EFFICACY OF SEASONAL INTERMITTENT PREVENTIVE TREATMENT WITH SULPHADOXINE-PYRIMETHAMINE ON REDUCTION OF CLINICAL MALARIA AND ANAEMIA IN UNDER FIVE CHILDREN PRESENTING IN SEVENTH-DAY ADVENTIST HOSPITAL, JENGRE, PLATEAU STATE.

Summary

Background

Malaria and anaemia are the leading causes of morbidity and mortality in children in subSaharan Africa. Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in other African countries. We have investigated the effect of intermittent preventive treatment with sulphadoxine-pyrimethamine on anaemia and malaria in children in an area of intense, prolonged, seasonal malaria transmission in Nigeria.

Methods

182 children aged 12–59 months from the study area were individually randomised to receive three doses of placebo or sulphadoxine-pyrimethamine (SP) monthly over a period of four months. The primary outcome measures were episodes of anaemia (Hb<10.0 g/dl), malaria or severe malaria detected through active and passive surveillance.

Results

Monthly sulphadoxine-pyrimethamine reduced the incidence of malaria and anaemia compared to placebo. The protective efficacy for malaria, severe malaria and Anaemia were 74%, 71% and 95% respectively. There were statistically significant reductions in the episodes of malaria, severe malaria and anaemia in the intervention group compared to the placebo group.

For clinical malaria; at 2^nd visit 23.8% had malaria in the intervention group compared to 76.2% in the placebo group. (p- value 0.011). At 3^rd visit 28.6% had malaria in the intervention group compared to 71.4% in the placebo group (p-value 0.014). At 4^th visit

10.7% had malaria in the intervention group compared to 89.3% in the control group.(p-value

0.0005).

Kaplan Meier test was used to compare the time it takes for clinical malaria among participants in the study groups.The time of visit was measured in time intervals of 28 days in between visits. It showed that participants in the intervention group had significant lower probability of having clinical malaria than in the control group with in the earlier time of study.(Breslow test: 𝑥²=8.5573,df=1,p=0.003).

Tarone-Ware ( 𝑥² =8.763,df=1,p=0.003) and Mantel Cox( 𝑥² =8.825,df=1,p=0.003) test revealed that the control group have a higher probability of having clinical malaria than the intervention group in between the 2^nd and 3^rd visit and at the end of the time frame.

For Anaemia ; At 2^nd visit 3.3% had anaemia in the intervention group compared to 13.2% in the control group.(p = 0.015). At 3^rd visit 0.0% had anaemia in the intervention group compared to 14.3% in the control group. (p= 0.0005). At 4^th visit 0.0% had anaemia in the intervention group compared to 34.1% in the control group.(p= 0.0005).

For Severe malaria; At 2^nd visit 50% had severe malaria in both the intervention and control group.(p=1.000).At 3^rd visit 33.3% and 66.7% had severe malaria in the intervention and control group respectively.(P=0.560).At 4^th visit, none(0.0%) in the intervention group had severe malaria compared to four (100%) in the control group.(p=0.043).

Conclusion

IPTc is safe and efficacious in reducing the burden of malaria in an area of Nigeria with a prolonged, intense malaria transmission season.

 

TABLE OF CONTENT

Title Page        -           -           -           -           -           -           -           -           -           -           i

Declaration      -           -           -           -           -           -           -           -           -           -           ii

Dedication       -           -           -           -           -           -           -           -           -           -           ii

Acknowledgement      -           -           -           -           -           -           -           -           -           iii Certification 1  -           -           -           -           -           -           -           -           -           iv

Table of Contents        -           -           -           -           -           -           -           -           -           v

Chapters          -           -           -           -           -           -           -           -           -           -           vi

List of Figures             -           -           -           -           -           -           -           -           -           x

List of Tables -            -           -           -           -           -           -           -           -           -           xi

List of Abbreviations  -           -           -           -           -           -           -           -           -             xii

Abstract           -           -           -           -           -           -           -           -           -           -           1

CHAPTER ONE

1.0     INTRODUCTION

1.1     BACKGROUND

The word malaria comes from 18th century Italian word mala meaning "bad" and aria meaning "air". Most likely, the term was first used by Dr. Francisco Torti, Italy, when people

thought the disease was caused by foul air in marshy areas.¹

It was not until 1880 that scientists discovered that malaria was a parasitic disease which is transmitted by the anopheles mosquito. The mosquito infects the host with a one-cell parasite called plasmodium. By the end of the 18th century, scientists found out that malaria was transmitted from person-to-person through the bite of the female mosquito, which needs Red blood cells for the production of her eggs.¹

Malaria is caused by infection of red blood cells with protozoan parasites of the genus plasmodium. The parasites are inoculated into the human host by a feeding female anopheles mosquito. The four plasmodium species that infect humans are P. falciparum, P. ovale, P. vivax, and P. malariae. Increasingly, human infections with the monkey malaria parasite, P. knowlesi, have also been reported from the forested regions of the South-East Asia².

Approximately 40% of the total global population is at risk of malaria infection. During the

20th century the disease was effectively eliminated in most of non-tropical countries.¹ According to the World Health Organization¹ (WHO):

• Approximately 660,000 people died from malaria in 2010 globally, most of them were African children.
• There were an estimated 219 million cases of malaria infection in 2010 worldwide.
• Malaria is a preventable and curable disease.
• Malaria mortality rates have fallen by over 25% since 2000. In the WHO African region rates have dropped by 33%.
• The malaria burden in many parts of the world is being dramatically reduced thanks to increased malaria prevention and control measures.
• Travelers from malaria-free areas who enter endemic areas are especially vulnerable to severe symptoms when they become infected.
• About 80% of all malaria cases occur in just 17 countries.
• Nigeria and the Democratic Republic of the Congo account for more than 40% of all malaria deaths worldwide

Ninety per cent of malaria deaths occur in Africa, where malaria accounts for about one in six of all childhood deaths. The disease also contributes greatly to anaemia among children — a major cause of poor growth and development.³ Malaria is both preventable and treatable, and effective preventive and curative tools have been developed. Sleeping under Insecticide Treated Nets (ITNs) can reduce overall child mortality by 20 per cent. There is evidence that ITNs, when consistently and correctly used, can save six child lives per year for every one thousand children sleeping under them.³ Prompt access to effective treatment can further reduce deaths. Intermittent preventive treatment of malaria during pregnancy can significantly reduce the proportion of low birth weight infants and maternal anaemia.³ Unfortunately, many children, especially in Africa, continue to die from malaria as they do not sleep under insecticide-treated nets and are unable to access life-saving treatment within 24 hours of onset of symptoms.  Due to the efforts of many partners and a focus on sustaining funding, from 2000 to 2010, the proportion of children sleeping under an ITN in sub-Saharan

Africa grew from 2 per cent to 39 percent.³

The burden of severe forms of Plasmodium falciparum malaria is concentrated in young children and a recent pooled analysis showed that this is even more pronounced for malaria leading to death than for less severe forms of the disease.⁴ The targeted provision of insecticide-treated nets to pregnant women⁵ and children under 5 years of age has helped protect those at an increased risk.⁶ Measures that target the very young may provide a useful additional strategy for malaria control.

Antimalarial drugs have been used in various ways to prevent malaria in the resident populations of endemic areas for nearly 100 years. The primary aim of most early studies was to interrupt transmission. Chemoprophylaxis is highly effective in reducing mortality and morbidity from malaria in young children and pregnant women living in endemic areas, but is difficult to sustain and, in some studies, has impaired the development of naturally acquired

immunity acquired

immunity.⁷

While our tools for controlling and eventually eliminating malaria are greater now than in days of the first malaria eradication effort, they are not limitless. Strides have been made in reducing the burden of malaria disease using insecticide treated nets (ITNs) for prevention and artemisinin based combination therapy (ACT) for treatment. Indoor residual spraying (IRS), once the prime tool in the fight to eradicate the disease, is now used somewhat sparingly taking into consideration costs, logistics, and local epidemiological and ecological conditions. Vaccines are under development and new vector management technologies are being explored, but one other available strategy, intermittent preventive treatment (IPT) has not been deployed to its full potential.⁸

Intermittent preventive treatment (IPT) has been a mainstay for preventing malaria among pregnant women in countries with high and stable transmission of malaria for a dozen years.¹The treatment dose of sulphadoxine-pyrimethamine (SP) is given after quickening during antenatal care (ANC) at monthly intervals to clear malaria parasites (particularly Plasmodium falciparum) from the woman and her placenta in order to prevent anaemia, interuterine growth retardation (leading to low birth weight),⁹ still birth, neonatal death,¹⁰ and even maternal death.

As was reported in the May 2012 issue of Africa Health, extensive research had been done at multi-country sites to determine the efficacy and feasibility of implementing IPT for infants and children (IPTi and IPTc). The authors were concerned at the time that the results were not being put into practice to save children’s lives.⁸

Interestingly, IPTi and IPTc have undergone a slight transition and name change. In 2012, the World Health Organization issued guidance on ‘Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa.¹¹ SMC is an adaptation of IPTi and IPTc for a specific geographical area where well-timed doses of anti-malarial drugs could play a major role in saving lives and reducing transmission. WHO explains that, ‘The word chemoprevention as used in SMC reported, means that areas meeting seasonality definition of 60% of annual incidence within four consecutive months were observed more frequently in the Sahel and sub-Sahel than in other parts of Africa, and thus provide an ideal focus for intervention.¹² Malaria transmission in much of the Sahel is confined to less than four to five months of the year.¹³

From their data the Cairns group concluded that, a protective efficacy of 65% would be a reasonable estimate of protection provided by three courses over a 4-month peak.⁸ Four monthly courses over four months might provide protective efficacy of ~80%.’ They did

caution that effective delivery of the intervention may pose challenges.⁸

Similarly Meremikwu et al ¹⁴conducted a Cochrane Review on IPTi studies relevant to

SMC.¹⁴ They concluded that, ‘in areas with seasonal malaria transmission, giving antimalarial drugs to preschool children (age <6 years) as IPTc during the malaria transmission season markedly reduces episodes of clinical malaria, including severe malaria.

This benefit occurs even in areas where insecticide-treated net usage is high.’ As reflected in their finding, a multi-strategy approach that includes insecticide-treated nets is beneficial, especially in light of the implementation challenges of achieving three or four treatment contacts on a monthly basis.

As reported in Nature, pre-emptive treatment of children living in regions where [malaria] is prevalent only during the rainy season could avert 11 million cases of malaria and 50 000 deaths a year.¹⁵’ WHO explained that, ‘At test sites in Burkina Faso, bed nets have halved the number of malaria cases, and seasonal chemoprevention has reduced the remaining cases by about 80%.¹⁶ WHO noted that higher burden countries like the Democratic Republic of Congo have year-round malaria transmission making the strategy more difficult and less effective than the focused approach possible with ‘just the right conditions’ in the Sahel.

The objective of IPTc is to maintain therapeutic anti-malarial drug concentrations in the blood throughout the period of greatest risk¹¹. This will reduce the incidence of both simple and severe malaria disease and the associated anaemia and result in healthier, stronger children, able to develop and grow without interruption by disease episodes. SMC has been shown to be effective, cost effective and feasible for the prevention of malaria among children in areas where the malaria transmission season is no longer than four months¹¹.

1.2     RELEVANCE OF THE STUDY TO FAMILY MEDICINE DISCIPLINE. 

Family Medicine encourages the use of cost effective primary care and prevention strategies.

This is particularly relevant as malaria affects most families in Africa (especially the West African region). The disease entity which is preventable (by tools such as, the use of ITNs and chemoprophylaxis e t c.) requires continuous, coordinated care offered mainly by

Primary care Physicians.

The information gained from the study will help to reduce the huge burden of mortality and morbidity due to malaria and thus, spare already scarce resources expended by the family and health care providers on malaria.

This study will generate important Public Health Information on the efficacy of IPTc in preventing clinical malaria and anaemia among children in an area with intense and prolonged malaria transmission season. This will compliment on-going prevention efforts like ITNs and Indoor Residual Spraying (IRS).

1.3      STATEMENT OF THE PROBLEM

Malaria has remained a major public health problem in Nigeria. It accounts for over 60% of out-patient visits and 30% of hospital admissions in Nigeria. The disease has impacted negatively on the economy with about 132 Billion Naira lost to the disease as cost of treatment and loss in man hours¹⁷.

Thirty countries in sub-Saharan Africa account for 90% of global malaria deaths. Nigeria, Democratic Republic of Congo (DRC), Ethiopia and Uganda account for nearly 50% of the global malaria deaths. Malaria is the second leading cause of death from an infectious disease in Africa, after HIV/AIDS. Almost one out of five deaths in children under five years in Africa are due to malaria.¹⁸

Malaria is a major public health problem in Nigeria where it accounts for more cases and deaths than in any other country in the world.¹⁸ Malaria is a risk for 97% of Nigeria’s population. The remaining 3% of the population live in the malaria free highlands. There are an estimated 100 million malaria cases with over 300,000 deaths attributable to malaria per

year in Nigeria. This compares with 215,000 deaths per year in Nigeria from HIV/AIDS.¹⁸

Malaria has the greatest prevalence, close to 50%, in children age 6 – 59months in the SouthWest, North Central and North West regions. Malaria has the least prevalence, 27.6 percent in children aged 6 – 59 months on the South-East region¹⁸. Most malaria deaths occur among children living in Africa where a child dies every minute from malaria.

WHO country-level burden estimates available for 2010 showed that 80% of malaria deaths occurred in just 14 countries and about 80% of cases occurred in 17 countries. Together, the Democratic Republic of Congo and Nigeria account for over 40% of the estimated malaria deaths globally. Children who survive malaria do not escape unharmed. Repeated episode of fever and anaemia take a toll on their mental and physical development, impairing their education and growth into productive adults. Pregnant women and their unborn children are also particularly vulnerable to malaria, even in areas of stable transmission, since malaria infection may lead to malaria-related anaemia in the mother and the presence of parasites in the placenta, which contributes to low birth weight.

Depending on various factors such as the parasite, the vector, the human host and the environment, the infected person will become ill with malaria after about a week to several months, but mostly within 17 – 21 days of malaria infection.

The two most powerful and most broadly applied interventions for malaria vector control and prevention are insecticide treated mosquito nets (ITNs) and indoors residual spraying (IRS). However, malaria vector control with ITNs, IRS or other interventions is only effective with sustained high coverage. In 2010, WHO recommended the universal use of diagnostic testing to confirm malaria infection, followed by appropriate treatment based on the result. According to the new guidelines, treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible. Treatment should be with Artemisinin based Combination Therapy [ACT] ¹⁹.

 

 

DEFINITION OF TERMS

Incidence – Is the frequency (number) of new occurrences of disease (Malaria). That is the number who becomes ill in the study population during the time of the study.

Seasonal Malaria Chemoprevention: Intermittent administration of full treatment courses of an antimalarial treatment combination during the malaria season to prevent illness and

death from the disease.²⁰

Uncomplicated Clinical Malaria: 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 non-specific. Malaria is therefore suspected clinically mostly on

the basis of fever or a history of fever.²¹

Severe Falciparum malaria: Acute falciparum malaria with signs of severity and/or evidence of vital organ dysfunction. The presence of one or more of the clinical or Laboratory features classifies the person as suffering from severe malaria.²¹

Clinical Anaemia: A haemoglobin level of less than 10g per deciliter (Packed Cell Volume Less Than 30% Percent) or presence of signs (Pallor, shortness of breath, tachypnoea) in children in this age group.²²

1.4 STUDY HYPOTHESIS

The study hypothesis is that monthly therapeutic doses of S-P administered over the course of

3 months to children under the age of five during the season of high malaria transmission will

Improve haematocrit and reduce the incidence of clinical malaria.  

1.5 JUSTIFICATION OF THE STUDY

The burden of malaria is quite high. It is responsible for 300-500 million clinical cases per year, 80% of these occur in Africa. It is responsible for 1 million deaths per year, all virtually due to plasmodiumfalciparum; with 90% of these occuring in Africa.¹⁷Malaria impedes human development and is both a cause and consequence of under development. Every year, malaria is said to cost Africa an estimated $12 billion in lost productivity. Nigeria loses over N133 billion from the cost of treatment and absenteeism from work, schools and farm to the cost effective drugs and insecticides¹⁷.

Other effects of malaria could be seen in the following areas.

• Technology – In research and development (RRD) due to increasing drug resistance to hitherto cost effective drugs and insecticides.
• Socials – The nuisance of mosquitoes with the noise and sleep disturbance.
• International co-operation: malaria ties negative effects on tourism and travels especially during the high transmission seasons.
• The roll back malaria (RBM) strategies and goals are far from being reached. A malaria situation analysis carried out by the FMOH (Federal Ministry of Health) in the Year 2000 revealed the following findings:
• The perception of the cause of malaria is poor and very few people link mosquito to malaria.
• 80% of malaria cases are inadequately managed at community level by the facility and home based caregivers.
• Only 5% of antimalaria drugs are produced in Nigeria.
• 85% of health facilities surveyed in rural areas had stock out. None had prepackaged drugs.
• 51% of mothers obtain drugs from patent medicine vendors, 89% of the drugs were found to be sub-standard and 43% of syrups unsatisfactory.

WHO estimated that in 2010, there were 219 million cases of malaria (with an uncertainty range of 154 million to 289 million) leading to approximately 660,000 deaths (with an uncertainty range of 610,000 to 971,000), mostly among African children. Most death occurs among children living in Africa where a child dies every minute from malaria. Between 2000 and 2010 malaria mortality rates fell by more than 25% globally. Although those reductions constitute major achievements in the global fight against malaria, these rates of decline are lower than global targets for 2010.¹⁹

Children who survive malaria may not escape unharmed. Repeated episodes of fever and anaemia take a toll on their mental and physical development, impairing their education and their growth into productive adults. Pregnant women and their unborn children are also particularly vulnerable to malaria, even in areas of stable transmission, since malaria infection may lead to malaria related anaemia in the mother. The presence of parasite in the placenta, which contributes to low birth weight is a leading cause of impaired development and infant mortality¹⁹.

A study conducted by A l Zoakah et al²³ on the prevalence and outcome of malaria amongst under five children at comprehensive health centre, Gindiri revealed that malaria was still the commonest cause of morbidity and mortality amongst under-fives especially in children less than one year in north central Nigeria²³.

A study carried out by J C Daboer et al²⁴, on malaria parasitaemia and household use of insecticide treated bed nets; a cross-sectional survey of under-fives in Jos, Nigeria revealed that malaria parasitaemia was high in that community and sleeping under insecticide treated bed nets has been found to significantly reduce the prevalence of parasitaemia in the children studied. With parasitaemia prevalence of 38%, malaria was still a major public health problem among under-five in the study environment²⁴. Amongst communities, malaria remained a leading health concern.²⁵

Countries in regions of stable and intense malaria transmission have adopted a policy of IPT for pregnant women (IPTp) using the drug sulphadoxine-pyrimethamine (SP) twice during the pregnancy after quickening. SP has a one-dose malaria regimen and thus is ideal for administration as directly observed treatment (DOT) during antenatal care (ANC) visits. The benefits of IPTp and IPTi have been demonstrated by several researchers and are currently being promoted by WHO for women and infants living in endemic areas. Studies conducted in most African countries have also demonstrated the beneficial effect of IPTc (intermittent preventive treatment in children) especially during the season of high malaria transmission (August to October).⁸ Studies on both IPTi and IPTc are lacking in Nigeria, which together with Democratic Republic of Congo account for over 40% of the estimated total malaria

deaths globally.⁸

This study seeks, therefore, to administer monthly therapeutic doses of Sulphadoxinepyrimethamine as seasonal malaria chemoprevention to children less than five years to determine if it would be efficacious and protective against clinical malaria and anaemia in under-fives.

 

1.6   AIM

To investigate the effect of Seasonal Intermittent Preventive Treatment using S-P on the incidence of clinical malaria and anaemia in children between 1-5years in the under-five clinic at the Seventh-Day Adventist Hospital, Jengre, Plateau State so as to formulate a treatment protocol to be adopted in my centre.

 

 

 

1.7 OBJECTIVES

• To determine the short term effect of S-P as seasonal intermittent preventive treatment on the incidence of clinical malaria in children less than five years of age.
• To determine the effect of S-P as seasonal intermittent preventive treatment on anaemia in children under-five years.
• To find out the effect of S-P as seasonal intermittent preventive treatment on the incidence of severe malaria in children under-five years of age.

 

EFFICACY OF SEASONAL INTERMITTENT PREVENTIVE TREATMENT WITH SULPHADOXINE-PYRIMETHAMINE ON REDUCTION OF CLINICAL MALARIA AND ANAEMIA IN UNDER FIVE CHILDREN PRESENTING IN SEVENTH-DAY ADVENTIST HOSPITAL, JENGRE, PLATEAU STATE.

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