERADICATION AND CONTROL

Despite all the efforts made in the use and implementation of such malaria control interventions, it is thought that in order to decrease substantially the burden of disease and advance towards the aspiration of malaria eradication, effective vaccines against malaria are needed and should play a crucial role. Moreover, malaria vaccines have been an elusive goal of research. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-attenuated sporozoites, which provided significant protection to the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans (Vanderberg, 2009).  

Despite the morbidity and mortality burden attributable to malaria, there are other factors that make an effective malaria vaccine desirable. The resistance profile of malaria parasites to an increasing number of antimalarial drugs and readily available insecticides, the unequal and inadequate distribution of malaria control tools in different settings or the increased movement of migrant populations and tourists to endemic areas are important arguments in favour of concentrating resources towards malaria vaccine research. However, despite current advances towards getting an effective malaria vaccine, scaling up available malaria control interventions seems the current realistic strategy to reduce the health burden of malaria and in many cases may probably be sufficient to approach the desired elimination goal.

Malaria control means reducing the malaria disease burden to a level at which it is no longer a public health problem.

Malaria elimination is the interruption of local mosquito-borne malaria transmission. Reduction to zero of the incidence of infection caused by human malaria parasites in a defined geographical area as a result of deliberate efforts; continued measures to prevent reestablishment of transmission are required.

Malaria eradication is the permanent reduction to zero of the worldwide incidence of infection caused by a particular malaria parasite species. Intervention measures are no longer needed once eradication has been achieved.

On the ground of slide positivity rate (SPR) and of the population at risk of malaria, the WHO distinguishes areas with advance malaria control activities in (I) pre-elimination phase, (II) elimination phase, (III) prevention of reintroduction and (IV) malaria-free stages. Most malaria cases and deaths occur in the African Region. As a consequence of implementation programs, high burden countries of African Region, such as Madagascar, Sao Tome, Eritrea, Rwanda and Zambia, showed a decrease in malaria cases up to 50% between 2000 and 2009 (Autino, 2012). Rwanda showed a decrease by 74% of confirmed malarial cases between 2005 and 2010 and slide positivity rate decreased from 35% to 9%. Moreover, number of malaria hospital admissions and malaria deaths showed a decrease of 65% and 55% respectively. Zanzibar, belonging to United Republic of Tanzania, showed a dramatic decrease of malaria admissions and deaths due not only to the efficacy of control strategies, but also to favourable geographic position. In low transmission

countries of African Region control strategies have also been performed. Thanks to these strategies, Algeria is in the malaria elimination phase and 

Cape Verde is in pre-elimination phase.  In 15 countries of the WHO Region of the Americas, where P. vivax is the most represented species, reductions of more than 50% in the number of the reported cases were observed. During 2010, malaria transmission occurred in 21 countries, of which 17 are in the control stage and 4 are in the pre elimination stage. Bahamas and Jamaica are in the prevention of reintroduction phase. In Ecuador, malaria cases dropped from 105.000 in 2000 to 4.120 in 2009, a reduction of 96% due to IRS, LLINs distribution, strengthening of malaria diagnosis and treatment and also due to Global Found, UNICEF, USAID and government funds invested in malaria control. In 2010, 2.4 million confirmed malaria cases were reported in WHO South-East Asia Region. India accounts for 66% of confirmed cases, even though a reduction of 28% of the cases between 2000 and 2010 was observed. In 2010, malaria deaths were 2.426 as reported from eight countries of the region, most of all reported in India. Democratic People’s Republic of Korea and Sri Lanka are actually in pre-elimination phase. Bangladesh, Bhutan, the Democratic Republic of Timor-Leste, India, Indonesia, Myanmar, Nepal and Thailand are in the control phase. In the WHO European Region, the number of

autochthonous cases decreased from 32.394 in 2000 to 176 in 2010. All malaria cases are now attributable to P. vivax infection; no P. falciparum cases occurred since 2008. Malaria cases were identified in Azerbaijan, Kyrgyzstan, Tajikistan, Turkey and Uzbekistan. Georgia reported no cases in 2010 and Turkmenistan was declared malaria-free in October 2010.  A particular case is represented by Greece, a country that was declared malaria-free from1974. Since June 2011 a total of 63 autochthonous malaria cases have been reported, all due to P. vivax infection. Cases occurred mostly in the southern region of the country, specifically of the Evrotas delta area of Laconia district in agricultural area with large migrant populations. Other cases occurred in the Evia/Euboea (island east of the Central Greece region), Eastern Attiki, Voitia and Larissa districts.

In the WHO Eastern Mediterranean Region, Islamic Republic of Iran and Saudi Arabia are in the elimination phase, while Egypt, Iraq, Oman and Syrian Arab Republic are in prevention of reintroduction phase. Morocco was confirmed malaria-free in May 2010. Afghanistan, Djibouti, Pakistan, Somalia, Sudan, South Sudan and Yemen are in the control stage, and they still represent high malaria transmission areas. As many as 262.000 confirmed cases were reported from the WHO Western Pacific Region in 2010. Papua New Guinea, Cambodia and Solomon Island account for 70% of these malarial cases. China, Philippines, Republic of Korea and Vietnam showed a decrease in malaria cases up to 50% between 2000 and 2010, while other countries showed a more slowly decrease (e.g. Cambodia, Lao People’s Democratic Republic, Malaysia, Solomon Island, Vanuatu).

The prevention and treatment of the disease have been investigated in science and medicine for hundreds of years, and, since the discovery of the parasite which causes it, attention has focused on its biology. These studies have continued up to the present day, since no effective Malaria vaccine has yet been developed and many of the older antimalarial drugs are losing effectiveness as the parasite evolves high levels of drug resistance.

According to 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 (Howitt et al, 2012).

In 1969, the WHO abandoned the strategy of the eradication and replaced it with that of the control, in other words, a planned reduction of morbidity and mortality. In 1992 drew up a new strategy with emphasis on early diagnosis and immediate treatment in the context of programs managed by the basic health care system (Majori, 2012).  Many countries such as Thailand, China, Brazil, Solomon Islands, Philippines, Vietnam, obtained good results in terms of control. For many others, and especially for those in sub-Saharan Africa, the malaria situation is still critical. There were an estimated 216 million episodes of malaria and 655,000 malaria deaths in 2010, of which 91% were in Sub-Saharan Africa.

The estimated incidence of malaria globally has reduced by 17% since 2000 and malaria-specific mortality rate by 26%. These rates of decline are lower than internationally agreed targets for 2010, but nonetheless they represent a major achievement (Majori, 2012).  In Africa, malaria deaths have been cut by one third within the last decade; outside of Africa, 35 out of the 53 countries affected by malaria, have reduced cases by 50% in the same time period. In countries where access to malaria control interventions has improved most significantly, overall child mortality rates have fallen by approximately 20%, a percentage more than twice that of all childhood death attributable to malaria. Part of this reduction may be due to the fact now recognized that malaria is also an important risk factor for other severe infections, namely bacteraemia in African children (Schumacher, 2012). 

Use of artemisinin based combination therapies (ACTs) and increased coverage with insecticide-treated nets and indoor residual spraying have undoubtedly contributed to the falling number of cases. This improvement has been associated with a change in the observed age pattern of clinical malaria: in costal Kenya the mean age of children admitted to hospital with a positive malaria blood slide has increased from 3 years to 5 years (Schumacher, 2012).  

Use of topical insect repellent is an important component of the prophylaxis against arthropod bite vector borne diseases too. Rational repellent prescription for a child must take into account age, active substance concentration, topical substance tolerance, nature and surface of the skin to protect, number of daily applications, and the length of use in a benefit-risk ratio assessment perspective. Efficacy and duration of protection for the repellant are markedly affected by ambient temperature, amount of perspiration, exposure to water, abrasive removal, etc. 

All newborns and infants in their first months are protected best from mosquitoes by using an infant carrier draped with mosquito netting with an elastic edge for a tight fit or make sure to tuck the bed net firmly under the mattress.