Obesity as a Risk Factor in Pediatric Sepsis: Α Retrospective Comparative Study Under the Phoenix Definition

1. Introduction

Sepsis is defined as a severe and potentially life-threatening syndrome caused by the body’s overwhelming and dysregulated response to an infection, leading to widespread inflammation, tissue damage, and organ dysfunction [1]. Prompt recognition and treatment are critical to improving outcomes, as sepsis can progress rapidly to septic shock and multiple organ failure. Since there is not a specific treatment for sepsis yet, effective management involves a combination of early diagnosis, timely administration of broad-spectrum antibiotics, fluid resuscitation to stabilize blood pressure, and addressing the underlying infection source [2,3]. Advanced therapies, such as vasopressors for circulatory support and organ-specific interventions like mechanical ventilation or dialysis, may be required in severe cases [4]. Comprehensive care guided by standardized protocols, such as the Surviving Sepsis Campaign guidelines, plays a pivotal role in improving survival rates and minimizing long-term complications [5]. Identifying risk factors such as weakened immune systems, chronic illnesses, advanced age, or the presence of invasive devices is also vital in preventing sepsis and ensuring early detection in high-risk populations [6,7,8,9]. Obesity has been identified as a significant risk factor for many diseases including cardiovascular disease, type 2 diabetes mellitus (DM), hypertension, stroke, dyslipidemia, osteoarthritis, and some cancers [10,11]. However, when it comes to adult sepsis, the “obesity paradox” has been suggested from numerous studies, where higher body mass index (BMI) has been associated with improved sepsis survival [7,8,9,10,12], although this paradox is not linear, as morbid obesity can worsen the outcome [9].

The relationship between obesity and outcomes in pediatric sepsis is complex and less well-defined compared to adult populations [13]. Several factors unique to pediatric sepsis contribute to these inconclusive results, including physiological differences between children and adults, variations in immune responses, comorbidities, developmental physiology, and inconsistencies in study designs [14]. Notably, pediatric studies on obesity and sepsis tend to be smaller in scale and often lack standardization in their definitions of both obesity and sepsis [15,16,17]. A critical distinction between adult and pediatric sepsis lies in their respective definitions, which have evolved differently over time. From 2005 until 2024, pediatric sepsis was defined according to the 2005 International Pediatric Sepsis Consensus Conference. This definition, referred to as Sepsis-2, was based on systemic inflammatory response syndrome (SIRS) criteria and was shared with adult sepsis at the time [18]. However, the definition for adult sepsis was updated in 2016 to Sepsis-3, which introduced significant changes. Under Sepsis-3, sepsis was defined as a suspected or confirmed infection with life-threatening organ dysfunction, assessed using the Sequential Organ Failure Assessment (SOFA) score, with a threshold of at least 2 points [19]. For nearly eight years, these differing definitions created a gap in the criteria for diagnosing sepsis between adults and children. Only recently, in March 2024, a new International Consensus Criteria for Pediatric Sepsis and Septic Shock was introduced, aligning pediatric definitions more closely with Sepsis-3 [20]. This updated definition is based on the Phoenix Sepsis Score, which identifies sepsis in children as a suspected or confirmed infection with life-threatening dysfunction by evaluating four systems—respiratory, cardiovascular, coagulation, or neurological. Septic shock, under this new definition, is characterized as sepsis accompanied by cardiovascular dysfunction indicated by at least 1 or more points in the cardiovascular organ system. Importantly, like Sepsis-3, the Phoenix definition requires acute organ dysfunction for the diagnosis of sepsis, making all pediatric sepsis cases equivalent to “severe sepsis” under previous definitions [19,20].

Given the introduction of the Phoenix criteria, it is now possible to re-examine the association between obesity and sepsis in pediatric patients with greater precision. The updated definition, with its emphasis on organ dysfunction, provides a more consistent framework for evaluating outcomes in children. In the current study, we aimed to investigate the relationship between obesity and pediatric sepsis using the new Phoenix criteria. Additionally, we compared these findings to data derived from the previously used Sepsis-2 definition. By doing so, we sought to clarify the role of obesity as a potential risk factor in pediatric sepsis and its outcomes.

2. Methods

2.1. Study Design

This study was conducted as a retrospective, single-center cohort analysis and received approval from the Institutional Review Board at Boston Children’s Hospital (IRB approval number IRB-P00041981). The requirement for informed consent was waived due to the retrospective nature of the study. The cohort included 806 pediatric patients who were admitted to the intensive care unit (ICU) at Boston Children’s Hospital between January 2014 and December 2019. These patients were identified as having sepsis based on diagnostic codes from the International Classification of Diseases (ICD-9 and ICD-10) and defined according to the Sepsis-2 criteria.

2.2. Study Participants and Data Collection

Among the 806 patients enrolled in this study, 640 were younger than 18 years old. For these pediatric patients, we collected comprehensive data from the electronic medical record (EMR), including demographic information, vital signs (such as oxygen saturation and mean arterial blood pressure) at the time of ICU admission, and the presence or absence of respiratory support. Additionally, we recorded the length of ICU stay, types of microbes detected (if any), laboratory data (including complete blood count, chemistry panels, liver and kidney function tests, and arterial blood gas analysis), and medications administered during their ICU stay. To evaluate organ dysfunction, we employed the organ dysfunction scoring system used to develop for the Phoenix criteria [20]. Initially, eight organ domains were assessed using various established organ injury scoring systems, including the International Pediatric Sepsis Consensus Conference (IPSCC), Pediatric Logistic Organ Dysfunction version 2 (PELOD-2), Pediatric Organ Dysfunction Information Update Mandate (PODIUM), Proulx, and Pediatric Sequential Organ Failure Assessment (pSOFA). These domains included respiratory, cardiovascular, coagulation, neurological, renal, hepatic, immunologic, and endocrine systems. Among these, the immunologic and endocrine systems were assessed exclusively in the PODIUM system. Most organ dysfunction scoring systems, however, consistently evaluated six core domains: respiratory, cardiovascular, coagulation, neurological, renal, and hepatic. Consequently, we focused our analysis on these six domains (Table 1). This was the case for adult sepsis in sepsis-3 definition. Neurological status was evaluated based on available documentation. At our institution, the Glasgow Coma Scale (GCS) is not routinely reported unless a patient has an evident neurological issue. Therefore, patients without documented neurological abnormalities were assumed to be neurologically intact. For patients on sedation, neurological status was assessed based on routine pupil reactivity checks. The Phoenix criteria define sepsis as a Phoenix Sepsis Score of ≥2 points in the presence of suspected infection, with the criteria specifically evaluating the respiratory, cardiovascular, coagulation, and neurological domains [20]. Of the 640 pediatric patients diagnosed with sepsis under the Sepsis-2 definition, 631 also met the Phoenix criteria for sepsis. Pediatric obesity in this cohort was defined based on Body Mass Index (BMI), which estimates weight relative to height. BMI classifications followed the 2000 Centers for Disease Control and Prevention (CDC) growth charts, with underweight defined as a BMI <5th percentile, normal weight as a BMI between the 5th and 85th percentiles, overweight as a BMI between the 85th and 95th percentiles, and obesity as a BMI ≥95th percentile [21].

2.3. Statistical Analysis

We presented the number and percentage for categorical variables, mean and standard deviation (SD) for continuous variables with normal distribution, or median and interquartile range (IQR) for variables with skewed distribution. The Shapiro-Wilk test was used to assess normality. P< 0.05 was considered statistically significant. The statistical analysis was performed using STAT13 (College Station, TX, USA).

3. Results

3.1. Obese Children Had Worse Survival and More Organ Dysfunction Under Sepsis-2 Definition

The data on pediatric sepsis, defined using the previous Sepsis-2 definition, is summarized in Table 2. The study analyzed patient characteristics and outcomes based on body habitus, categorizing patients into the four groups: underweight, normal weight, overweight, and obese. No significant differences in age were observed among these groups. However, the underweight group had a higher proportion of female patients compared to other groups. Notably, the obese group exhibited a higher mortality rate compared to the normal weight group (Figure 1). This finding aligns with observed differences in organ injury scores. Specifically, the average respiratory and renal organ injury scores during hospital admission were significantly higher in the obese group compared to the normal weight group (Figure 2). These findings suggest that obesity may exacerbate the severity of respiratory and renal dysfunction in pediatric patients with sepsis. Neurological impairment associated with infection was not apparent in this cohort, as no significant differences in neurological scores were identified among the groups. When analyzing the worst organ injury scores recorded during the hospital stay, the same trends persisted (Figure 3). Additionally, the total worst organ injury score was significantly worse in the obese group than in the normal weight group (Figure 3), further corroborating the higher mortality observed in obese patients (Figure 1). These findings highlight the association between obesity and worse clinical outcomes, including higher organ injury scores and increased mortality, in pediatric patients with sepsis.

3.2. Obese Children Also Had Worse Survival and More Organ Dysfunction Under the Phoenix Criteria

We then analyzed the data on pediatric sepsis defined under the newly established Phoenix criteria, which incorporates stricter diagnostic guidelines compared to the previous Sepsis-2 definition. Nine patients who were previously classified as having sepsis under Sepsis-2 did not meet the criteria under the Phoenix system. This refined cohort data is detailed in Table 3. As with the Sepsis-2 analysis, no significant differences in age were identified among the four body habitus groups: underweight, normal weight, overweight, and obese. However, the underweight group again showed a higher proportion of female patients compared to the other groups (Figure 4).

The obesity group had the highest mortality rate among all groups, consistent with the findings under Sepsis-2 criteria (Figure 4). When examining organ injury scores during admission, the obese group demonstrated significantly greater respiratory and renal dysfunction compared to the normal weight group, as reflected in the average organ injury scores (Figure 5). This trend persisted when the worst organ injury scores recorded during the hospital stay were analyzed. The obese group consistently exhibited the highest levels of respiratory and renal dysfunction compared to the normal weight group (Figure 6). Furthermore, the total worst organ injury score was significantly higher in the obese group than in the other groups (Figure 6), mirroring the higher mortality rate observed in this group (Figure 4). These findings reaffirm that still under the Phoenix criteria, pediatric sepsis patients with obesity exhibit severe clinical outcomes, including increased organ dysfunction and mortality, compared to their no-obese counterparts.

3.3. No Difference in the Frequency of Gram Positive, Negative, Fungal or Viral Sepsis Was Identified Based on the Body Habitus

Different microbial pathogens interact differently with the host immune system, potentially influencing the severity and outcomes of infections [22]. To assess whether the type of pathogen contributed to differences in clinical outcomes across body habitus groups (underweight, normal weight, overweight, and obese), we analyzed the incidence of these microbes in our cohort. We categorized the identified pathogens based on their type—Gram-positive bacteria, Gram-negative bacteria, fungi, and viruses—and compared their distribution across the body habitus groups. No significant differences were observed in the incidence of these pathogens among the groups (Figure 7). These findings suggest that body habitus, rather than the specific pathogen type, might play a more significant role in influencing morbidity and mortality in pediatric sepsis.