CHAPTER ONE INTRODUCTION

1.1   ACUTE FEBRILEILLNESS

Fevers can be arbitrarily classified as acute, subacute and chronic fevers based on duration.Acute fevers that last less than 7 days are typical of diseases such as plasmodium  and viral-related upper respiratory tract infection while those that last more than 2 weeks in duration are categorized as sub-acutefevers,usually seen in cases of salmonella infection an dintra-abdominal abscess, among others (Ogoina, 2011).. Acute febrile illness (AFI) is characterised by a rise in body temperature above the normal range of 36.5–37.5 °C (Hutchison et al., 2008). Chronic or persistent fevers whichlast morethan2weeksindurationaretypicalofchronicbacterialinfectionssuchastuberculosis,viral infections , cancers and connective tissue diseases (Ogoina, 2011). Any acute fever which is left untreated can become chronicfever.

1.2   PLASMODIUM FEVER

Plasmodium isoneofthefebrileillnessandthemostcommonfataldiseaseintheworldcausedbyone ormorespeciesofplasmodium.ThesearePlasmodiumfalciparum,P.vivax,P.ovale,P.Plasmodium e, and P. Knowlesi (Singh & Daneshvar, 2013; Samatha et., 2015). The most virulent species, P. falciparum is also the most prevalent in Africa, while P. vivax is the most widely distributed parasite outside of Africa (Gething et al.,2012).

1.2.1    Global Distribution of Plasmodium

Globally, about 214 million new cases of plasmodium  was diagnosed in 2015 of which Africa accounted for 88%, South-East Asia (10%) and the Eastern Mediterranean region (2%) (WHO, 2015).Withinthesameperiod,atotalof438,000plasmodium deathswasrecordedworldwideofwhich 90 % (394,200 deaths) occurred in Africa (WHO, 2015). The remaining deaths were recorded in South-East Asia Region (7%) and the Eastern Mediterranean Region (2%). Of the 306,000deaths recorded globally among children under-fives, 95% (292,000 deaths) was from the African Region.

In Nigeria plasmodium  occurs throughout the year and affects people of all ages. The demographic healthsurveyconductedin2014showedthatincidenceofplasmodium infectioninchildrenunderfive yearsrangedfrom11.2%to40%withtheruralareasmostlyhavingthehighestprevalence(37.7%) (GDHS,2014).

1.2.2    Transmission ofplasmodium

Plasmodium  parasites are usually transmitted through the bite of an infective female Anopheles mosquito. It can also be transmitted trans-placentally (Congenital plasmodium ) (Valecha et al., 2007), transfusion of infected blood (Chauhan et al., 2009) and needle stick injury.

1.2.3    Presentation of plasmodium fever

The clinical course of plasmodium  infection may be uncomplicated or severe/complicated. Clinical symptomsthatareassociatedwithuncomplicatedplasmodium includefever,chills,sweats,headaches, cough, muscle pains, joint pains, nausea, abdominal pain, diarrhoea and vomiting which may progresstoseverecomplications(Caraballo&King,2014).Complicatedplasmodium isassociated with severe anaemia, kidney failure, coma, hypoglycemia, respiratory distress and death (Caraballo & King, 2014). Plasmodium  tends to be particularly severe in infants, children < 5 years, pregnant women, non-immune persons and adults with compromised immunity.

1.2.4    Diagnosis of plasmodium

Plasmodium  is diagnose by the identification of the parasite in blood. The gold standard is by examination of blood films using microscopy. Rapid diagnostic tests (RDT) detect the antigen of theparasite(Holland&Kiechle,2005)andquantitativebuffycoatmethod(Bhandarietal.,2008). Serological methods such as immunofluorescence or enzyme immuno assay can be used to detect plasmodium l antibodies which can give indication of recent infection. Plasmodium  can also be diagnose using polymerase chain reaction (PCR).Confirming clinical diagnosis with appropriatelaboratory test is veryvital.

1.2.5    Treatment andmanagement

Plasmodium  is a preventable and curable disease. Artemisinin-based combination therapy (ACTs) for uncomplicated plasmodium  are highly effective against Plasmodium falciparum (WHO, 2016). In Nigeria, artermether lumefantrine, artesunate-amodiaquine, or dihydroartermisinin piperaquine is also recommended (MOH, 2015). For preventive measures it is recommended that people sleep under insecticide treated nets. The interventions such as antiplasmodium l drugs (quinine and its derivatives), transfusion, and fluid replacement are mostly used in severe plasmodium .

1.3   SALMONELLA INFECTION

Salmonella infection is a systemic protracted febrile illness commonly caused by Salmonella typhi. Similar but mild form, Parasalmonella infection is caused by S. paratyphi A, S. paratyphi B and S. paratyphi C (Andualem et al., 2014). Salmonella infection causes serious morbidity in many regions of the world, accounting for 21 million cases and 222,000 deaths annually (WHO, 2015). Salmonella infection is common in plasmodium  endemic settings, usually leading to mix-infection. South and Central Asia,AfricaandSouthandCentralAmericaareconsideredendemicwithratesexceeding100per 100,000 population per year ( Bhan et al.,2005)

In Africa, due to scarce resource and limited laboratory capacity to diagnose the disease accurately, most data on salmonella infection are not credible. A survey conducted in Egypt found an incidence of 59 cases per 100,000 persons per year for salmonella infection (Srikantiah et al., 2006).

1.3.1    Causativeagent

Salmonella typhi belongs to the Enterobacteriaceae family and genus Salmonella. It affects only humanandcausessalmonella infection(Bhanetal.,2005).Salmonellatyphiisagram-negativeaerobic and facultative anaerobic rod-shaped bacterium (Todar, 2008). They are non-sporing and withthe exceptionofSalmonellatyphi,non-capsulate(Cheesbrough,2006).Itgrowsoptimallyat35-37°C, rod-shaped with a length of 2-3 μm and a diameter of 0.4-0.6 μm (Cheesbrough, 2006). It moves with the aid of its flagella (H-d antigen). Salmonella typhi contains somatic or O, antigens associatedwithtoxin,H-dassociatedwithflagella;andVi-antigenforvirulence.Itinterfereswith the complement (C3b) mediated opsonization of Salmonella typhi. This prevents it from binding with the phagocytes and subsequently inhibitsphagocytosis.

1.3.2    Transmission

Salmonella infection is spread through ingestion of contaminated food and water. Humans excrete the bacteria in their faeces during the infection and usually persist if they become carriers. Other medium of transmission is by eating raw fruits and vegetables contaminated with human feces, milk products and shellfish. The bacterium can be viable for a long duration on food surface, seawaterandsewagewater.Itcansurviveinfreezingtemperaturefor3months..Foodsareusually contaminated by flies which act as mechanical carriers and the bacteria can proliferate to cause typhoidinhuman(Guzmanetal.,2006).Itusuallyentersthebloodstreamtotheintestinalmucosa andsubsequentlymultiplyinginthelymphnodes.Mostoftentheincubationperiodvariesbetween 7 to 21days.

1.3.3    Clinicalmanifestation

The main clinical symptoms related to salmonella infection are prolonged fever, malaise, anorexia, vomiting, severe headache, bradycardia, splenomegaly (Heymann et al., 2008). Initially the fever is minimal but rises gradually until second week where it can be high and persistent (39–40 ◦C). Other symptoms include abdominal discomfort, dry cough, myalgia and constipation is more common in adults than diarrhoea seen in children. A transient, macular rash of rose-colored spots canoccasionallybeseenonthetrunk(Holmberg,2012).Physicalmanifestationsthatarenormally seen are coated tongue, tender abdomen, hepatomegaly or splenomegaly. Most often nausea and vomiting are not common but can be present in severe cases. Complications occur in about 15% of all cases, and include intestinal haemorrhage or perforation, psychosis, meningitis, and hepatosplenomegaly.

Prior to the discovery of antibiotics case fatality rates were high in untreated cases (10─20%). With the advent of antibiotics, case fatality rate is only about 1% although relapse may occur in 15─20% of pregnant women while 10% of untreated pregnant women would be infectious within 3 months and 2─5% would turn out to be chronic carriers (Heymann et al., 2008). Generally, reinfection of typhoid is rare because of the development lifelong immunity after primary infection.

1.3.4    Diagnosis

The presence of clinical symptoms characterised by fever is indicative of salmonella infection but needs laboratory confirmation (WHO, 2003). The Salmonella typhi can be isolated from blood within a week and in urine and faeces after first week. Even though blood culture is mostly used for diagnosis, bone marrow culture can also be used to isolate Salmonella typhi. The sensitivity and specificity of the conventional Widal test are low due to cross-reactivity with other microorganisms.

1.3.5    Treatment

Antibiotic treatment is used to resolve salmonella infection infection symptoms (Bhan, Bahl, & Bhatnagar, 2005) . Sensitivity patterns of Salmonella isolates in the area determine choice of antibiotics (Bhan et al., 2005). With increasing multidrug resistance (MDR), previously effective drugs such as ampicillin, chloramphenicol are no longer recommended (Gupta et al., 2008; Lutterlohetal.,2012).Fluoroquinolones(ofloxacin,ciprofloxacin)areusedfortreatingadultsbut should be guided by appropriate antimicrobial susceptibility testing (Heymann et al., 2008 ;Bhan et al., 2005; WHO,2003).

Third-generation cephalosporin’s such as cefotaxime and ceftriaxone can be used in cases with isolates resistant to nalidixic acid. Ceftriaxone used for children and azithromycin for treating uncomplicatedsalmonella infection(Effa&Bukirwa,2008).Whenthereisintestinalperforation,surgery is commonlyrecommended.

1.4   CO-INFECTION OF PLASMODIUM  AND SALMONELLA INFECTION

Plasmodium  and salmonella infection co-infection was first described during the American civil war by Woodward in 1862 among young soldiers presenting with intermittent pyrexia. It was suggested thatitcouldbeamixinfections(Smith,1982a).Subsequently,manystudieshavelongestablished this association (Ammah et al., 1999; Gopinath et al., 1995). People with poor hygiene can contracting both diseases. Pregnant women with co-infection mostly associated with nausea, vomiting, abdominal pain, diarrhea and continuous fever (Khan et al., 2005). Anaemia due to massive haemolysisordyserythropoesiscanoccurduringplasmodium infectionwhichcanleadtoincreaseiron in the liver and which support the growth of Salmonella (Bashyam, 2007). Some studies have shown that Complement C1q and C4B deficiency can make a person susceptible to salmonella infection infection (Warren et al., 2002; Bishof et al.,1990).

1.5   PROBLEMSTATEMENT

Plasmodium  and salmonella infection are well known undifferentiated febrile illnesses which may be responsible for varying degrees of morbidity and mortality in developing and middle income countries including Nigeria. Due to lack of availability of diagnostics in low and middle income countries, most cases of acute febrile illnesses are diagnosed as plasmodium  (Stoler & Awandare, 2016).InAkpanMunicipalHospital(GWMH),thenumberofplasmodium casesincreasedfrom3934 in2015to4603in2016(DHIMS2,2017).Salmonella infectionalsoincreasedfrom1369to2033during the same period (DHIMS 2, 2017). Meanwhile, people in endemic areas are atrisk of contracting both infections concurrently (Uneke, 2008 ; Nsutebu et al.,2003). Predisposition to co-infection is usually influenced by their similar epidemiological factors such as dense population, poor hygiene, and sanitation practices (Iheukwumere et al., 2013; Sharma et al., 2016). Due to their similar clinical presentations and the likelihood of a misdiagnosis and mistreatment of febrile pregnant women, it has been suggested that plasmodium  and salmonella infection should be treated concurrently in endemic communities (Uneke, 2008; Iheukwumere et al., 2013). However, concurrent treatment may have some public health implications in the sense that, irrational use of antibiotic or anti- plasmodium l may result in increasing surge of drug resistance, unnecessary cost and exposure of pregnant women to side effects of antibiotic ( Sharma et al., 2016).

Febrile pregnant women reporting to the GWMH are usually tested for plasmodium  using mRDT at the outpatient department and subsequently treated separately or concomitantly without investigation of other possible causes. This tests lack sensitivity at low levels of parasitaemia and persistently positive tests (for some antigens). In severe cases, pregnant women are requested to do Widal test for typhoid at the laboratory which is prone to error (Mbuh, Galadima, & Ogbadu, 2003).Meanwhile reliable diagnosis is by microscopic examination of blood film for plasmodium  or blood, stool orbone marrow culture for Salmonella. It is therefore advisable to performed both test on individuals presenting with fever of plasmodium - typhoid signs and symptoms using accurate diagnostic methods to ascertain true co-infection followed by appropriate treatment ( Mbuh et al., 2003). Due to drug resistance, it is usually necessary to carry out sensitivity tests before making an informed choice of an antibiotic fortreatment.

1.6   JUSTIFICATION /RATIONALE

Treatment of both diseases is common among pregnant women especially in the tropics even if their diagnosishasnotbeenconfirmed.Thismayinterferewithdiagnosisand alsomeansofincreasing antibiotic resistance. Studies have shown that there are more typhoid cases in areas of drug resistantplasmodium andacrossreactionbetweenplasmodium parasitesandSalmonellaantigensmaycause false positive Widal agglutination test. An accurate diagnosis such as positive blood culture is crucial for effective management of pregnant women. A number of studies have shown that plasmodium  could be co-infecting with typhoid (Nwuzo et al., 2009). Even though similar studies have been done in other countries, there is limited data on co-infection of plasmodium  and salmonella infection in Nigeria. The presentstudywillprovideanepidemiologicaldataonco-infectionofplasmodium andsalmonella infectionin Akpan Municipal Hospital and help inform policies towards effective management of febrile pregnant women against irrational administration of anti-plasmodium l drugs and antibiotics. Data from these study will also help to plan better control and prevention strategies in themunicipality.