European Journal of Cardiovascular Medicine

Typhoid fever is also called enteric fever. It is a prospectively, multisystemic illness that has been a public health problem, especially in the developing world. It is caused by Salmonella typhi and Salmonella paratyphi. ^[1] Enteric fever is a cumulative term that illustrates both typhoid and paratyphoid fever. Paratyphoid is clinically indistinct from typhoid fever; thus, enteric and typhoid fever are used mutually. ^[2] Typhoid fever is one of the major causes of mortality and morbidity in overcrowded and unhygienic areas though comprehensive research and public health interventions have decreased the occurrence. ^[3] The disease course ranges from early gastrointestinal distress to nonspecific systemic illness but ultimately may lead to multiple complications. Salmonella is said to spread by the 'four Fs" (flies, fingers, feces, fomites). Fever characteristically comes in a step-wise pattern (i.e., rises and falls alternatively) followed by headache and abdominal pain. ^[4]

The main causative agent of typhoid fever is Salmonella typhi and Salmonella paratyphi, both are members of the Enterobacteriaceae family. Salmonella is a genus that has two species Salmonella enterica serovar and enteritidis classified through extensive analysis by multiplex quantitative polymerase chain reaction (PCR). ^[5] Both Salmonella typhi and Salmonella paratyphi (A, B, C) are Salmonella enterica serotypes. Nontyphoidal salmonella (NTS) is more typical in children and is mostly limited to gastroenteritis. ^[5]

Salmonella is transmitted by the fecal-oral route through contaminated water, undercooked foods, fomites of infected patients, and is more common in areas with overcrowding, social chaos, and poor sanitation. It is only transmitted from an infected person to another person, as humans are its only host. Major sources of salmonella are poultry, eggs, and rarely turtles. In one study done on the distribution of salmonella isolates by whole-genome sequencing in chicken slaughterhouses in China, 57% of samples were positive. ^[6]

Normal flora of the gut is protective against the infection. The use of antibiotics such as streptomycin destroys the normal flora, which heightens its invasion. Malnutrition decreases normal gut flora and thus increases the susceptibility to this infection as well. Hence, the use of broadspectrum antibiotics and poor nutrition amplify the incidence of typhoid fever. ^[7]

The pathogenesis of typhoid fever depends upon a number of factors, including infectious species, virulence, host's immunity, and infectious dose. The larger the infectious dose, the shorter the incubation period, and the higher the attack rate. ^[8] Salmonella is an acid-sensitive bacteria except for a few resistant strains, so typically it is destroyed in the stomach by gastric acid unless a large dose is ingested. ^[9] In patients with achlorhydria, intake of antacids and antihistamines, colonization of Salmonella occurs even with smaller doses. Food and beverages also act as buffers against gastric acid that facilitates bacteria reaching the small gut. ^[10]

This is a prospective study, which was conducted at the Tertiary Care Teaching Hospital over a Period of 1 year.

Inclusion Criteria

A total of 90 children aged one to 15 years who were either blood culture positive for the Fastidious Antibiotic Neutralization (FAN) or had significant Widal test titer (at least four-fold rises or 1:160 dilutions of both O and H antibodies) were included in the study.

Exclusion Criteria

Those who had enteric fever with comorbidities (malignancy, nephrotic syndrome, chronic kidney disease, chronic liver disease, etc.) or complications (multiorgan failure, encephalopathy, etc.) were excluded from the study.

Blood Culture

After the blood collection, it was inoculated in blood agar or MacConkey agar medium and observed for the organism's growth. If the organism's growth occurs, the colony is transferred to Mueller-Hinton agar, a microbiological growth medium commonly used for antibiotic susceptibility testing, specifically disk diffusion test. Then, an antibiotic was given at a specific distance, and a sensitivity report was given depending on the bacterial inhibition zone ^[11].

Widal test

After centrifugation of blood, serum was collected and transferred to a tube. Then, Widal test reagents (containing Salmonella typhi and paratyphi antigen) were added and observed for agglutination. Reports were given depending on antibody titer. A titer of 1:160 or more was considered significant ^[12].

Data collection

The research participants' clinical history was recorded as per standard regulations. The required clinical and laboratory information was collected in the preformed spreadsheet.

Data analysis

Data were processed and evaluated using computer software called Statistical Package for Social Sciences (SPSS; IBM Corp., Armonk, NY).

In this cross-sectional study, 65 (72.2%) patients were from the age group 6-10 years, and only 10 (11.1%) patients were from the age range 1-5 years (Table 1). Among all the patients, 60% were male, and 40% were female (Figure 1). The majority of our study population (77.8%) was from lower-class families, followed by the middle class (13.3%) and upper class 8.9% (Table 2). Table 3 shows the clinical features of the study population, where all patients suffered from both fever and anorexia. 60% of patients had vomiting, 54.4% had diarrhea, half had abdominal pain, 43.3% had constipation, and only 3(3.3%) patients had myalgia. According to the Widal test report, 56 (62.2%) patients were reported positive, and 34 (37.8%) patients were reported negative. In the Blood C/S test report, 56 (62.2%) reported negative and 34 (37.8%) patients reported positive (Table 4).

Figure 2 shows the bar diagram of the study population by the total leucocyte count, 45% of patients had >11000 count/mm3, 32.81% of patients had <4000 count/mm3, and 21.88% of patients had 4000-11000 count/mm3.

Despite advances in public health and hygiene that have led to a disappearance of enteric fever from much of the developed world, it still remains the commonest bacteraemic illness in South Asian countries with children being especially susceptible. ^[13] The emergence of multi–drug resistance is very concerning due to the limited therapeutic options, high financial implications and its continuing burden in impoverished, low–income countries. ^[14]

Outcomes such as resistance, relapse, and mortality were not reported in all studies, leading to an incomplete representation. Confounders, such as co–morbidities, resistance, socio–economic status, heterogeneous access to health could not be adjusted for since individual level data were not analyzed. Current trends in resistance especially nalidixic acid resistance and emerging fluoroquinolone resistance have not been extensively reported. ^[14] Most studies were from South Asia, especially India and Pakistan. Regions were categorized based on the World Bank list of economies, which gives geographic classifications for low– income and middle–income economies only, while high income countries that may reflect any geographical region with an improved developmental status. Furthermore, our review is not fully representative of non–English language speaking regions of the world, although data from translated abstracts were used where possible. ^[15]

Notwithstanding the above, our review highlights a number of key findings of the epidemiological pattern of enteric fever in different categories, which will assist the clinician in his diagnosis and help in the fight against enteric fever. Most of our data are from urban, hospitalized children who were more likely to have the following features: high–grade fever, nausea/vomiting, diarrhea, constipation, hepatomegaly, splenomegaly, neutrophilia, abdominal distension and GI bleeding. ^[16] Young children (under 5 years) were more likely to show anaemia, diarrhea, leukocytosis, hepatitis and hepatomegaly and had a higher mortality. Older children commonly showed an altered mental status, signs of URTI leucopenia, and abdominal pain/tenderness. Adults were more likely to present with splenomegaly, GI perforation, and thrombocytopenia. ^[17]

In previous literature, the commonest complications are reported to be gastrointestinal bleeding, intestinal perforation, encephalopathy and shock, though our review suggests that DIC, pneumonia, arthritis/arthralgia altered mental status, hepatitis, and meningitis predominate. The high frequency of DIC in our review was determined from 4 studies with one study forming the majority of the data. ^[18] Of note, the ‘classic’ stepladder temperature pattern was only present in 25% of adult patients. Amongst children in the preschool years, a high case–fatality rate of 6% was found from the included studies, and death was 4.5 times more likely to occur compared to school–aged children. One included study had a particularly strong association of mortality in younger children with anaemia. ^[19]        Other related or underlying factors influencing the clinical profile and outcomes of enteric fever are varying strain virulence, inoculum size, delays in or duration of treatment received, numerous host factors such as immune response, co–existing illnesses or infections, or underlying malnutrition. ^[20] These findings must be considered with caution, as our review was limited to studies with full reporting of clinical features and many studies with only outcome data were excluded. Others have recently reported increased disease severity with emergence of fluoroquinolone resistance. ^[21]

There is insufficient and inconsistent reporting of clinical features data in MDR isolates, especially in the 1980s when the first few outbreaks were reported. ^[22] This may be due to a publication bias, since chloramphenicol resistance data was being reported at 10% from that time period. ^[23] The complications are higher with multi–drug resistant strains and these isolates have been shown to be more virulent than sensitive strains. ^[24] In this review, the case–fatality rates from all resistant and all sensitive S. typhi were almost the same (1.0% in MDR strains vs 1.3% in sensitive strains), reflecting a general decrease in overall mortality in treated cases since the advent of antibiotic usage and improved health care, as our review is mostly derived from inpatient reports (77% of studies). ^[24]

Widespread antibiotic pre–treatment was present in all regions, except Europe and Central Asia, due to prevalence of self–medication and poor health–seeking behaviors. ^[25] This has implications for the development of newer diagnostic tests that can replace blood culture, and ideally be more rapid, specific and cost-effective as well as sensitive. Rational use of antibiotics based on culture sensitivity patterns in different regions in imperative in curtailing the further evolution of multi–drug resistance which is already rife.

Our findings indicate variability in disease presentation in adults compared to children, in different regions and in resistant vs sensitive cases. Majority of studies are from hospitalized cases, and are not disaggregated by age. Despite higher complications in MDR enteric fever, case fatality rate are comparable to sensitive cases, with an overall hospital based CFR of 2%, which is similar to recent global estimates. This study underscores the importance of further epidemiological studies in community settings among children and adults, and the need for further preventable measures to curtail the burden of disease.

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