Klebsiella pneumoniae is a prevalent Gram-negative bacterium known for its ability to cause various infectious diseases, including pneumonia, hepatic abscess, bloodstream infections, and urinary tract infections (Holmes et al., 2021). K. pneumoniae, first identified by Carl Friedländer in 1882 as a causative agent of pneumonia, continues to be a prevalent nosocomial pathogen globally (Pendleton et al., 2013). It remains one of the world’s most prevalent nosocomial pathogens and is a leading cause of neonatal sepsis, ranking among the top three causative agents in most settings (Okomo et al., 2019). Notably, Klebsiella species are particularly notorious for their ability to develop resistance to multiple antibiotics, including extended-spectrum β-lactam (ESBL) and carbapenems. The World Health Organization recognizes ESBL-producing and carbapenem-resistant K. pneumoniae (CRKP) as a critical public health threat (Tacconelli, 2017). In Europe alone, K. pneumoniae strains reportedly account for >90,000 infections, >7,000 deaths annually and 25% of the total disability-adjusted life years lost to multidrug-resistant (MDR) bacterial infections, resulting in poorer clinical outcomes (Musicha et al., 2017). The host’s immune response, as a crucial of infectious disease outcomes, is crucial to pathogen clearance and preventing disseminated infection (Metzemaekers et al., 2023; van der Geest et al., 2023). A thorough understanding the clinical characteristics of immune cells, especially during K. pneumoniae infections, is crucial for optimizing clinical management and improving patient outcomes.

Neutrophils, the front-line soldiers of the innate immune system, are known for their pivotal role in pathogen elimination (Burn et al., 2021; Tsai et al., 2021; Fine et al., 2020). They are equipped with various bactericidal mechanisms, including phagocytosis, degranulation, and the release of reactive oxygen species and neutrophil extracellular traps (Liew and Kubes, 2019). Neutrophils recognize K. pneumoniae through pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). This recognition triggers an inflammatory response, leading to the activation of neutrophils and the release of cytokines and chemokines that recruit more immune cells to the site of infection (Chalifour et al., 2004). Increased neutrophil levels frequently serve as a critical indicator of bacterial infection, reflecting the body’s immune response to pathogenic invasion. However, the role of neutrophils during infectious diseases is intricate (Koenderman et al., 2022; Metzemaekers et al., 2020). While neutrophils can effectively eliminate pathogens, they can also create a microenvironment conducive to pathogen survival and proliferation (Metzemaekers et al., 2020; Xu et al., 2021). In addition, sustained elevations in neutrophil counts contribute to tissue damage, exacerbate disease’s severity, and worsen clinical prognosis (Pechous, 2017; Hou et al., 2018; Nguyen et al., 2020). Thus, elucidating the multifaceted roles of neutrophils during infectious diseases are of paramount importance, offering insights that can enhance clinical management and improve patient outcomes.

Clinically, the correlation between neutrophil counts and hospital mortality rates has been well-established in patients with infectious diseases (Salciccioli et al., 2015; Liu et al., 2022). In sepsis and bloodstream infections caused by organisms such as Staphylococcus aureus and Escherichia coli, neutrophil counts and their functional status have been correlated with disease severity and patient outcomes (von Köckritz-Blickwede and Winstel, 2022; Bruns et al., 2011). Similarly, in viral infections, particularly influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), neutrophilia and neutrophil activation have been associated with worse outcomes and increased mortality (Jimeno et al., 2021). These studies have highlighted the importance of neutrophils in the pathogenesis of these infections, as well as their potential prognostic value. However, the specific role and prognostic value of neutrophils in infections caused by K. pneumoniae have not been as extensively studied. Moreover, there is a lack of data that specifically delineates the clinical profiles of neutrophils during K. pneumoniae infections, especially among critically ill individuals whose immune response is frequently dysregulated and may exhibit distinct neutrophil dynamics. Giving the importance of understanding neutrophil clinical attributes for effective clinical management, there is a pressing need for focused studies that explore the behavior of neutrophils and their influence on outcomes in severe patients with K. pneumoniae infections.

In the present study, we present a detailed analysis of neutrophil characteristics and clinical trajectory in severe patients with K. pneumoniae infections using two extensive databases: the Medical Information Mart for Intensive Care (MIMIC)-IV and the eICU Collaborative Research Database (eICU-CRD). Moreover, we thoroughly investigated the association between neutrophil levels and mortality among the enrolled patients, which holds significant implications for prognostic assessment and clinical management.

K. pneumoniae infections pose a significant challenge due to its elevated morbidity and mortality rates. Considering the limited clinical understanding of neutrophils’ involvement in such infections, we aimed to address this knowledge gap by comprehensive analyses using two large clinical databases. Our findings revealed that non-survivors had significantly higher neutrophil counts compared to survivors. Patients with respiratory infections, without liver disease, and below 60 years of age exhibited higher neutrophil levels and had different dynamic profiles. The peak levels of neutrophils were observed at the time of admission or approximately 1-2 weeks later. Importantly, neutrophil counts appeared to follow a “U”-shaped relationship between neutrophil counts and hospital mortality. Patients with a neutrophil count ≥ 8.0×10⁹/L emerged as a subgroup of particular concern during hospitalization, as this parameter was identified as an independent risk factor for hospital mortality in patients with K. pneumoniae infection. These findings contribute to our understanding of the pathophysiology of K. pneumoniae infections and assist clinicians in identifying patients who may require closer monitoring and more intensive management strategies.

Our findings revealed a crucial aspect regarding the timing of neutrophil peaks, which occurred at the time of admission or approximately 1-2 weeks later. This observation reflects a dynamic pattern of neutrophil response during the course of infection and holds significant clinical implications in the management of K. pneumoniae infected patients. In the human body, the circulatory lifespan of neutrophils averages around 5.4 days (Pillay et al., 2010). However, during inflammatory processes, the longevity of neutrophils can be magnified manifold, ensuring the recruitment of primed neutrophils to the precise sites of inflammation (Koenderman et al., 2022). Elevated levels of neutrophils remained detectable even at 7 to 14 days post-infection. Of particular interest, the rapid recruitment of neutrophils within the initial 48 hours following infection does not exhibit a direct correlation with a reduction in bacterial burden (Ahn et al., 2016; Peñaloza et al., 2019; Wang et al., 2020). The resolution of inflammation involves a multifaceted interplay between anti-inflammatory and pro-resolving phases, which can influence the generation and recruitment of neutrophils. This intricate balance between pro-inflammatory and anti-inflammatory factors throughout the progression of infection, coupled with the re-emergence of pathogens, likely contributes to the dynamic profiles exhibited by neutrophils (Ji and Fan, 2021; Bruserud et al., 2023).

The observation of a distinctive ‘U’-shaped relationship between neutrophil levels and hospital mortality is an interesting finding, which suggests that there might be an optimal range of neutrophil counts for fighting K. pneumoniae infections. Notably, while higher and lower levels of neutrophils were both correlated with increased mortality rates, this association does not necessarily imply a direct causative relationship. In present study, non-survivors exhibited higher neutrophil counts than survivors. Furthermore, patients with elevated or decreased neutrophil levels (groups of level 1, 3, and 4) exhibited increased hospital and ICU mortalities compared to the reference group (group of level 2). This finding likely reflects the intricate interplay between neutrophils and other factors in the context of severe infections. While an increase in neutrophil counts, or neutrophilia, is a typical response to bacterial infections like K. pneumoniae and is generally perceived as advantageous as it indicates the host’s active immune response, the scenario in severe infections is less clear-cut. In such cases, very severe infections might precipitate either an increase or a decrease in neutrophil counts and functions. This can lead to an immune system malfunction, coupled with multiple organ dysfunction, which may further intensify disease progression (Pechous, 2017; Metzemaekers et al., 2020; Zanza et al., 2022). As neutrophil counts are influenced by a multitude of factors, including the severity of the infection, the host’s immune response, and the overall clinical condition, it is essential to interpret neutrophil levels within the broader clinical context.

Our study identified neutrophil counts were independent risk factors for hospital mortality. This finding aligns with previous research (Lv et al., 2022). Importantly, we validated a critical cut-off value at 8.0×10⁹/L, which serves as significant biomarker for differentiating patients at increased risk of mortality due to elevated neutrophil levels. These findings emphasize the necessity for close surveillance of neutrophil dynamics in the clinical setting, especially in cases where they exceed the established cut-off. Integrating this biomarker with other clinical data empower healthcare professionals to make more informed decisions about patient management. This facilitates the implementation of targeted therapeutic interventions, encompassing early antimicrobial therapy and adjunctive treatments, thereby optimizing patient care and outcomes.

In current study, patients with respiratory infections caused by K. pneumonia exhibited higher levels of neutrophils compare to those with bloodstream infections and other sites of infections. Neutrophils in K. pneumoniae patients with different infection sites have distinctive features and dynamic clinical trajectories. Previous studies have demonstrated that the lungs serve as a natural reservoir of mature neutrophils, which can be rapidly mobilized to sites of inflammation or infection (Ostrand-Rosenberg et al., 2023). Furthermore, it has been suggested that all blood neutrophils undergo a temporary pulmonary sequestration due to the lungs receiving the entire cardiac output (Summers et al., 2010; Fay et al., 2016; Pararajasingam et al., 1999). Considering these factors, the higher neutrophil levels observed in patients with respiratory infections may be attributed to the recruitment and accumulation of neutrophils in the lung tissues. Since neutrophil counts have been identified as an independent risk factor for hospital mortality, it is necessary to promptly identify the site of infection, particularly focusing on patients with respiratory infections.

In present study, patients who had liver disease or were aged ≥ 60 years displayed lower neutrophil levels in comparison to the control group consisting of patients without liver disease or younger than 60 years old. Concurrently, we conducted a comprehensive analysis, comparing and illustrating the fluctuations of neutrophil levels across both groups. This analysis provided a detailed depiction of neutrophil dynamics in relation to liver disease status and age demographics. The liver plays a central role as an immunological organ, housing various myeloid immune cells, including neutrophils, macrophages, and Kupffer cells (Kubes and Jenne, 2018; Ahmed et al., 2021). Therefore, the presence of liver disease may contribute to a decrease in neutrophil levels. It is important to note that while the absolute number of neutrophils does not vary significantly with age, there is evidence to suggest that aging is associated with impaired phagocytosis, chemotaxis, and superoxide generation functions of neutrophils (Hornigold et al., 2022; Lewis et al., 2022). Additionally, elderly patients may experience decreased anti-pathogen activity due to increased apoptosis of neutrophils, resulting in a higher susceptibility to more frequent and severe infections (Hornigold et al., 2022; Wen et al., 2022).

Despite significant findings regarding the dynamic profiles of neutrophils and their association with hospital mortality, several potential limitations in this study should be acknowledged. Firstly, retrospective analyses inherently possess limitations in establishing causal associations definitively. A more comprehensive understanding of the immunological mechanisms encompassing both the quantitative dynamics and functional integrity of neutrophils is warranted. Secondly, the database lacked comprehensive data on inflammatory biomarkers such as C-reactive protein and procalcitonin, which precluded any in-depth analysis or comparison of these markers with neutrophil counts in this study. Thirdly, while our findings are focused on primary K. pneumoniae infections, the potential influence of coinfections and reinfections on neutrophil counts was not addressed. Further studies should take these factors into account to refine the understanding of neutrophil dynamics in the context of infectious diseases. Lastly, while the statistical association between hospital mortality and neutrophil levels has been demonstrated, it is essential to include data from other clinical databases that help confirm the robustness of the associations. Meanwhile, its practical application in clinical practice should be evaluated across different clinical scenarios.

In summary, neutrophils in K. pneumoniae infected patients have distinctive features and dynamic clinical trajectories. Closely monitoring severe patients infected with K. pneumoniae upon admission and during the first 1-2 weeks after admission is of utmost importance. This is particularly significant for patients with a neutrophil count exceeding 8.0×10⁹/L, as elevated neutrophils levels were correlated with a poor prognosis in individuals with K. pneumonia infection. To effectively manage severe cases of K. pneumoniae infections, it is essential to further investigate the intricate mechanisms of neutrophils during K. pneumoniae infections.