Antimalarial Drug Prescribing Practice In Pediatrics In A University Teaching Hospital

ABSTRACT

Objective: The study was carried out to describe the antimalarial drug prescribing practice in pediatrics in the University of Nigeria Teaching Hospital, Enugu. The specific objectives were to determine: the cases that were diagnosed based on laboratory investigation; the specific antimalarial drugs prescribed for the treatment of uncomplicated malaria cases between 2003-2011; the changes- if any- in the prescription pattern of the prescribers following the introduction of the Treatment Guidelines and the level of their compliance to the guidelines

Method: The patients’ medical charts were assessed. The exclusion criteria were patients with uncomplicated malaria below 6 months of age and above 5 years of age, and patients with special disease conditions like HIV. Inclusion criterion was patients with uncomplicated malaria between the ages of 6 months and 5 years. A total of 3034 prescriptions were collected for data extraction and analysis. With the use of a modified WHO prescribing indicator form, these data were collected; demographic data, clinical presentations (symptoms), laboratory investigation and the specific antimalarial drugs prescribed. Data were grouped into two; the pre-policy period (2003-2005) and the post-policy period (2006-2011), and then analysed using Excel spreadsheet and SPSS.14.0 software for descriptive and inferential statistics respectively.

Results: The results of the study showed that the number of malaria cases that were diagnosed based on positive malaria parasite test were 4.8% of 2765 patients diagnosed of malaria.  Artemether-Lumefantrine combination was the most prescribed antimalarial drug with 45.4%. It was 2% of the prescriptions in the pre-policy period and 63.3% in the post-policy period. Although there was a significant increase in the prescription of ACT in the post-policy period (32.6%), the compliance to the Antimalarial treatment guideline (ATG) was low (23.8%).

Conclusion:  This study revealed an increase in the prescription of Artemisinin-based combination therapy after the introduction of the National Antimalarial Treatment Guideline. Nevertheless, prescribers did not adhere strictly to the guideline. Many of the Artemisinin-based combination therapy prescribed were not the recommended ones. There was a high incidence of empirical diagnosis/treatment of malaria as opposed to parasitological/confirmatory diagnosis/treatment. Among the WHO drug use indicators, there was still a lot of room for improvement in the prescription of drugs in generics by prescribers.

 

 

TABLE OF CONTENTS

Title Page                                                                                                                    i

Certification                                                                                                                ii

Dedication                                                                                                                  iii

Acknowledgement                                                                                                      iv

Table of Contents                                                                                                       v

List of Tables/graphs                                                                                                   vii

Abstract                                                                                                                      viii

CHAPTER ONE:       INTRODUCTION AND LITERATURE REVIEW

• Background of the study…………….…………………………………………1
• Statement of the problem……………………….………………………………..4
• Significance of the study………………………………………………………5
• Malaria A General Overview…………………………….……………………6

1.5.1                Epidemiology of malaria…………………………………………………………..8

1.5.2                Classification of malaria ………………………………….………………….15

1.5.3                Pathophysiology of malaria……………………………………….………….18

• Malaria Prevention, Eradication and Control…………………………………19

1.6                   Malaria in children……………………………………………………………23

• Clinical manifestations of Malaria infection…………………………………29
• Diagnosis of Malaria…………………………………………………………29
• Treatment of uncomplicated malaria…………………………………………34
• Antimalarial Drugs……..………………………………………………………..38
• Resistance to antimalarial drugs………………………………………………40
• Malaria situation in Nigeria………………………………………………….44

1.7                   Antimalarial treatment policy…………………………………………………47

1.8                   Objectives of the study…………………………………………………..……50

CHAPTER TWO:       METHODS

2.1                   Design…………….…………………………………………………………..51

2.2                   Study setting….…………………….…………………………………………51

2.3                   Population for the study.….……….…………………………………………….51

2.4                   Exclusion criteria…………..…………………………………………………52

2.5                   Inclusion criteria……………..………………………………………………52

2.6                   Data collection………………..………………………………………………52

2.7                   Drug Use Indicators…………………………………………………………..53

2.7                   Data analysis………….………………………………………………………54

 

CHAPTER THREE:   RESULTS

3.1                   Demographic and Clinical Characteristics…………………………………..56

3.2                   Malaria Diagnosis…………………………. ………………………………..58

3.3.                  Antimalarials used during the two periods under study…..……..…………..59

3.4                   Other prescribed drugs……………………………………………………….60

3.5                   Antimalarials in the DU90% segment………………………..……………….63

3.6                   Drug use indicators…………………………………………………………..64

3.7                   Drug use indicators per prescription…………………………………………66

 

CHAPTER FOUR: DISCUSSION AND CONCLUSION

 

4.1                   Discussion ……………………….…………………………………………..75

4.2                   Limitations of the study………………………..…………….……………….78

4.3                   Conclusion….……………………………………………………………………..79

4.4                   Recommendations…..………………….…………………………………….79

 

REFERENCES

APPENDIX

 

 

CHAPTER ONE

INTRODUCTION

 

• 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 20^th 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.

 

• 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.

 

• 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).

 

 

• 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:

1. proportion of individuals in a population with a palpable enlargement of spleen (spleen rate [SR]),
2. proportion of individuals in a population with a laboratory-confirmed parasite infection (parasite rate [PR]),

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

1. 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:

1. areas without P. falciparum malaria risk,
2. unstable risk areas (P. falciparum annual parasite incidence [PfAPI]: < 0.1 per 1.000 people per annum [pa]) and

• 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 insufficient 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, affected 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.

1. 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).

 

 

 

 

 

 

• 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.

 

• 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.

 

 

• MALARIA IN CHILDREN

 

It has not been easy to assess epidemiology of malaria in children because most of the clinical symptoms are non-specific and most of the cases occur in settings where no routine testing is available. Figures for disease burden vary widely, reflecting disparity in the data sources used to derive different estimates (Crawley, 2010).  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 (WHO, 2009; Crawley, 2010). Apart from the transmission of the plasmodia through the blood meal of an infected female anopheles and through infusion of infected blood products, neonates and young infants might also be vertically infected by plasmodia crossing the placenta.

Despite substantial advances in treatment and prevention over the past decade, malaria still threatens the lives of millions of children in tropical countries. The symptoms of malaria are non-specific and parasitological diagnosis uncommon, making precise calculation of disease burden difficult and causing both over-treatments with antimalarial drugs and under treatment of non-malarial causes of fever. Our understanding of the complex pathological mechanisms underlying uncomplicated and severe malaria in children is limited, and often derived from studies in adults. Once the disease becomes severe, therapeutic options are scarce and risk of mortality is high (Crawley, 2010).

The clinical manifestations of malaria, the severity and course of a clinical attack depends on the species and strain of the infecting plasmodium parasite, as well as the age, genetic constitution, immune status, malaria specific immunity, and nutritional status of the child, the mode of transmission of infection, whether the individual was on prophylaxis or had previous exposure to antimalarial drugs, as the latter may present with only minimal symptoms or signs.

In children symptoms are varied and often mimic other common childhood illness particularly gastroenteritis, meningitis/encephalitis, or pneumonia. Fever and headache may be the sole symptom and gastrointestinal symptoms may predominate. Fever is the key symptom, but the characteristic regular tertian and quartan patterns are seen in < 25% of children; however, children are more likely to have high fever (>40°C), which may also lead to febrile convulsions. Nausea and vomiting are also common (especially for P.falciparum) and may hamper treatment with oral anti-malaria drugs. Pneumonia and acute diarrhea are the most common comorbid conditions associated with malaria and are both strong predictors of mortality. The diagnosis of pneumonia in a child with malaria might be a coexisting bacterial or viral respiratory illness, but the diagnosis might also be given to a child with malaria-related respiratory distress. Likewise, acute

diarrhoea might be a feature of clinical malaria, or the result of concurrent diarrheal disease from an enteric pathogen. Even if rigors frequently accompany infections with P.vivax, compared with adults, children are less likely to complain chills, arthralgia/myalgia or headache but are more likely to have hepatomegaly, splenomegaly and jaundice.

In general, severity of symptoms and risk of death increase with increasing parasitaemia.  P.falciparum malaria is the most severe form of malaria, with fatality rates up to 15% in non-immune children with anaemia and severe respiratory distress if appropriate therapy is not promptly instituted. Since P.falciparum is the only Plasmodium species that infects all ages of erythrocytes, it can lead to intense parasitaemia that can reach 60% or more. Malaria caused by the other species of Plasmodium usually results in parasitaemias of less than 2%. P.vivax and P.ovale preferentially infect reticulocytes, and P.malariae infects mostly senescent red cells. Thus, severe complications of malaria are more often encountered in P.falciparum infection. However, only a small proportion of the large number of people infected with P.falciparum develop severe malaria.

The likelihood of death is increased in children with pre-existing health problems such as anaemia, malnutrition and immunocompromised states. Asplenic patients develop rapidly progressive malaria. Malaria complications result from haemolytic anaemia and microvascular obstruction with subsequent tissue ischemia. Features of severe or complicated malaria include respiratory distress, acidosis (pH <7.3), hypoglycaemia (<2.2 mmol/l), elevated aminotransferases, severe anaemia (Hb <5g/dl), and high parasitaemia (defined as >5%-10% infected erythrocytes or more than 500 000 infected erythrocytes per microliter). It is important to remember that there are no clinical features that are pathognomonic for severe malaria. The well known clinical (fever, impaired consciousness, seizures, vomiting, respiratory distress) and laboratory (severe anaemia, thrombocytopenia, hypoglycaemia, metabolic acidosis, and hyperlactataemia) features of severe falciparum malaria in children, are equally typical for severe sepsis. Leukocytosis does not allow for discrimination either, as it has been described in up to 20% of young children with severe malaria. This can be (partially) explained by the activation of the same cytokine pathways in both conditions: Releasing debris from both, parasites and erythrocytes, including the so called malaria toxin glycosylphosphatidylinositol as well as malarial pigment (haemozoin) leads to the activation of peripheral blood mononuclear cells and consequently kicks off the cascade of pro-inflammatory cytokines which probably determines disease severity. Last but not least bacteraemia may complicate malaria in up to 8% of severe cases, especially in younger patients, increasing the risk for fatal outcome. Since severe malaria is a multisystem, multi-organ disease, children frequently present with a combination of the classical clinical phenotypes: cerebral malaria (CM), severe malarial anaemia (SMA), respiratory distress, and hypoglycaemia.

The former two, CM and SMA, are the most common complications of malaria in children.

Children with CM may develop focal neurological signs, decerebrated or decorticated posturing due to raised intracranial pressure, decreased level of consciousness or coma, behavioural changes, hallucinations, and seizures. Seizures can be protracted or multiple and may be followed by a long postictal state or they may be difficult to recognize if they present only by conjugate eye deviation, nystagmus, oral automatisms, salivation, and hypoventilation. Although most children with CM regain consciousness within 48 h and seem to make a full neurological recovery, approximately 20% die and up to 10% have persistent neurological sequelae (Schumacher, 2012). These are particularly associated with protracted or multiple seizures which may cause cognitive deficiency and/or epilepsy.

Severe malarial anaemia (defined as haemoglobin concentration < 5 g/dl in the presence of P.falciparum parasitaemia) is more common in children than in adults. While mortality of SMA is low in asymptomatic children (approx. 1%), the presence of respiratory distress and metabolic acidosis is often (up to 30%) associated with a fatal outcome. According to the world malaria report 2011, the fatality rate for high risk populations approaches 40%. The role of iron supplementation in the prevention and treatment of anaemia in malaria-endemic regions has been much debated. Iron deficiency has an adverse effect on child health, cognitive development and overall survival, and WHO guidelines thus recommend routine iron supplementation for children aged 6 months to 24 months living in areas where anaemia prevalence is 40% or more. Alterations of iron metabolism in the human host are, however, thought to increase resistance to infection by restricting the availability of iron to microorganisms. With effective malaria control, iron supplementation should not be withheld from children with anaemia in endemic areas.

Not only does the severity of malaria infection change with age, but the clinical manifestation of disease as well: CM occurs more often in children aged 3 to 6 years; SMA is most likely to develop in children younger than 2 years. CM is more often associated with dehydration, hypoglycaemia, acidosis and respiratory distress; SMA is more often associated with spleen and liver enlargement. However due to its more subtle onset with less dramatic clinical manifestations than CM, this condition is often overlooked by the care giver in the initial phase and appropriate management of the malaria attack is delayed. SMA and CM account for most of all malaria related deaths.

Respiratory distress (deep breathing, Kussmaul’s respiration) is a clinical sign of metabolic acidosis, and has emerged as a powerful independent predictor of fatal outcome in falciparum malaria. It can be misinterpreted as cardiac failure and circulatory overload, especially if associated with severe

tachycardia.  Hypoglycaemia (blood glucose concentration < 2.2 mmol/l) is also associated with a poor outcome in children with malaria as in other severe childhood infections. Clinical evidence suggests that hypoglycaemia in African children with severe malaria results from impaired hepatic gluconeogenesis rather than from quinine-induced hyperinsulinaemia (Crowley et al, 2010) but quinine therapy may increase the risk.

 

Congenital Malaria

Pregnant women are more likely than others to be inoculated with and infected by malaria parasites and are more prone to severe forms, making adverse outcomes particularly common in primigravida women and their offspring. Besides the mother, malaria can infect also the placenta and the fetus, leading to low birth weight through intrauterine growth retardation and/or prematurity. Estimates for malaria induced low birth weight range from 7.8–45.3 of every 1000 live births and the associated mortality risks during the first month of life is about 40 times that of babies with normal birth weight (Schumacher, 2012).

All four types of human malaria can be transmitted congenitally, but the disease most often is associated with P.vivax. That congenital malaria is not seen more frequently is due in part to the effective barrier function of the placenta. Although congenital malaria develops in 0.1% of immune and 10% of no immune mothers in endemic areas, placental infection occurs in as many as one third of pregnant women. In endemic areas, distinguishing malaria acquired congenitally from that acquired by post-natal transmission from mosquitoes is difficult. The onset of symptoms is insidious and usually occurs at 2 to 8 weeks of age. The typical malaria paroxysm is usually absent, with the infant presenting instead more sepsis like symptoms: irritability, poor feeding, vomiting and diarrhoea. Fever and hepatosplenomegaly may be found on physical examination. The most common laboratory finding is anaemia, but thrombocytopenia and (unspecific) hyperbilirubinaemia are also common. Therapy for the infected species of malaria is curative, but in contrast to the mother, the infant does not need treatment of the exo-erythrocytic stages of the parasite. Interestingly, new evidence suggests that a subset of those vertically affected infants is also at higher risk of malaria infections later in life.

Imported Malaria occurs in children in many nonendemic countries. Over 1000 imported cases in children are diagnosed in Europe each year (Schumacher, 2012). Returning to country of origin to visit friends and relatives is the main risk factor. Over three quarters of these individuals did not take the recommended malarial chemoprophylaxis for the region to which they were travelling. The diagnosis often is delayed because of lack of consideration of malaria as a cause of illness and unfamiliarity with the disease.  In children with acquired immunity, the signs and symptoms of disease may be subtle and nonspecific, but fever is universal.

It therefore more prudent to consider the diagnosis of malaria  in every child with fever or a history of recent fever who has visited a malaria-endemic area, irrespective of antimalarial prophylactic.

Treatment of malaria depends on the (presumptive) identification of the species of Plasmodium causing the infection, knowledge of the presence of resistant organisms in the area in which the malaria was contracted, national guidelines, antimalarial availability, individual patient factors and

whether the malarial illness is categorized as either uncomplicated or severe. For falciparum malaria, the urgent initiation of appropriate therapy is especially critical, because P.falciparum infections can cause rapidly progressive illness and death. In endemic areas children with uncomplicated malaria, low parasitaemia, no vomiting and who maintain their nutrition and hydration orally may be treated with oral antimalarials, on an outpatient basis. Artemisinin and its derivatives are now a standard component, due to their high plasmodium killing rates and their capacity to target both, sexual and asexual stages they prevent both, clinical deterioration and transmission. Combination of an artemisinin derivative with a long-acting antimalarial drug reduces treatment duration to only 3 days. Artemisinins are generally safe and well tolerated, and are recommended by WHO as first-line treatment for P. falciparum and chloroquine resistant P.vivax infection. The main artemisinin-based combination therapies (ACTs) are:

• artesunate combined with mefloquine.
• artesunate combined with amodiaquine.
• artemether combined with lumefantrine,
• dihydroartemisinin with piperaquine.

The artemisinin derivatives are safe and well tolerated by young children, and so the choice of ACTs will be determined largely by the safety and tolerability of the partner drug.

Sulfadoxine-pyrimethamine should be avoided in the first weeks of life because it competitively displaces bilirubin with the potential to aggravate

neonatal hyperbilibinaemia. Furthermore the correct dosing in young children still needs to be defined (Barnes et al, 2006; Schumacher, 2012).

Primaquine should also be avoided in the first month and in children known to have severe G6PD deficiency.

Alternatives such as clindamycin and doxycycline may also be given, but only in children >8 years because of risk of dental hypoplasia and permanent teeth discoloration. With these exceptions there is no evidence for specific serious toxicity for any of the other currently recommended antimalarial treatments in infancy. Chloroquine remains recommended for the treatment of infections caused by P.malariae, P.ovale and P.knowlesi, also ACT seem to be equally effective. In P.vivax and P.ovale infections, patients recovered from the first episode of illness may have additional attacks, or relapses, after months or even years without symptoms, because these Plasmodium species have dormant liver stage parasites (hypnozoites) that may reactivate. Treatment with primaquine phosphate for 14 days should be included in the treatment of the first attack to eradicate the hepatic hypnozoites. Of course, HIV-infected children should receive prompt, effective antimalarial treatment according to the WHO guidelines. While there is evidence that Lopinavir/ritonavir based antiretroviral treatment can lower the risk for malaria in children (Achan et al, 2012; Schumacher, 2012) other combinations may be associated with a higher incidence of neutropenia (artesunate and amodiaquine) (Gasasira et al  2008; Schumacher, 2012) or hepatotoxicity (artesunate and amodiaquine plus efavirenz) (German et al, 2007; Schumacher, 2012).

With regard to paracetamol use, current WHO guidelines on the management of fever recommend its use in children with a temperature of 38.5°C or above.

 

 

 

• CLINICAL MANIFESTATIONS OF MALARIA INFECTION

 

The main manifestation of malaria is fever.  Other symptoms of malaria as well as fever are non-specific are similar to the symptoms of a minor systemic viral illness. They comprise headache, lassitude, fatigue, abdominal discomfort, muscle and joint aches, usually followed by fever, chills, perpiration, anorexia, vomiting and worsening malaise.

Children with uncomplicated malaria caused by all species of Plasmodium, typically present with fever and vomiting. Headache, chills, muscle aches, and anorexia are common. Additionally, P. vivax infections can be accompanied by intense rigors (Crawley, 2010).  Vomiting, diarrhoea, and abdominal discomfort might be misinterpreted as gastroenteritis, whereas respiratory symptoms (tachypnoea, difficulty breathing, cough ) might suggest pneumonia (Crawley, 2010). Therefore, Malaria is often over-diagnosed if based on symptoms alone, especially in endemic areas like Nigeria, because of this non-specificity of symptomatology. If treatment is not delayed and effective treatment is given, there is full rapid recovery. Hovever, if ineffective treatment is given or treatment delayed, malaria can progress to a severe one especially in children manifesting as coma (cerebral malaria), metabolic acidosis, severe anaemia, hypoglycaemia, acute renal failure or acute pulmonary oedema.  The severity and course of a clinical attack depends on the species and strain of the infecting plasmodium parasite, as well as the age, genetic constitution, malaria-specific immunity, and nutritional status of the child, and previous exposure to antimalarial drugs (Crawley, 2010).

 

• DIAGNOSIS OF MALARIA

 

Malaria, particularly pernicious malaria (falciparum malaria), poses a diagnostic dilemma at early stage as the disease can mimic many other conditions. Malaria must be recognized promptly in order to treat the patient in time to prevent further spread of infection in the community. The diagnosis of malaria can be clinical, parasitological, immunological and molecular. There are certain difficulties in the diagnosis and management of malaria, they include;

1. Misdiagnosis due to technical reason like inadequate smear, faulty microscopy, faulty staining, inadequate technical hand and so on.
2. Malaria maybe missed clinically in the presence of epidemics of dengue, meningitis, viral hepatitis, heat hyperpyrexia, alcoholic liver disease (NAMP, 1998).
3. Where malaria is not endemic any more (such as United States) clinician seeing a malaria patient may forget to consider malaria among the potential diagnosis.
4. In some areas where malaria is endemic, like sub-Saharan Africa, a large proportion of the population is infected but not made ill by the parasites. Such carriers have developed enough immunity to protect them from malaria illness but not from malaria infection. In that situation, finding malaria parasite in an ill person does not necessarily mean that the illness is caused by the parasites.
5. In many malaria-endemic countries, lack of resources is a major barrier to reliable and timely diagnosis.

 

 

Clinical (presumptive) diagnosis

The symptoms of malaria (most often fever, chills, sweats, headaches, muscle pain, nausea & vomiting) are applied in clinical diagnosis of malaria, although reliable diagnosis cannot be made on the basis of signs and symptoms alone because of the non-specific nature of clinical malaria. Clinical diagnosis of malaria is common in areas where malaria is endemic. In most of the endemic countries, resources and trained health personnel are scarce that presumptive clinical diagnosis is the only realistic option.

Clinical diagnosis offers the advantages of ease and low cost. In areas where malaria is prevalent, clinical diagnosis usually result in all patients with fever and no apparent other cause being treated for malaria. This approach can identify most patients who truly need antimalarial treatment, but it is also likely to misclassify many who do not (Oliver et al, 1991). Misdiagnosis can be considered to contribute to misuse of antimalarial drugs. Considerable overlap exists between the signs and symptoms of malaria and other diseases, especially acute lower respiratory tract infection (ALRTI) and this greatly increases the frequency of misdiagnosis and mistreatment (Redd et al, 1992). Because of the low specificity of clinical diagnosis of malaria especially in an endemic area, and the contribution of presumptive malaria treatment to the constant evolution of antimalarial drug resistance, there is a compelling need to make use of parasite detection techniques.

 

Parasitological diagnosis  

The most preferred and reliable diagnosis of malaria is microscopic examination of blood films because each of the parasite species has distinguishing characteristics. Simple microscopy is the oldest laboratory method for the diagnosis of malaria. It has been in use for the past 120 years (Adesanmi et al, 2011). Microscopy is still the gold standard for the diagnosis of malaria infection. The technique of slide preparation, staining and reading are well known and standardized, and so is the estimate of the parasite density, which is an added value of microscopy and that can easily be estimated on a thick film. Two types of blood films are traditionally used- thick and thin films. Thin films are similar to usual blood films and allow species identification because the parasite’s appearance is best preserved in this preparation. Thick film allows the microscopes to screen a larger volume of blood and is about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much difficult.

With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis (Kwiatkowski, 2005). However, microscopic diagnosis can be difficult because the early trophozoites (ring form) of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites. It also has other limitations for instance it requires the need for technical expertise, elaborate equipment and electricity. It is also time consuming, requiring on the average 60 mins. (Adesanmi et al, 2011).

Nevertheless, simple microscopy has its advantages:

1. It is used in making a diagnosis of malaria infection
2. It is used for assessing the degree of parasitaemia and in monitoring response to treatment.
3. It is useful in epidemiological surveys to assess parasite rates within a given population as well as the degree of transmission of malaria (Adesanmi, 2011)

 

 

 

 

 

Immunological (antigen detection) diagnosis

A third diagnostic approach involves the rapid detection of parasite antigen using rapid immunochromatographic techniques.  Multiple experimental tests have been developed targeting a variety of parasite antigen (Khusmith et al, 1987). It is of great importance in areas where microscopy is not available. It requires only a drop of blood (Carter, 2002). A number of commercially available kits (Paracheck-PF^® Becton-Dickson, Malaquick^® etc.) are based on the detection of histidine rich protein 2 (HRP-II) while OPTMAL^® and Flow Inc. Portland are based on detection of a specific enzyme lactate dehydrogenase or (pLDH)

Advantages of this technology are that

1. No special equipment is required
2. Minimal training is needed
3. The test and reagents are stable at ambient temperatures and
4. No electricity is needed.
5. It can be performed in approximately 15 mins (Uzochukwu et al, 2010).

This method saves the cost and time wasted on presumptive treatment particularly with high cost artemisinin-combination therapy (ACTs).

The principal disadvantage is a currently high per-test cost and an inability to quantify the density of infection. Furthermore, for tests based on HRP-II detectable antigen can persist for days after adequate treatment and cure therefore, the test cannot adequately distinguish a resolving infection from treatment failure due to drug resistance especially after treatment (WHO, 1996).

 

Molecular Diagnosis  

Detection of parasite genetic material through polymerase chain reaction (PCR) technique is becoming a more frequently used tool in the diagnosis of malaria, as well as the diagnosis and surveillance of drug resistance in malaria. Specific primers have been developed for each of the four species of human malaria. One important use of this new technology is in detecting mixed infections or differentiating between infecting species when microscopic examination is inconclusive (Beck, 1994)

In addition, improved PCR techniques could prove useful for conducting molecular epidemiological investigations of malaria clusters or epidemics (Freeman et al, 1999)

Primary disadvantages of these methods are

1. Overall high cost
2. High degree of training required
3. Need for special equipment
4. Absolute requirement for electricity and
5. Potential for cross-contamination between samples.

 

 

Establishing Malaria Parasitic counts

It is necessary to establish parasitic count for the blood because of the following reasons

1. The physician may want to know how severe the malaria is.
2. The physician may need to know whether the malaria parasite is responding to the antimalarial treatment being given. This can be monitored over time by plotting the parasite count on the day of treatment and comparing it with the count in a blood film at a specified later day.
3. The data may be needed for special purposes, such as testing the sensitivity of parasite to antimalarial drugs.

 

Method 1: Parasite per micro litre of blood

The number of parasite per microlitre of blood in a thick film is counted in relation to a standard number of leukocytes (8000). There are 2 steps involved;

Step 1

1. If 10 or more parasites are identified and counted after counting 200 leukocytes, then the results is recorded in terms of number of parasites per 200 leukocytes.
2. If 200 leukocytes have been counted, and 9 or less than 9 parasites are identified and counted on the tally counter, the result is recorded in terms of the number of parasites per 500 leukocytes.

 

 

 

Step 2

In case of a) and b) above, the number of parasites relative to the leukocytes count can be converted to parasite per microlitre of blood by simple mathematical formula

A/B  x  8000/200 = parasite per microlitre of blood (case I)

A/B  x  8000/500 = parasite per microlitre of blood (case II)

Where A is number of parasite and B is number of Leukocytes

 

 

Method 2: The Plus System 

This system is simpler than method 1 but gives a relative and less accurate result. It makes use of plus signs to grade level parasite in a thick film. The plus signs are used as follows:

+          =          1-10 parasites per 100 thick film fields

++        =          11-100 parasites per 100 thick film fields

+++     =          1-10 parasites per single thick film field

++++   =          >10 parasites per single thick film field

 

 

Criteria for diagnosis in stable malaria areas;

• Fever
• Unexplained pallor.

 

A parasitological diagnosis of malaria is always desirable. This may be by standard microscopy or by the rapid diagnostic tests (RDT). In children under 5, a clinical diagnosis is adequate for the treatment of uncomplicated malaria. This is to avoid any delay in treatment because malaria is very common and may be rapidly fatal in this age group. However, lab diagnosis is needed for confirming the diagnosis and in suspected cases of treatment failure (FMOH, 2005)

 

 

• TREATMENT OF UNCOMPLICATED MALARIA

 

Treatment of malaria depends on the (presumptive) identification of the species of Plasmodium causing the infection, knowledge of the presence of resistant organisms in the area in which the malaria was contracted, national guidelines, antimalarial availability, individual patient factors and whether the malarial illness is categorized as either uncomplicated or severe.

Treatment with antimalarials leads to reduction of malaria transmission by two mechanisms:

1. Reduction of gametocytes by eliminating the asexual blood stages from which gametocytes derive. The faster the clearance of asexual blood parasites the greater the effect on reducing infectivity.
2. Lowering parasite infectivity through either a direct effect on gametocytes (gametocytocidal effect) or on the parasite developmental stages in the mosquito (sporonticidal effect).

Treatment of uncomplicated falciparum malaria has three main objectives. The first is to cure the infection. The second is to prevent the development of antimalarial drug resistance, and the third is to reduce transmission (WHO, 2006). Cure of the infection means eradication from the body of the causative organism.

Rational use of antimalarial drugs refers to appropriate use of antimalarials for the right indication and at the correct/adequate dosages. Antimalarial drugs will be needed for treatment of uncomplicated malaria, severe malaria and chemoprophylaxis for groups at risk. The appropriate use of antimalarial drug is determined by the goal of treatment and the person responsible for taking the primary decision on use of the drug either at home or at the different health care levels.

In treatment evaluations, it is necessary to follow patients for sufficient time to appropriately assess cures. The duration of post-treatment follow-up is based on the elimination half-life of the antimalarial medicine being evaluated. The current recommended follow-up is a minimum of 28 days for all antimalarial medicines, while it is extended for longer periods of time depending on elimination half-life (42 days of combinations of mefloquine and piperaquine) (WHO, 2009). When possible, blood and plasma levels of the antimalaria should also be measured in prospective assessments so that drug resistance can be distinguished from treatment failures due to inadequate drug exposure (WHO, 2009).

The drugs traditionally used to treat uncomplicated malaria have become ineffective in many parts of the world including Nigeria due to the development of drug resistance. Besides, the high rate and increasing antimalarial drug resistance to hitherto first and second line drugs (Chloroquine and Sulphadoxine-Pyrimethamine) has compounded malaria therapy in the country.

The treatment of choice for uncomplicated malaria is Artemisinin-based Combination Therapy (ACT). This consists of the use of an artemisinin derivative and another effective antimalarial medicine (FMOH, 2005). This is because of its prompt and effective action and quick resolution of the illness. It will also delay development of resistance to either of the components of the drug. While consumption of milk or food enhances lumefantrine absorption, adequate exposure is achieved with a standard African diet (Bassat et al, 2011). Due to the short half-life of artemether, AL is administered twice a day to ensure that infecting parasites are exposed to artemether above the minimum effective concentration throughout most of their life cycle (White et al, 1999; Bassat et al, 2011). A three-day regimen of AL is used to cover two full parasite life asexual cycles and thus maximize efficacy. High levels of adherence to this regimen have been described when AL is employed in the community (Bassat et al, 2011) Since AL was first licensed in 1999, it has been recommended that the drug be dosed according to body weight ranges, i.e. 5 to < 15 kg, 15 to < 25 kg, 25 to < 35 kg and > 35 kg. 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 (Borrman et al, 2011).

Artemisinin derivatives are sesquiterpenoids with an endoperoxide which is the essential component of the anti-malarial activity with their structure distinction from all other antimalarials. Artemisinins have so far been shown to be effective against multidrug-resistant strains of P. falciparum (Abdoulaye, 2010) The efficacy of amodiaquine (AQ) combined with artesunate (AS) varies in Africa, achieving high (≥ 90%) cure rates in some countries  but lower rates in countries such as Kenya (80%), Rwanda (80%), and Tanzania (89%) (Sirima et al, 2009). In Burkina Faso, where the failure rate of chloroquine was 81% by Day (D) 28 in a previous trial, two small studies have evaluated loose AS combined with AQ (AS+AQ). The cure rates of AS+AQ were 100% in 33 children aged 1 to 15 and 82% in 61 children aged 6 to 10 years (Sirima et al, 2009). AS+AQ is generally well tolerated as treatment.  Several reports in Nigeria, in Africa and in Asia evaluating the use of ACT for the treatment of uncomplicated malaria have confirmed its efficacy and safety. Results from a longitudinal randomized clinical trial carried out in Uganda suggested that both AL and DP are safe for treating uncomplicated malaria in young HIV-infected and uninfected infants and children. Adverse events were uncommon and generally of mild severity, with only cough, diarrhea, vomiting and anaemia occurring in more than 1% of treatments with study drugs. (Katrak et al, 2009). A study reported day 28 cure rates of 95.2% and 92.0% for dihydroartemisinin-piperaquine and Artesunate-Amodiaquine combinations respectively in Rwanda (Karema et al, 2006). Another study carried out in Oyo state, Nigeria, showed a 28-day cure rate of about 95% with Artemether-lumefantrine and 93% for Artesunate-Amodiaquine combinations (Falade et al, 2008)  while a similar study in Enugu State, Nigeria reported day 14 cure rate of 95% for Artesunate-Amodiaquine (Okoli et al, 2010). Study in India reported 92.42% cure rate at 28-day with the use of Artesunate-Amodiaquine combination (Anvikar et al, 2012). The recommended ACT for uncomplicated malaria is Artemether-lumefantrine (FMOH, 2005). Other available ACTs are;

• Artesunate plus Amodiaquine
• Artesunate plus Mefloquine
• Dihydroartemisinin plus Piperaquine plus Trimethoprim.

 

Monotherapy with dihydroartemisinin, other artemisinin derivatives and other antimalarial medicines are not recommended.

 

Practical issues in management of Uncomplicated Malaria

• Use of antipyretics: If temperature is high i.e. >38.5℃ wipe the body with wet towel, avoid over clothing and give paracetamol 10mg/kg in children or 500-1000 mg in adults 4 times daily.
• Vomiting- repeat full dose; if vomiting persist- treat as severe malaria.
• Febrile seizures- treat as severe malaria
• Where oral administration of drug is not possible-use rectal Artesunate, parenteral (i.m. or i.v. quinine)

 

Follow-up (FMOH, 2005)

Tell the patient to return:

• If fever persists for two days after commencement of treatment (FMOH, 2005).
• Immediately, if condition gets worse or develops signs of severe disease.

When patient returns:

• Check that they complied with the treatment as advised
• Repeat or do blood smear for malaria parasites.
• Do a complete assessment to exclude any other possible cause of fever.

 

 

 

 

 

 

• ANTIMALARIAL DRUGS

 

Antimalarial drugs destroy the malaria parasites and reduce their multiplication. Those are their main therapeutic effects. Essential antimalarial drugs are those that meet the needs of appropriate antimalarial treatment in the vast majority of the people. They should therefore be available at all times, in adequate amounts, appropriate dosage forms and affordable to the people.

 

Criteria for Selection

The criteria for selection of essential antimalarial drugs should be the same as for the selection of essential drugs in general. They are as follows:

 

• The drugs should satisfy the antimalarial treatment needs of the vast majority of the people at all levels of health care.
• They should be drugs for which there is sufficient evidence of efficacy and safety from local and global controlled clinical studies and from experience in general use.
• The preferred dosage forms should be those which have reasonable shelf-life and are able to withstand adverse environmental conditions unavoidable in our distribution chain. For example, tablets and capsules are more suitable under our prevailing ambient temperatures and humidity than mixtures, syrups and elixirs. Preferably, therefore, paediatric doses should be achieved from the use of either paediatric tablet strengths or scored tablets of standard tablet.
• They should be registered for wide distribution in the country.
• They should be drugs for which quality certification can be readily obtained from local institutions, from the country of origin or through the auspices of the World Health Organization.
• They should be drugs that can either be manufactured locally using locally produced or imported raw materials or that can be imported in bulk cheaply.
• Drugs with known serious side effects but with acceptable risk/benefit ratio considering the severity of the situations in which they are to be used (e.g. quinine) have been included in the expectation that their procurement, storage, distribution and use would be subject to the strict technical and ethical control associated with such drugs.

 

 

Considering the complex biological cycle of malaria plasmodia, the ideal drug to meet the clinical targets should have the following properties:

• to act rapidly against the replicating blood erythrocytic asexual forms, primarily schizonts, that are responsible for the clinical manifestation of the disease(parasitologicalcure)
• to act against liver hypnozoites, when appropriate (radical cure)

 

In endemic areas, furthermore, the ideal drug to meet the epidemiological targets should have the following properties:

• to act against the sexual forms (gametocytes) that are responsible for the transmission of the infection in the population via the vector mosquitoes; this gametocidal effect is time-sensitive because the appearance of sexual forms is delayed of several days from the clinical malaria attack;
• to avoid selecting plasmodia resistant strains (high resistance barrier)

The World Health Organization (WHO) recommends that first line antimalarials should have a treatment failure rate of less than 10%, and failure rates higher than this should trigger a change in treatment policy. Treatment failure can be classified as:

Early treatment failure:

• the development of danger signs or severe malaria on days one, two, three in the presence of parasitaemia
• parasitaemia on day two higher than on day 0;
• parasitaemia and axillary temperature > 37.5 °C on day three;
• parasitaemia on day three > 20% of count on day 0.

or late treatment failure:

• development of danger signs, or severe malaria, after day three with parasitaemia;
• presence of falciparum parasitaemia and axillary temperature > 37.5 °C on or after day four;
• presence of falciparum parasitaemia after day seven.

 

The late reappearance of P. falciparum parasites in the blood can be due to failure of the drug to completely clear the original parasite (a recrudescence) or due to a new infection, which is especially common in areas of high transmission. A molecular genotyping technique called polymerase chain reaction (PCR) can be used in clinical trials to distinguish between recrudescence and new infection, giving a clearer picture of the efficacy of the drug and its post-treatment prophylactic effect (Sinclair et al, 2009).

 

 

• RESISTANCE TO ANTIMALARIAL DRUGS

 

Drug-resistant Plasmodium falciparum has rendered many anti-malarial drugs ineffective with a consequential increase in childhood morbidity and mortality, especially in Africa (Sirima et al, 2009). Many countries, most of them in Africa, are now using artemisinin-based combination therapy (ACT) following the demonstration of their superiority over standard monotherapies and the subsequent recommendation by the World Health Organization (Sirima et al, 2009). Antimalarial drug resistance is a shift to the right of the dose-response curve; in other words doses or concentrations which kill sensitive parasites will not kill the resistant parasites. There are mechanisms by which resistance are developed by the malaria parasite. Malaria infections with resistant parasites are more likely to fail treatment, i.e. recrudesce, and as resistance gets worse these will respond more slowly to treatment. Both increased rates of recrudescence and slow responses to treatment increase the probability of generating gametocyte densities sufficient for transmission. Thus resistant infections are more likely to transmit to others than sensitive infections. It is this transmission advantage which drives the spread of resistance. The development of resistance, defined as the ‘ability of a parasite strain to multiply or to survive in the presence of concentrations of a drug that would normally destroy parasites of the same species or prevent their multiplication’ has threatened the continuing usefulness of the presently available antimalarial drugs (FMOH, 2005). Resistance to Chloroquine has spread rapidly through South America, Southeast Asia to East Africa and eventually to all endemic countries of the continent. A similar process has happened to Sulphadoxine–Pyrimethamine (SP) except that resistance to the drug in Africa is low in West Africa, and is beginning to increase in East African countries where Sulphadoxine–Pyrimethamine (SP) has replaced Chloroquine as the first line antimalarial drug (FMOH, 2005). The factors responsible for the emergence and rate of spread of parasite resistance are not fully known. What is clear, though, is that parasite resistance can occur for any antimalarial drug and that drug selection pressure is a critical and essential prerequisite for the development of resistance (Talisuna et al, 2004). However, what determines the rate at which resistance spreads is still a matter for scientific investigation. Several theoretical models have been proposed, however, the various factors that have been considered in the models include the degree of drug use, the drug elimination half-life, host heterogeneity, parasite biomass, malaria transmission intensity and its proxy factors such as the number of parasite clones in a single infection (clone multiplicity), the immunity of hosts, and intra host dynamics (Talisuna et al, 2004). Resistance to antimalarial drugs has been documented for P. falciparum, P. vivax, and recently P. malariae. With some differences with respect to the geographical distribution and the level and rate of spread, resistance of P. falciparum has been observed against almost all currently used antimalarials, except for the artemisinins, while for P. vivax only resistance against Chloroquine is described. The epidemiology of drug resistant malaria has been the subject of several reviews (FMOH, 2005). In a race to combat the ever increasing resistance of Plasmodium falciparum to older anti-malarial drugs; artemisinin, a natural product found in the leafy portion of Artemisia annua and its derivatives, have emerged as alternative drugs for the treatment of falciparum malaria (Klayman, 1985). But as these drugs are so valuable it is essential that they be protected from resistance development. This is done by prescribing only antimalarial combinations which ensure that no malaria parasites are exposed to an artemisinin compound alone, but only together with longer-acting antimalarials such as mefloquine, lumefantrine, amodiaquine etc. 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 parasitaemia 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. The first-line treatment of choice for uncomplicated malaria is Artemisinin-Based Combination Therapy (ACT). This consists of the use of an artemisinin derivative and another effective antimalarial medicine (WHO, 2010). However, the decision of which ACT to adopt into national malaria control programmes has been based on a combination of research and expert opinion (Sinclair et al, 2009).

The drugs traditionally used to treat uncomplicated malaria have become ineffective in many parts of the world including Nigeria due to the development of drug resistance.

 

• Chloroquine resistance has been reported from all falciparum-endemic areas, with the exception of Central America and the Caribbean. Resistance was first documented on the border between Thailand and Cambodia and in Columbia in the late 1950s. Since then, Chloroquine resistance has spread throughout the tropical world. In Africa, Chloroquine resistance was first detected in Tanzania in the late 1970s, and has since spread and intensified across the Continent (WHO, 2006).

 

• Amodiaquine is generally more effective than Chloroquine. However, there is cross-resistance between the two drugs, and the efficacy of amodiaquine is declining in many areas. High levels of resistance are much in Asia, and there is increasing resistance in East Africa, Papua New Guinea, and in the Amazon region. The drug is still reasonably effective in many countries in Central and West Africa, and in parts of South America (WHO, 2006).

 

• Sulphadoxine-Pyrimethamine: very high levels of resistance are found in many parts of South-East Asia, southern China, and the Amazon region. In many parts of Eastern and Southern Africa, SP treatment failure rates have risen to unacceptable levels. Lower levels of resistance are found on the Pacific coast of South America, southern Asia east of Iran, western Oceania and parts of central and Western Africa (WHO, 2006).

 

• Quinine: despite widespread use of quinine, resistance levels are low, and quinine is still generally effective. It remains the first drug of choice for the treatment of severe falciparum malaria in many countries. Decreasing sensitivity has been observed in some areas of South-East Asia, where it has been used extensively for many years as first-line treatment.

 

• Mefloquine; resistance is prevalent in Eastern Myanmar, Thailand, Cambodia and Southern Vietnam. In the Amazon region, low level mefloquine resistance has been reported. In Africa, mefloquine resistance is rare, but a few treatment failures have been observed in Tanzania, Malawi and Nigeria.

 

Besides, the high rate and increasing antimalarial drug resistance to first and second line drugs (chloroquine and sulphadoxine-pyrimethamine) has compounded malaria therapy in Nigeria. The important consequences of drug resistance are: an increase in morbidity and mortality, delay in initial therapeutic response and, an increasing cost to the community. These consequences need to be prevented urgently.

WHO guidelines advise policy review when adequate clinical and parasitological response hits the 75% mark. This means that an antimalarial agent may not be used as first line when the level of resistance is 25% and above in an area (WHO, 2001; Oshikoya, 2007). The result of the 2002 Efficacy Studies indicated that Chloroquine and SP were no longer adequate for national first line use (FMOH, 2005).

 

 

Table 1: Therapeutic Efficacy of Anti-malarial Drugs in Nigeria

(Adequate Clinical and Parasitological Response ACPR)

 

s/n	Zones	Chloroquine*	Sulphadoxine/Pyrimethamine*	Artemether/Lumefantrine	Artesunate/Amodiaquine
1	SE	3.7%	14.9%	100%	100%
2	SS	9.1%	8.5%	87%	82.5%
3	NC	53.2%	82.7%	100%	96%
4	NW	77.3%	94.2%	100%	100%
5	SW	40.9%	75.6%	100%	100%
6	NE	50.8%	64.8%	100%	100%

 

(Reproduced from National Antimalarial Treatment Policy)

*2002 Drug efficacy study     **2004 drug efficacy study

 

The need to move from monotherapy to more effective combination therapy was recognized. As a result, further efficacy trials were conducted in 2004 by Federal Ministry of Health on two suitable Artemisinin based combination therapy. Both combination therapies were found to be highly efficacious and thus suitable for use in the treatment of uncomplicated malaria. There is an urgent need to preserve and prolong the usefulness of the presently available antimalarial drugs.

 

 

 

 

 

• MALARIA SITUATION IN NIGERIA

 

After almost a century in attempts to eliminate malaria in the world, it continues to be a major public health problem in Nigeria and causes illness and death in children and adults. It is the commonest cause of hospital attendance in all age groups in all parts of Nigeria. It is also one of the four commonest causes of childhood mortality in the country, the other three being acute respiratory infection (pneumonia), diarrhea and measles. It is estimated that 50% of the population has at least one episode of malaria each year while children under 5 have on the average of 2-4 attacks in a year (FMOH, 2005).  Malaria causes 25-30% of below 5 mortality in Nigeria i.e. at least 250,000 Nigerians below 5 years die yearly from malaria (Nkanginieme, 1999).

 

Plasmodium falciparum is the most predominant parasite species accounting for about 98% of all cases of malaria in the country and it is the species that is responsible for the severe form of the disease that leads to death. P.malariae usually occurs as a mixed infection with P.falciparum. Malaria is characterized by a stable, perennial, transmission in all parts of the country. Transmission is higher in the wet season than in the dry season. The peak transmission of malaria coincides with the onset of high rainfall i.e. between April-June. However, no part of Nigeria at any time of the year can be considered to be free from malaria. This seasonal difference is more striking in the northern part of the country (FMOH, 2005).  Anopheles gambiae is the main vector of malaria in Nigeria, but An. funestus and An. arabiensis are also commonly encountered. An. melas is found in the coastal areas (FMOH, 2005).

 

The prevalence of severe malaria in children varies between 25-34% (Olanrewaju, 2001). The associated mortality varies between 11-30% (Ibeziako, 2002). Children aged 6 months to 5 years in areas holoendemic for malaria are most vulnerable to severe malaria because of their semi-immune status. In the children’s Emergency Room at the University of Nigeria Teaching Hospital (UNTH) Enugu, Enugu State, South East of Nigeria, severe malaria with severe anemia is the 2^nd commonest ailment seen. It constitutes 18.4% of admissions and is the leading cause of death beyond the neonatal period, constituting 30% of mortality in this age group (Ibeziako, 2002). Severe malaria is also the commonest cause of severe anemia requiring blood transfusion in children aged less than 5 years at UNTH and other parts of Nigeria (Ojukwu, 2002). In Nigeria, it is a disease of major public health significance with levels of endemicity ranging from holoendemic to hyperendemic depending on the climatic and geographical characteristics of the area.

Economic Burden

In Nigeria, the burden of malaria is well documented and has shown to be a big contributor to the economic burden of the disease in communities where it is endemic. Each year, the nation loses more than 132 billion Naira from cost of treatment and absenteeism from work, schools and farms. It impedes human development and is both a cause and consequence of under development. (FMOH, 2005; Jimoh, 2007)

A strong correlation between malaria and poverty has also been recognized. Not only does malaria thrive in poverty but it also impedes economic growth and keeps households in poverty (Uzochukwu et al, 2010). Poverty can increase the risk of malaria, since those in poverty do not have the financial capacities to prevent or treat the disease. Hence, the poor bear a disproportionate burden of the disease (White, 2008).

The strategies employed to prevent and control malaria have been effective in reducing the burden of disease in many countries. Yet, as analyses of health outcomes become more refined, it is increasingly evident that poor and marginalized populations might not be benefiting from investments in malaria prevention and control. Poverty is increasingly considered multidimensional and its definition goes well beyond the narrow association of poverty with low income and consumption. Poverty encompasses other forms of deprivation, including economic opportunities, education and health outcomes, access to services, and resources and skills. This definition also covers additional aspects, such as voicelessness, vulnerability and powerlessness to influence decisions that affect their lives. While malaria is not exclusively a disease of the poor, the deprivation associated with poverty can increase the risk of malaria. The relationship between malaria and poverty plays out along a number of distinct, yet interrelated, pathways. Poorer and marginalized communities might be more likely to suffer from malaria than less poor communities, because their geography and environment are more hospitable to mosquitoes than areas inhabited by non-poor communities (Ricci, 2012).

Poverty also might reduce the likelihood that households will adopt appropriate preventive measures (such as sleeping under an insecticide treated net [ITN]) and curative measures (seeking timely health care for fevers). This can result in greater malarial morbidity and mortality among the poorer than the non-poor. Conversely, malaria might further impoverish poorer households through the costs of preventive and curative measures, as well as for the inability to work while ill. In the Pacific areas, for example, income or consumption poverty tends to be low or nonexistent, but households there can be vulnerable to natural disasters; be isolated or remote; lack economic choices (or opportunities to earn a cash income); have limited access to educational, health and financial services; and suffer from social exclusion (Ricci, 2012).

An estimated 58% of malaria deaths occur among the poorest 20% of the world’s population.  The inequality of this distribution is higher than that for any other diseases of public health importance. The socioeconomic situation is significantly associated with malaria even in endemic rural areas where economic differences are not much pronounced.

In a recent survey in Nigeria on children health, about 16% of children reported having fever in the two weeks preceding the survey. The prevalence of fever was highest among children from the poorest households (17%), compared to 15.8% among the middle households and lowest among the wealthiest (13%) (p<0.0001). Of the 3,110 respondents who had bed nets in their households, 506(16.3%) children had fever, while 2,604(83.7%) did not. (p=0.082). In a multilevel model adjusting for demographic variables, fever was associated with rural place of residence (OR=1.27, p<0.0001, 95% CI: (1.16, 1.41), sex of child: female (OR=0.92, p=0.022, 95% CI: 0.859, 0.988) and all age categories (> 6 months), whereas the effect of wealth no longer reached statistical significance.  Malaria might cause and perpetuate poverty at the household level in a number of direct and indirect ways. As outlined above, the total costs of malaria include the direct, indirect and opportunity costs of falling ill and seeking treatment for malaria. Households suffer significant costs when a household member is sick with malaria. The direct and indirect costs of malaria might be substantial, further impoverishing poor households. Mean direct cost of seeking care for malaria was estimated at 2%-2.9% of household income. Yet that might mask important economic inequalities

Malaria burden is hard to estimate, particularly in low income countries where data collection and reporting quality is poor. Incomplete and discontinuous reports from single health facilities may alter final global malaria prevalence. Malaria cases are often under-diagnosed in hyper endemic countries, where mild symptoms of chronic malaria may possibly lead to misdiagnosis. On the contrary, over-diagnosis may also occur. In fact, not all reported malaria cases are confirmed by microscopy or others assay, such as rapid diagnostic tests (RDTs). Furthermore, in hyper endemic areas febrile illnesses from different causes might be misdiagnosed with malaria. Anyway, the WHO guidelines recommend that microscopy or RDTs should be used to confirm all malaria cases. Another issue is the lack of population denominator that makes the real incidence of malaria difficult to assess. Data emerging from WHO reports just estimate malaria incidence and mortality, reporting malarial cases and malarial death from the different WHO regions, collected by Ministries of Health of different countries. These data do not reflect the real incidence in the general population. Nevertheless, they are good indicators to assess malarial control programmes and to estimate the impact of malaria infection in health systems.

Studies comparing cognitive functions before and after treatment for severe malaria illness continued to show significantly impaired school performances and cognitive abilities even after recovery (Fernando et al, 2010). Consequently, severe and cerebral malaria have far reaching socioeconomic consequences that extend beyond the immediate effects of the disease (Ricci, 2012).

 

1.7       ANTIMALARIAL TREATMENT POLICY

 

This is a set of recommendations and regulations concerning antimalarial drugs and their utilization in the country. This policy is continuously evaluated, reviewed and updated whenever necessary by the national malaria control programme. The policy contains information on whether sick patient requires antimalarial treatment or not. It contains the recommended treatment for uncomplicated or severe malaria, chemoprophylaxis for various risk groups, criteria for review of antimalarial treatment policy and regulation and deployment of antimalarial medicines. The policy also states the relationship among the various health care levels in the country and their management capabilities of malaria.

In 1996, Nigeria developed her first National Malaria Control Policy. A yearly Plan of Action was developed for 1997 and 1998 and a three-year Plan of Action was also developed for 1999 – 2001. Malaria Control units in the States were revitalized or reestablished and awareness to funding malaria activities was created. The strategy for the implementation of the national malarial treatment policy is that of Roll Back Malaria (RBM). This strategy seeks to establish a social movement in which the local communities, public and private sectors, all tiers of government and non-governmental development agencies come together in a partnership and network to implement malaria control interventions.

Roll Back Malaria is a global initiative that has set specific deadlines for the attainment of explicitly defined milestones. One of these is the reduction of malaria burden everywhere by 50% by the year 2010. The RBM intervention strategy has four key elements:

1. Patients with malaria should have access to appropriate and adequate treatment within 24 hours of the onset of symptoms
2. Pregnant women particularly in their 1st and 2nd pregnancies should have access to effective antimalarial prophylaxis and treatment

iii. Insecticide treated nets and other materials should be available and accessible to persons at risk of malaria particularly pregnant women and children under 5 years of age.

1. Epidemics of malaria should be recognized and steps initiated for their containment within one week of their onset.

It is obvious that achieving the goal of this policy would require the availability of appropriate antimalarial drugs and their proper management, including storage and rational use. This means that proper financial provisions should be made at all levels for the regular availability of these drugs at costs that the people can afford. The consumers and providers have to be properly educated on malaria and its treatment and an effective monitoring and evaluation system set up to ensure that objectives are being properly pursued. Finally, malaria is a moving target. New understandings of old problem would be needed and new problems requiring clarification will arise.

Antimalarial drug resistance arose to all classes of antimalarial drugs except the artemisinin derivatives. It has resulted in a global resurgence of malaria and it is a major threat to malaria control. Widespread and indiscriminate use of antimalarial drugs places a strong selective pressure on malaria parasites to evolve mechanisms of resistance. Prevention of antimalarial drug resistance is one of the main goals of these antimalarial treatment recommendations. Resistance can be prevented by combining antimalarial drugs with different mechanisms of action, and ensuring very high cure rates through full adherence to correct dose regimens.

Since the inception of the 2005 Nigeria’s antimalarial treatment policy many research have been carried out to assess the compliance of different levels of health facilities to the anti-malarial treatment guideline. Studies in different parts of Nigeria have shown that there is a high use of ACTs in the tertiary and secondary health sectors. For example a study in a tertiary and a secondary hospital in Abuja showed an increased use of artemisinin-based combination therapy (Igboeli et al, 2010). Also in a research carried out in Ibadan on the “Feasibility, acceptability and use of artemisinin-based combination therapy for home management of Malaria” (Ajayi, 2009) showed progress is being made in the use of such combination.

Another one done in Cross River State compared the antimalarial drug prescribing pattern in public and private health facilities (Meremikwu et al, 2007). They found out that Clinicians in the private sector were less likely to record history or physical examination than those in public facilities, but otherwise practice and prescribing were similar. 665 patient records  were assessed and 77% showed monotherapy, either Chloroquine (30.2%), Sulphadoxine-Pyrimethamine (22.7%) or Artemisinin derivatives alone (15.8%). Some of the patients (20.8%) were prescribed combination therapy; the commonest was Chloroquine with Sulphadoxine-Pyrimethamine. A few patients (3.5%) were prescribed Sulphadoxine-Pyrimethamine-mefloquine in the private sector, and only 3.0% of the patients were prescribed artemisinin combination treatments.

Presumptive treatment has resulted in overuse of antimalarial drugs, increasing drug resistance (White, 2004) and importantly, failure to treat alternative causes of fever (Reyburn, 2004). The WHO recommends that parasitological confirmation by microscopy or rapid diagnostic test should be obtained in all patients with suspected malaria before the commencement of treatment.

More than 50% of deaths from severe childhood illnesses, including malaria, occur within 24 hr of hospital admission, and early identification and treatment of children at highest risk of death are therefore of great importance. (Crawley, 2010)

Key to reducing mortality and morbidity from malaria is the prompt delivery of effective drug treatment to sick children, yet few children aged under 5 years who have fever are treated with ACTs in Africa (Crawley, 2010).

Experience from Asia suggests that rapid diagnostic tests and ACTs used by village Health Workers can substantially reduce morbidity and mortality. Several research groups are now Assessing whether a similar approach can be used in Africa.

In fact recently the Nigerian Federal Ministry of health in its Implementation Guide for RDT deployment published in 2011 stated the advantages of parasitologically based diagnosis as follows:

• Improved patient care.
• Identification of parasite-negative patients in whom another diagnosis must be sought and early specific treatment given.
• Promotion of rational use of medicines: prevention of unnecessary use of antimalarials, reducing frequency of adverse effects in parasite-negative patients and selection pressure of drug resistance.
• Improved case detection and reporting.

 

 

 

1.8       OBJECTIVES OF THE STUDY

 

The general objective of this research was to study the prescribing practice of antimalarial drugs for children with uncomplicated malaria in a teaching hospital.

The specific objectives:

• To determine the cases that were diagnosed based on laboratory investigation and/or clinical manifestation.
• To find out the anti-malarial drugs used in the treatment of uncomplicated malaria cases from 2003 to 2011.
• To determine the changes if any in the prescription pattern following the implementation of the National Treatment Guidelines of 2005.
• To assess the level of compliance of the prescribers to the National treatment guidelines.

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