Enteric Fever in Primary Care

Enteric fever is a bacterial infection caused by Salmonella typhi and paratyphi . It is endemic in many parts of Africa and South Asia where there is poor access to safe portable water and below par food quality assurance. It is important to ensure prompt recognition, diagnosis and management of symptoms to forestall complications. Due to the rising global burden, significant effort has to be made to improve primary care services like vaccination, antimicrobial stewardship and encourage-ment of hygiene measures. Hence, it is imperative to be aware of its current burden and options available in primary care for its prevention and treatment.


Introduction
Typhoid fever (now more appropriately called Enteric fever) is a bacterial infectious disease caused by Salmonella enterica subspecies enterica and serovar typhi. It is mainly transmitted through the faeco-oral route via contaminated food, water and asymptomatic carriers [1]. It is endemic in developing countries and lowresource settings where hygiene and sanitation measures are subpar. In developed countries and high-income settings, it is less common but cases still occur in recent travellers to endemic areas [2]. There are a number of factors which contribute to the disease burden including lack of access to clean, portable water, poor food quality control and lack of public health services (e.g well managed public latrine and hand washing facilities); all of which can be attributed to lack of awareness, low political will and sociocultural factors. Symptoms of enteric fever vary significantly and are generally nonspecific. These include pyrexia, headache, myalgia, arthralgia, nausea, rash, abdominal pain, constipation and occasionally diarrhoea [3].
Enteric fever, if left untreated can be life-threatening and result in a myriad of complications including intestinal haemorrhage and perforation, peritonitis, sepsis, meningitis, osteomyelitis, multiorgan failure and death [1,3]. Hence, it is expedient to ensure early diagnosis and management to mitigate complications.
Central to the actualisation of universal health coverage is an effective primary health care system which is usually the first point of contact for most patients. Hence, the role of the primary care clinician in the prevention, diagnosis and management of enteric fever and its complications cannot be overemphasised. This is what this chapter aims to address. O and H antigen have a unique code number and a varied combination of these form the basis for the determination of serotypes [12]. Of the over 2500 serotypes of Salmonella that have been identified, only 100 are thought to be responsible for most human infections [7]. These infections can be broadly divided into nontyphoidal and typhoidal. The typhoidal infection is mainly caused by S. typhi and less commonly paratyphi. Salmonella typhi and paratyphi A are thought to be restricted to humans alone. A key virulence factor in most strains of S.typhi is the Vi capsular antigen which possesses immunomodulatory properties that are thought to contribute to disease pathogenesis, including limiting complement deposition, reducing immune activation, assisting with phagocytosis evasion, and inhibiting serum bactericidal activity [7,13,14]. Without it, S. typhi will be more susceptible to attack and destruction by the host immune system. Hence, the Vi antigen has been harnessed as a major component of typhoid vaccines including the new conjugate vaccines [7].
Transmission is through the faeco-oral route from contaminated food, water and unrestricted contact with chronic carriers especially in an unhygienic environment. When Salmonella typhi is ingested, it evades degradation by enzymes and gastric acid before entering the host's system primarily through the terminal ileum [15]. At the distal ileum, through specialised structures called fimbrae, they attach to the epithelial cells overlying clusters of lymphoid tissues called Peyer patches. These serve as a relay point for macrophages travelling from the gut to the lymphatic system. Activation of the macrophages at the Peyer's patches release cytokines which attract more macrophages to the site. These macrophages serve as a vehicle by which S. typhi is transported to several parts of the reticuloendothelial system including the liver, spleen and bone marrow where they replicate up to a critical density at this point [16], they break into the bloodstream and invade other parts of the body. One of such places invaded is the gall bladder. The gall bladder is infected haematogenously or through infected bile. Infected bile is then secreted into the gut where it once again comes in contact with the Peyer patches at the distal ileum. This second sensitization of the macrophages at this site results in inflammation and hypertrophy of the lymphoid tissues (typhoid ileitis) [15,16]. This enlargement encroaches on the blood supply resulting in ischaemic coagulative necrosis and consequently perforation and peritonitis. Some of the salmonella is excreted in the stool which is serves as a source of infection spread. This is the source of transmission of Salmonella in chronic carriers where the salmonella is thought to avoid enzymatic and chemical degradation in the gall bladder for a long time by forming biofilms or entering an intracellular 'comfort zone' in the gall bladder epithelium.

Clinical presentation
Enteric fever presents with a number of nonspecific symptoms and a wide variation in severity. Symptoms must be correlated with laboratory investigation to reach a diagnosis. Symptoms generally include fever, constipation, diarrhoea, abdominal pain, lethargy, nausea and vomiting, malaise, headache, truncal rash (rose spot), anorexia etc. The incubation period for enteric fever is 1-3 weeks and symptoms progressively get worse over the course of illness if not promptly treated [17].
In the first week, patients may complain of headache, malaise, intermittent fever, cough and constipation. Bradycardia may also be elicited on clinical examination. In the presence of fever, this is termed Faget sign or sphygmothermic dissociation. This is also seen in yellow fever, Brucellosis, Tularaemia and Colorado Tick fever.

Salmonella spp. -A Global Challenge
In the second week, the patient appears dull with diarrhoea and apathy, sustained pyrexia, distended, tender abdomen and sometimes red macules (rose spots). Splenomegaly may also be present in 75% of cases.
In the third week if still untreated, patient become very ill, delirious and toxic with high pyrexia, intestinal haemorrhage and perforation. Toxic myocarditis may also ensue.
10% of cases relapse within the first 3 weeks of apparent recovery or completion of treatment, hence adequate monitoring and follow up should be arranged.
In the United Kingdom, any Salmonella infection is notifiable to Public Health England. Most cases occur in travellers returning from endemic areas. The PHE has developed certain criteria which would serve as an invaluable tool especially for primary care physicians in the early identification of suspicious cases for further escalation, assessment and confirmation.
According to Public Health England (PHE), cases can be classified into confirmed, possible and probable cases based on the following criteria ( Table 1) [18]: It must be noted that the typical presentation of course of enteric fever may deviate significantly from that described above. These may include pneumonia, delirium, arthralgias and severe jaundice. Younger children, people living with AIDS and one third of immunocompetent adults may present with diarrhoea instead of the classical constipation. The typical step ladder pyrexia is now only seen I 12% of cases with the fever pattern now mostly of the insidious persistent type [7]. Untreated or poorly treated infections may result in orchitis, intestinal ileitis, haemorrhage and perforation, meningitis, osteomyelitis.

Diagnosis
The diagnosis of enteric fever is made by correlation of clinical and laboratory investigations. The current gold standard as recommended by the world health organisation (WHO) is blood culture, although this may be culture of bone marrow, stool or urine depending on the time in the course of infection at which the sample was taken [4,7,15]. Even blood culture has been found to be an imperfect gold standard, hence there is an advocacy in some quarters for the use of a composite reference standard (CRS) to improve estimation of diagnostic accuracy [19]. The CRS involves combination of several diagnostic tests to increase the sensitivity rather than relying on individual tests. However, at present there is no consensus as to which tests should be included in the CRS [19]. This may be the future gold standard but further research is needed.
In low-and middle-income countries where the disease is endemic, access to contemporary diagnostic tests may be a challenge and a lot of patient in these countries pay out of pocket for health service delivery which they may not be able to afford. Hence, there is a case for empirical treatment based on clinical symptoms. However, this should be seen as a last resort and priority should be given to improving access to a simple, effective rapid diagnostic test (RDT) which is both reliable and valid. At present, although there are RDTs available commercially in endemic areas such as Typhidot, TUBEX and Test-it, their diagnostic accuracy is uncertain [20].
A lot of laboratories in low resource settings are still very much dependent on the Widal test. The Widal test is a serologic agglutination test developed by F Widal in 1896 [21]. The test is based on the presence of antibodies against the flagellar H and somatic O antigens of Salmonella typhi. Over the years, it has become a lot more controversial and largely abandoned in developed countries [21]. The main limitations with the test include a high cross-reactivity with other infectious agents (like nontyphoidal salmonella, plasmodium and tuberculosis), past enteric fever and BCG vaccination history. Other limitations include poor performance technique and result interpretation. Therefore, its use should be restricted to situations where there is no other supportive confirmatory test [21].
There are lots of other tests in development which hold promise for the future of enteric fever diagnosis. The antibody-in lymphocyte-supernatant (ALS) test has demonstrated good sensitivity and specificity in endemic settings [7,22]. Others include PCR-based assays and high through-put technologies on clinical specimens using mass spectrometry [23].

Clinical management
In primary care, a thorough history and clinical examination could be suggestive. Unstable patients or those at high risk of deterioration should be referred to secondary care for same day hospital assessment and treatment. The mainstay of enteric fever treatment is antibiotics. The route of administration is often oral and parenteral in primary and secondary care respectively. There are several options of antibiotics and first line choice is usually determined by national and local guidelines according to sensitivities and antibiotics resistance pattern. In most places, fluoroquinolones such as ciprofloxacin and ofloxacin are first line. Second line antibiotics include third generation cephalosporins such as ceftriaxone, ampicillin, co-amoxiclav and trimethoprim-sulphamethoxazole [7]. Over the years, several options of antibiotics have been preferred but have changed based on resistance patterns. Decades ago, top on the list of antibiotics were chloramphenicol, ampicillin and co-trimoxazole [7]. The resistance to these traditional antibiotics resulted in multidrug resistance (MDR) typically conferred via IncHI1 plasmids, harbouring resistance genes such as catA, sul1, sul2, dfrA, bla TEM-1 , strA, strB, tetA, tetB, tetC, and tetD on composite transposons [7]. MDR strains were responsible for several outbreaks of enteric fever in the 1980/1990s and led to the widespread use of fluoroquinolones as first-line therapy [7,24]. In the event of MDR and fluoroquinolone resistance, third generation cephalosporins provided respite and an effective alternative. Unfortunately, there are now emerging resistant strains to fluroquinolone and cephalosporin especially in Africa, south-east Asia and the Indian subcontinent resulting in extreme drug-resistance [7]. Fluoroquinolone resistance occurs mainly via chromosomal mutations in the gyrA, gyrB, parC, and parE genes. The local pharmacologist or microbiologist should be involved in discussion of the treatment of such cases where recommendations can be made for the use of other options. Such options would likely include Azithromycin, tigecycline or the monobactam, Aztreonam. On a positive note, re-emerging sensitivity to the traditional antibiotics of chloramphenicol, ampicillin and co-trimoxazole is being reported after the prolonged decline in their use [25]. This makes a case for strict adherence to antibiotics stewardship and similar trend may be the case for lot of other infectious diseases which is worth exploring. It is inevitable that various forms of MDR may emerge in future and antibiotic guidelines have to evolve to reflect the trend.
Also, chronic carriers may be treated with a combination of medical and surgical interventions. About 80% clearance rate can be achieved with a 28-day course of ciprofloxacin 750 mg twice daily or norfloxacin 400 mg twice daily. Azithromycin may be beneficial in those with floroquinolone resistance. In chronic carriers with cholethiasis, cholecystectomy under antibiotic cover is indicated and those with schistosomal infection should be covered with praziquantel [7,24].

Prevention
As earlier discussed, central to the transmission and pathogenesis of enteric fever is poor sanitation and hygiene standards and lack of access to safe drinking water. Therefore, public health interventions targeted at addressing these will go a long way in reducing the global burden of the disease.
Another factor responsible for high global burden is the emergence of antimicrobial resistance strains which result in treatment failure and increased carriage rate [7,14,16]. In light of this, it is totally rational that the development of a highly efficacious vaccine will significantly reduce global burden. This is highly important especially for endemic areas with high disease burden and those at high risk of complications especially young children. A number of typhoid vaccines have been developed over the years and others are still in various stages of development with varying degrees of efficacy. Examples include Ty21a and Vi-polysaccharide vaccines which have shown efficacy at 2 years of 58% (95% CI 40-71%) and 59% (95% CI 45-69%), respectively [7]. Typhoid conjugate vaccines (TCVs) have been developed using the Vi-polysaccharide vaccine covalently linked to a protein to enhance immunogenicity, antibody quality, magnitude and duration [7]. Recent studies have shown better and long-lasting immunogenicity from TCV than Vi alone. For instance a prototype Vi-rEPA vaccine made up of Vi covalently linked to rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa demonstrated efficacy of up to 91% (95% CI 77-97%) at 2 years, when given as a two dose schedule in 2-5 year-old children and protection lasted at least 4 years [7,26,27].
In England, the two main vaccines available are the Vi vaccine given as a single injection and the Ty21a vaccine available in the form of three capsules to be taken on alternate days. It is also available in combination with hepatitis A vaccine with protection lasting 1 year and 3 years for hepatitis A and Typhoid respectively [28]. Vaccination is highly recommended for people who are travelling to high risk areas including the Indian subcontinent, Africa, South America, South and South-east Enteric Fever in Primary Care DOI: http://dx.doi.org /10.5772/intechopen.96047 Asia [28]. The Ty21a being live-attenuated, should not be given to immunocompromised patients or children below six years of age. However, the Vi vaccine can be given from the age of 2 years [28].
The World Health Organisation (WHO) strategic Group of Experts on immunisation, in October, 2017, recommended the inclusion of TCVs in vaccination programme schedules in endemic countries from 6 month of age and catch-up vaccinations in children and adolescents up to 15 years old where it is feasible and appropriate [7,29]. However, this is yet to be implemented in most of these countries due to several factors including lack of political will, poor funding and in some cases poor uptake due to local cultural beliefs.
In 2008, the Vaccine Alliance (Gavi) made TCVs a priority as part of the typhoid investment initiative but did not make any financial commitments due to unavailability of a suitable vaccine [29], however, with the development of promising vaccine candidates with clinically appreciable efficacy albeit in the short-tomedium term, in November 2017, Gavi committed an $85 million funding window to support the roll out of these vaccines in eligible countries between 2019 and 2020 [7,29] and in In January 2018, the WHO prequalified the TYPBAR-TCV. Since then, three countries have applied for support from Gavi, which includes a request for TCV use in response to an outbreak. The first Gavi-supported introduction of the TCV began in 2019 with Pakistan being the first country to request the vaccine in response to widespread transmission of an of extreme drug resistant strain (XDR) of Salmonella typhi. Following on this in the same year, Zimbabwe also applied for the TCV to combat an outbreak of drug resistant strains in Harare and was the first non-research use of the TCV in sub-Saharan Africa [29]. It is hoped that many more countries will apply for vaccine support and increase coverage to enhance reduction in global disease burden.
Another important factor driving an increase in disease burden is antibiotics resistance. This is mainly in endemic countries where the implementation of antibiotic stewardship is still a huge challenge. In these areas, a lot of antibiotics can be bought over-the-counter and patients often get them from the local chemist or patent medicine store without having to see a clinician. This has fostered the propagation of drug resistant strains of Salmonella typhi and paratyphi resulting in treatment failure, increased morbidity and mortality and increased tendency for chronic carriage. To mitigate this, there has to be a deliberate policy in these countries to better control access to antimicrobials, improved access to rapid diagnostic tests and public sanitation measures like clean, safe water, running pipe-borne water, clean toilet and waste disposal facilities.

Conclusion and recommendation
In conclusion, enteric fever caused by Salmonella typhi and paratyphi is still a huge global challenge and remains of major public health concern especially in low resource settings. The fundamental reasons for this unrelenting disease burden are multifactorial. Major factors include poor hygiene and sanitation measures, lack of access to portable drinking water, antibiotics resistance and poor access to vaccines. There has to be a strong political will for disease surveillance and primary care interventions such as ensuring the typhoid vaccines are included in routine immunisation schedules in endemic countries especially for children. The traditional typhoid vaccines held some challenges including convenience of administration and poor immunogenicity. However, the TCVs with better administration convenience especially in children as young as six months and longer-term protection, hold huge promise for the future of typhoid vaccine prophylaxis. Also, more countries need