Profile of Enteric Fever in Children Admitted to a Tertiary Care Center in North India

Abstract

Background Enteric fever is a community-acquired systemic infection which is more common in resource-limited overcrowded communities with poor access to sanitation and its management is compounded by the increasing antimicrobial resistance to the first-line antibiotics used.

Materials and Methods This descriptive study reports the clinical profile of children with enteric fever managed at the departments of pediatrics and microbiology of a tertiary care hospital from February 2020 to August 2021. All inpatients who were confirmed (blood culture positive) or probable cases (clinical and serological evidence by Widal test) of enteric fever were included. Profile of all cases and antibiotic sensitivity pattern in culture positive cases were studied.

Results Of the 70 cases enrolled, 40% were females and 60% males, and majority (52.9%) was in the age group of > 5 years. At admission, fever was the most common presentation along with abdominal symptoms. Widal test was positive in 84.6% cases and was found to be 80% sensitive when compared to the gold-standard blood culture. Both Salmonella Typhi (74.3%) and S. Paratyphi (12.9%) isolates were 100% sensitive to azithromycin, cotrimoxazole, and ceftriaxone. Quinolones and second-generation cephalosporin cefuroxime showed high resistance in comparison. None of the isolates was multidrug resistant. All cases were discharged after successful treatment.

Conclusion The burden of disease and antibiotic susceptibility of enteric fever needs to be monitored to guide clinicians in selection of antibiotics.

Keywords

enteric fever - children - Salmonella - blood culture

Introduction

Enteric fever is a community-acquired systemic infection which continues to be a public health problem in developing countries and resource-limited communities with poor access to sanitation.[1]

Salmonella Typhi is the leading cause of enteric fever, responsible for 12 to 21 million cases and over 140,000 deaths each year globally.[2] [3] The clinical features of enteric fever in children are nonspecific and overlap with a variety of infections in endemic areas.[4] Among blood culture-confirmed cases in children, as low as 4% cases are clinically suspected with enteric fever at initial presentation. A recent systematic review of enteric fever cases showed that the risk of mortality due to enteric fever is four times higher in children < 5 years compared to those > 5 years of age.[5]

The widespread and poorly regulated use of antibiotics and antipyretics in low-to-middle-income countries not only confounds the clinical picture but also leads to the origin and propagation of multidrug resistant (MDR) strains of Salmonella. If untreated, the febrile response reaches its peak in the second week of illness in a characteristic “stepladder” pattern. Chills and rigors are less common in children than adults while relative bradycardia, a classical finding in enteric fever, is identifiable in 11 to 30% of children.[5] Diarrhea and febrile seizures are reported more commonly in infants than in older children and adults. A lesser proportion of children may have constipation, which has been associated with disease relapse in children infected with MDR strains. Clinically tender hepatosplenomegaly is seen in 85 to 90% of pediatric cases. Hepatic and splenic abscesses with subsequent splenic abscess rupture are more commonly encountered in younger children, immunosuppressed, and those with hemoglobinopathies. The transient pancytopenia seen in acute illness may be partly because of seeding of Salmonella to the bone marrow.[6] While it is challenging to breakdown the complex dynamics between antimicrobial use, antimicrobial susceptibility, and disease burden, estimating the incidence of enteric fever in children will provide a better understanding of current disease burden and its transmission dynamics.[7]

Aim and Objective

To study the profile of children with enteric fever admitted in a tertiary care center in North India.

Material and Methods

This prospective study was conducted between February 2020 and August 2021 after clearance from the institutional ethical committee. All admitted pediatric patients, who were either confirmed or probable cases of enteric fever, were included with informed consent of guardians. Case definitions were adapted from the World health Organization and Indian Academy of Pediatrics (IAP) guidelines. Confirmed case: A patient with fever (38°C and above) for at least 3 days, with a laboratory-confirmed positive culture of Salmonella Typhi or S. Paratyphi A. Probable case: A clinically consistent case with positive serodiagnosis but without Salmonella isolation. The patients who did not meet case definition of enteric fever and those who did not give consent were excluded.

Samples received in microbiology lab were processed as per standard protocols.[8] Widal tube agglutination test was employed for serodiagnosis in the second week of illness. As per the prevalent local titers, “O” antigen titers of more than 80 and “H” antigen titers of more than 160 were considered significant. Blood cultures were sent at the time of admission, before starting antibiotics and processed in the Bactec or BacT/Alert automated culture systems for a maximum period of 7 days. Bacterial identification and susceptibility testing from positive culture bottles were done using the Vitek2 system. Serological testing was done by slide agglutination using antisera from Central Research Institute, Kasauli. Susceptibility was tested against azithromycin, ceftriaxone, cefixime, cefuroxime, ampicillin, chloramphenicol, cotrimoxazole, ciprofloxacin, and ofloxacin and results were interpreted on the basis of minimum inhibitory concentration breakpoints as per the Clinical and Laboratory Standards Institute guidelines. The isolates showing resistance to ampicillin, cotrimoxazole, and chloramphenicol were labeled as MDR.

Data was described in terms of range, mean ± standard deviation, frequencies (number of cases), and relative frequencies (percentages) as appropriate. Statistical analysis was done using SPSS (Statistical Package for the Social Science) version 21 software.

Results

A total of 70 patients were enrolled of which 61 were confirmed cases based on blood culture and 9 cases were probable cases with clinical features and positive Widal test. Sixty percent of these patients were male and 40% were female, with a male-to-female ratio of 1.5:1. All the children presented with fever, 54 (77.1%) had fever of > 5 days duration, while 16 (22.9%) had fever for < 5 days. The other presenting symptoms were loose stools and vomiting in 35 (50%), pain abdomen in 22 (31.4%), chills and rigor in 11 (15.7%), and abnormal body movements in 5 cases (7.1%). Notably, 25.7% (18/70) children had received oral antibiotics prior to hospitalization (cefixime 14, azithromycin 3, and ofloxacin 1). Apart from this, one patient had received intravenous vancomycin + ceftriaxone, and another intravenous amikacin + oral azithromycin before admission. Only one child had history of typhoid vaccination.

On examination, pallor was observed in 68 children (97.1%), hepatomegaly in 33 (47.1%), hepatosplenomegaly in 18 (25.7%), and edema in 1 patient (1.4%). Laboratory Investigations revealed anemia (hemoglobin < 11 g/dL) in 44 (62.9%), leukopenia (total leukocyte count [TLC] < 4000/µL) in 31 (44.3%), leukocytosis (TLC > 11000/µL) in 10 (14.3%), raised C-reactive protein in 64 of 66 (97%)—mean value 71.3, raised serum glutamic-oxaloacetic transaminase in 49 out of 52 (94.2%)–mean value 109.7, and raised serum glutamate pyruvate transaminase in 40 of 53 (75.5%)—mean value 89.7.

Widal test was reported positive in 33 out of 39 cases (84.6%). Among these, TO + TH was positive in 28 cases and TO + AH in 5 cases.

Blood culture was positive in 61 of the 70 cases (87.1%), 52 of which yielded growth of Salmonella Typhi and 9 showed growth of S. Paratyphi A. It was observed that azithromycin, cotrimoxazole, cefixime, and ceftriaxone were 100% effective for both S. Typhi and S. Paratyphi A. Most isolates were resistant to cefuroxime and ciprofloxacin, but 81 to 89% susceptibility to ofloxacin was observed ([Fig. 1]). None of the isolates were MDR.

Fig. 1 Antimicrobial susceptibility profile of Salmonella isolates.

Out of 70 cases, 24 were positive by both culture and serology, while 37 were diagnosed by culture alone and 9 by serological test alone. Blood culture is considered as the gold-standard test for enteric fever diagnosis and comparison of the two showed sensitivity of Widal test to be 80%with a positive predictive value of 73% ([Table 1]).

Table 1 Positivity of blood culture and Widal test

	Blood culture		Total
Widal	Positive	Negative
Positive	24	9	33
Negative	6	0	6
Total	30	9	39
Sensitivity: 80%, CI 61.43–92.29% Positive predictive value: 73%, CI 69.04–76.13%

Abbreviation: CI, confidence interval.

Antibiotic treatment (intravenous/oral) was given for 14 days as per standard protocol.

Most of the children were given intravenous antibiotics—ceftriaxone (62) and cefepime + tazobactam (4) along with antipyretics and fluids. On the basis of prolonged defervescence and previous antibiotic history, patients were started on cefepime + tazobactam.

After improved oral intake, oral cefixime was started in three cases and azithromycin in one along with intravenous ceftriaxone. The mean duration of defervescence of fever was 10.5 ± 2.86 days. All children recovered and one was given discharge on request of guardians.

Discussion

The present study describes the clinical and microbiological profile of enteric fever in hospitalized children. Majority of the children were aged > 5 years, with typhoid more common than paratyphoid fever. This high incidence in school-going children is in line with the trends reported by Sinha et al in their pediatric cohort study from North India.[9] However, Saigal et al reported maximum cases in the 1- to 5-year-old group. The difference may be because of inclusion of only admitted children in our study.[10]

Fever was the most common presenting complaint in all cases, similar to observations of other authors.[11] [12] Anemia was observed in nearly 63% children, and reflects the general anemia rate in Punjab (57.3%), attributed to the iron-deficient diet, childhood illnesses, and parasitic infections.[13] Edema noted in one patient was due to underlying hypoalbuminemia and failure to thrive, and may not be due to enteric fever itself.

In developing countries, Widal test has been used for diagnosis of enteric fever but is reported to have low sensitivity and specificity. In the present study, it was found to have 80% sensitivity when compared to blood culture, since the test was performed in the second week of fever. Similar results were reported by Maheshwari et al.[14] In most cases, fourfold rise or fall of titer in paired sera tested 7 to 10 days apart can provide a more reliable diagnosis.[8]

It was observed that despite prior antibiotic usage, blood culture had a high yield of 87.1%, which may be due to timely presentation, adequate sample collection, and good culture techniques. On the contrary, a low culture positivity of 43.5 and 20.2% was reported by various authors.[12] [15]

In our study, S. Typhi (74.3%) was predominant while S. Paratyphi was predominant in the study by Malini et al. S. Typhi in our study showed 100% sensitivity to azithromycin, cotrimoxazole, and ceftriaxone, 96% to ampicillin and chloramphenicol, and 2% to ciprofloxacin. Malini et al reported 100% sensitivity to azithromycin, ampicillin, and ceftriaxone, 89% to cotrimoxazole, and 0% to ciprofloxacin. S. Paratyphi isolates in our study showed 67% susceptibility to ampicillin while high susceptibility (91%) was observed by Malini et al.[15]

High susceptibility to first-line antibiotics like amoxycillin, chloramphenicol, and cotrimoxazole supports their use and the principle of antibiotic cycling in the treatment regimens. High levels of quinolone resistance were seen, and is concordant with the resistance patterns reported by several studies from India.[16] [17]

The absence of any MDR strains in our study is contrary to the findings of McAteer et al (22% MDR Salmonella) and Siddiqui et al (14% MDR S. Typhi and 57% MDR S. Paratyphi).[18] [19]

The IAP standard treatment guidelines for enteric fever recommend use of parenteral ceftriaxone or oral cefixime for 14 days as first-line therapy.[20] Following the guidelines and susceptibility pattern of Salmonella isolates, intravenous ceftriaxone was the most commonly used antibiotic in our study, as all cases were hospitalized.

The study describes the profile and local sensitivity pattern in enteric fever and will help guide proper antibiotic use. As majority of the cases get treated on outpatient basis or with over-the-counter antibiotics, this hospital-based study may not reflect the situation of enteric fever in the community. Another limitation of the study is that genomic sequencing of the isolates was not done, which could have provided more information on the emerging strains and antimicrobial resistance. A larger sample size and comparison of yearly trends would provide more useful data.

Conclusion

Enteric fever is a community-acquired systemic infection, common in developing countries with rising antimicrobial resistance. Though blood culture remains the gold standard, Widal test can be used as an inexpensive and reliable test for diagnosis, especially when drawing adequate sample for blood culture is difficult in smaller children. Though no MDR Salmonella were reported from children in our study, there is a need to monitor the burden of disease and antimicrobial resistance to guide treatment choices. The high morbidity, especially among children, underscores the need for improved water and sanitation practices as well as increasing vaccination coverage to control the disease.

Conflict of Interest

None declared.

Acknowledgments

None.

Ethical Clearance

This article has been approved by institutional ethical committee(IEC).

Author's Contribution

All authors contributed equally to the article.

Data Availability Statement

There is no data associated with this work.

• References

• 1 John J, Van Aart CJ, Grassly NC. The burden of typhoid and paratyphoid in India: systematic review and meta-analysis. PLoS Negl Trop Dis 2016; 10 (04) e0004616
• 2 Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004; 82 (05) 346-353
• 3 Buckle GC, Walker CL, Black RE. Typhoid fever and paratyphoid fever: systematic review to estimate global morbidity and mortality for 2010. J Glob Health 2012; 2: 010401
• 4 Rabasa A, Mava Y, Pius S, Timothy SY, Baba UA. Typhoid fever in children: clinical presentation and risk factors. Niger J Paediatr 2013; 40: 60-63
• 5 Azmatullah A, Qamar FN, Thaver D, Zaidi AK, Bhutta ZA. Systematic review of the global epidemiology, clinical and laboratory profile of enteric fever. J Glob Health 2015; 5 (02) 020407
• 6 Kumar S, Rizvi M, Berry N. Rising prevalence of enteric fever due to multidrug-resistant Salmonella: an epidemiological study. J Med Microbiol 2008; 57 (Pt 10): 1247-1250
• 7 John J, Bavdekar A, Rongsen-Chandola T, Dutta S, Kang G. NSSEFI Collaborators. Estimating the incidence of enteric fever in children in India: a multi-site, active fever surveillance of pediatric cohorts. BMC Public Health 2018; 18 (01) 594
• 8 Winn WC. Guidelines for the Collection, Transport, processing, Analysis, and Reporting of Cultures from Specific Specimens Sources. Koneman's Color Atlas and Textbook of Diagnostic Microbiology. 6th ed.. Philadelphia: Lippincot Williams & Wilkins; 2006: 67-110
• 9 Sinha B, Rongsen-Chandola T, Goyal N. et al; SEFI tier 1 collaborators. Incidence of enteric fever in a pediatric cohort in North India: comparison with estimates from 20 years earlier. J Infect Dis 2021; 224 (Suppl. 05) S558-S567
• 10 Saigal K, Ghosh A, Deepika D. et al. Varied presentations of enteric fever in pediatric population: North India. Bacterial infections. Int J Infect Dis 2021; 101 (S1): 120-158
• 11 Wani JN, Bhat AS, Yusuf S, Qureshi UA. Clinical spectrum of enteric fever in children admitted to a tertiary care hospital. Int J Contemp Pediatrics 2020; 7 (07) 1530-1533
• 12 Nusrat N, Islam MR, Paul N. et al. Clinical and laboratory features of enteric fever in children and antibiotic sensitivity pattern in a tertiary care hospital of a low- and middle-income country. Cureus 2022; 14 (10) e30784
• 13 Bharati S, Pal M, Bharati P. Prevalence of anemia among 6- to 59-month-old children in India: the latest picture through the NFHS-4. J Biosoc Sci 2020; 52 (01) 97-107
• 14 Maheshwari V, Kaore NM, Ramnani VK, Sarda S. A comparative evaluation of different diagnostic modalities in the diagnosis of typhoid fever using a composite reference standard: a tertiary hospital based study in central India. J Clin Diagn Res 2016; 10 (10) DC01-DC04
• 15 Malini A, Barathy C, Madhusudan NS, Johnson C. Clinical and microbiological profile of enteric fever among pediatric patients in a tertiary care center in South India: a cross-sectional study. J Clin Sci 2020; 17: 74-79
• 16 Sharma P, Dahiya S, Manral N. et al. Changing trends of culture-positive typhoid fever and antimicrobial susceptibility in a tertiary care North Indian Hospital over the last decade. Indian J Med Microbiol 2018; 36 (01) 70-76
• 17 Behera JR, Rup AR, Dash AK, Sahu SK, Gaurav A, Gupta A. Clinical and laboratory profile of enteric fever in children from a tertiary care centre in Odisha, Eastern India. Cureus 2021; 13 (01) e12826
• 18 McAteer J, Derado G, Hughes M. et al. Typhoid fever in the US pediatric population, 1999–2015: opportunities for improvement. Clin Infect Dis 2021; 73 (11) e4581-e4589
• 19 Siddiqui FJ, Rabbani F, Hasan R, Nizami SQ, Bhutta ZA. Typhoid fever in children: some epidemiological considerations from Karachi, Pakistan. Int J Infect Dis 2006; 10 (03) 215-222
• 20 Dahiya S, Malik R, Sharma P. et al. Current antibiotic use in the treatment of enteric fever in children. Indian J Med Res 2019; 149 (02) 263-269

Publication History

Received: 15 May 2023

Accepted: 21 July 2023

Article published online:
12 October 2023