Introduction

Diarrheal diseases remain a significant cause of morbidity and mortality in under-five children, particularly in low- and middle-income countries [1]. Among the many pathogens contributing to diarrhea-associated complications, Salmonella Typhi is a major concern due to its ability to cause systemic infections, particularly typhoid fever [2]. Globally, typhoid fever remains a significant health concern, with the highest incidence rates among under-five children observed in the WHO South-East Asian, Eastern Mediterranean, and African regions, where the incidence can reach up to 306 cases per 100,000 persons [2]. Bacteremia, where bacteria invade the bloodstream, is a severe complication of typhoid fever that can lead to life-threatening outcomes if not promptly treated [3,4].

Beyond Salmonella Typhi, several other pathogenic bacteria, including Non-Typhoidal Salmonella, Escherichia coli, Streptococcus spp., Staphylococcus spp., Methicillin-Resistant Staphylococcus aureus (MRSA), Klebsiella spp., Pseudomonas spp., and Acinetobacter spp., are also frequently associated with bloodstream infections in pediatric populations [2]. These pathogens often contribute to severe infections, more frequently in malnourished children who are already immunocompromised [2,5–7]. While the impact of nutritional deficiencies on susceptibility to infections is well-documented, the specific interplay between malnutrition and bloodstream infections due to different bacterial pathogens remains unclear [8–10].

Previous studies indicate that children with severe acute malnutrition (SAM) and moderate acute malnutrition (MAM) are at heightened risk for invasive bacterial infections due to immune suppression [11,12]. While some studies suggest that malnourished children may have an increased risk of developing Salmonella Typhi bacteremia [13,14], other studies found that malnutrition predisposes children more toward infections caused also by other invasive bacterial pathogens including Non-Typhoidal Salmonella, Escherichia coli, Streptococcus spp., Staphylococcus spp., MRSA, Klebsiella spp., Pseudomonas spp., and Acinetobacter spp. [2,15–17]. There are no studies that have documented any differences in nutritional status or other clinical factors between typhoidal bacteremia and other types of bacteremia.

This study compares the prevalence and characteristics of Salmonella Typhi bacteremia to other bacterial bloodstream infections in children with diarrheal diseases. We analyze nutritional status, comorbidities, and bacterial isolates to determine if malnourished children are more vulnerable to severe infections from other bacteremia while well-nourished children are disproportionately affected by Salmonella Typhi bacteremia.

Materials and methods

A retrospective case-control study was conducted (from January 2018 to June 2019) using International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) – Dhaka hospital’s electronic medical records to compare children diagnosed with Salmonella Typhi bacteremia to those with other bacterial bloodstream infections than typhoidal (Salmonella Typhi).

Cases were defined as children admitted with diarrheal diseases (acute diarrhea (≥3 loose stools per day), persistent diarrhea (>14 days), or dysentery, as per WHO criteria) [2] who were diagnosed with Salmonella Typhi bacteremia confirmed from blood culture during 2019−20. Controls were children admitted with diarrheal diseases who were found to have bloodstream infections caused by other pathogenic bacterial species, including Non-Typhoidal Salmonella, Escherichia coli, Streptococcus spp., Staphylococcus spp., MRSA, Klebsiella spp., Pseudomonas spp., and Acinetobacter spp.

Inclusion criteria: (1) Children under five years of age; (2) Admitted with diarrheal diseases; (3) Underwent blood culture testing for suspected bacteremia and then confirmed; (4) Complete records of anthropometric, laboratory, and clinical parameters.

Exclusion criteria: (1) Children with incomplete medical records; (2) Cases of viral or fungal bloodstream infections; (3) Patients with known primary immunodeficiency disorders. Children were excluded if they had missing (confirmed) blood culture results, missing anthropometric data, or incomplete clinical records. Additionally, participants with no bacterial growth or skin contaminants were also excluded.

The primary exposure variable was nutritional status, categorized as well-nourished, MAM, and SAM based on WHO-defined anthropometric criteria [5]. Other covariates included age, sex, presence of comorbidities, prior antibiotic use, and clinical outcomes.

Blood samples were collected and processed at the icddr,b microbiology laboratory. Blood cultures were performed using automated systems to identify bacterial growth. Antibiotic susceptibility testing was conducted according to Clinical and Laboratory Standards Institute (CLSI) guidelines.

Descriptive statistics were used to compare baseline characteristics between cases and controls. Categorical variables were analyzed using chi-square tests. Logistic regression models were applied to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the association between nutritional status and Salmonella Typhi bacteremia, adjusting for potential confounders such as age, sex, comorbidities (pneumonia, sepsis, and other systemic infections), and prior antibiotic use. A p-value of <0.05 was considered statistically significant.

Ethical approval was obtained from the institutional review board (IRB) of icddr,b. As this study used de-identified patient data, individual consent was waived from the icddr,b IRB.

Results

A total of 162 children with confirmed bloodstream infections were included in the study for analysis, with 74 cases of Salmonella Typhi bacteremia and 88 cases of bacteremia caused by including Non-Typhoidal Salmonella, Escherichia coli, Streptococcus spp., Staphylococcus spp., MRSA, Klebsiella spp., Pseudomonas spp., and Acinetobacter spp., serving as controls. The distribution of age, sex, nutritional status, comorbidities (pneumonia, sepsis, and other systemic infections), and prior antibiotic resistance use was analyzed to assess their association with typhoid versus other bacterial bloodstream infections.

The median age of children with Salmonella Typhi bacteremia was significantly higher (23.12 months, IQR: 15.3–36.3) compared to the control group (8.62 months, IQR: 4.88–12.84). Nutritional status differed between the two groups. Among cases, 66.13% were well-nourished, while only 33.87% of the controls were well-nourished (Table 1). In contrast, SAM was more prevalent among controls (78.12%) than in cases (21.88%), indicating that children with severe malnutrition were more prone to bacteremia caused by bacterial infections other than Salmonella Typhi.

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Table 1. Baseline characteristics of study participants.

https://doi.org/10.1371/journal.pone.0333580.t001

While among total, about near half (45%) had comorbidities, a significantly higher prevalence of comorbidities was observed among controls (61.36%) compared to cases (25.67%). The most common comorbidities included pneumonia, sepsis, and other systemic infections. The severity of illness among the control group was reflected in longer hospital stays and increased need for intensive care support. Antibiotic use before obtaining blood culture was higher among controls (79.55%) compared to cases (67.57%).

Among all bacteremia cases, Salmonella Typhi was the most frequently isolated pathogen (45.68%), followed by Escherichia coli (9.88%), Streptococcus spp. (6.79%), Pseudomonas spp. (6.79%), and Klebsiella spp. (3.70%) (Table 2). This distribution suggests that malnourished children were at greater risk of infections caused by opportunistic and highly resistant pathogens rather than Salmonella Typhi alone.

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Table 2. Distribution of bacterial pathogens by mortality outcomes.

https://doi.org/10.1371/journal.pone.0333580.t002

Mortality rates were significantly higher among controls (11.73%) compared to cases (1.35%). The highest case fatality rates were observed in infections caused by Klebsiella pneumoniae (66.67%). The increased mortality in the control group underscores the severity of infections caused by opportunistic bacterial pathogens, especially in malnourished children.

The distribution of nutritional status varied across bacterial pathogens (Fig 1). Among children with Salmonella Typhi bacteremia, 48.6% were well-nourished, 29.2% had MAM, and 9.7% had SAM. In contrast, higher proportions of malnutrition were observed in non-Salmonella infections: for example, among Acinetobacter sp. infections, 36.4% were well-nourished, 36.4% had MAM, and 18.2% had SAM, while 50% of children with Pseudomonas sp. infections had SAM. Klebsiella sp. infections showed a majority of well-nourished cases (66.7%), whereas E. coli infections affected both well-nourished (25.0%) and malnourished (56.2%) children. Overall, Salmonella Typhi bacteremia occurred more frequently in well-nourished children, while malnutrition, particularly SAM, was common among other bacterial infections.

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Fig 1. Nutritional status distribution by bacterial pathogen.

https://doi.org/10.1371/journal.pone.0333580.g001

Bivariate analysis revealed that nutritional status was a significant factor in determining the pattern of bacteremia among cases and controls. Multivariate logistic regression confirmed that malnourished children (both MAM and SAM) had significantly lower odds of developing Salmonella Typhi bacteremia compared to well-nourished children. The adjusted odds ratio (aOR) for SAM was 0.157 (95% CI: 0.045–0.548, p = 0.004), while for MAM, the aOR was 0.238 (95% CI: 0.089–0.640, p = 0.004) (Table 3).

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Table 3. Association between nutritional status and Salmonella Typhi bacteremia.

https://doi.org/10.1371/journal.pone.0333580.t003

The mortality rate among children with non-Salmonella infections was descriptively higher (~60%) compared to those with Salmonella Typhi bacteremia (0%). However, this difference did not reach statistical significance (Chi-square test, p = 1.0), likely reflecting limited sample size and few death events among Salmonella cases. Analysis of nutritional status showed that 50.5% of deceased children were well-nourished, whereas severe acute malnutrition (SAM) was more prevalent among survivors (53.8%) (Table 4).

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Table 4. Nutritional status distribution among deceased vs recovered.

https://doi.org/10.1371/journal.pone.0333580.t004

Discussion

This study explores into the relationship between nutritional status and the patterns of bacteremia in under-five children hospitalized with diarrheal diseases. Our findings demonstrate that while Salmonella Typhi bacteremia was significantly more common in well-nourished children, while malnourished children were at greater risk for severe bloodstream infections caused by other pathogens, including Escherichia coli, Klebsiella spp., Pseudomonas spp., and Acinetobacter spp.

Our findings align with previous research indicating that malnutrition is a major risk factor for bacterial infections. Studies have shown that malnourished children are more susceptible to invasive bacterial diseases due to impaired immune responses and increased mucosal permeability [18–21]. However, the observed inverse association between Salmonella Typhi bacteremia and malnutrition has never been well-documented and warrants further investigation.

The observation that Salmonella Typhi bacteremia occurred predominantly in well-nourished children contrasts with previous literature suggesting increased risk of typhoid bacteremia in malnourished children [19,21]. This discrepancy may reflect differences in study populations, pathogen exposure, or health-seeking behavior, and warrants further investigation. It suggests that well-nourished children may not necessarily be protected from invasive Salmonella Typhi infection, possibly due to differential exposure patterns in this population.

Although mortality appeared higher in non-Salmonella infections, the association was not statistically significant in this cohort, possibly due to small numbers of Klebsiella and E. coli infections and rare deaths in Salmonella Typhi cases. The observation that a larger proportion of deceased children were well-nourished, while SAM was more common among survivors, suggests that mortality risk may be driven more by pathogen virulence than by nutritional status alone [22–24]. These findings highlight that well-nourished children may not be inherently protected from severe outcomes, particularly with opportunistic pathogens, emphasizing the importance of pathogen-specific disease severity over nutritional background in determining outcomes.

This study faces limitations including a retrospective design, a hospital-based population, and a lack of longitudinal data. Future research should address these limitations selecting controls and explore long-term outcomes to better understand bacteremia in malnourished children.

This study provides new evidence that malnutrition influences bacteremia patterns in children with diarrheal diseases. While well-nourished children were more likely to develop Salmonella Typhi bacteremia, malnourished children exhibited higher susceptibility to bacterial infections, including Non-Typhoidal Salmonella, Escherichia coli, Streptococcus spp., Staphylococcus spp., MRSA, Klebsiella spp., Pseudomonas spp., and Acinetobacter spp. leading to increased mortality. These distribution of bacteremia patterns across patients’ nutritional status can provide insights and improve clinical management. These findings highlight the need for integrated strategies combining nutritional support, infection control, and antimicrobial stewardship to reduce the burden of bloodstream infections in vulnerable pediatric populations. Future research should focus on elucidating the biological mechanisms underlying these associations to inform targeted interventions and policy recommendations.