Introduction
The global incidence of carbapenem-resistant Klebsiella pneumoniae (K. pneumoniae) infections continues to escalate alarmingly. In the year 2021, China reported a CRKP detection rate of 27.1%. According to statistics from the China Antimicrobial Surveillance Network (CHINET, http://www.chinets.com/), the prevalence of imipenem-resistant K. pneumoniae in the country soared from 2.0% in 2005 to an alarming 24.8% by 2021, while resistance to meropenem jumped from 2.9% in 2005 to 26.0% in 2023. In clinical samples analyzed, it was observed that a higher number of patients presenting with sputum or bronchoalveolar lavage fluid infections surpassed those with bloodstream infections. Furthermore, mortality rates resulting from CRKP infections display alarming variability worldwide, with figures reported at 44.82% in Asia, 50.06% in Europe, 46.71% in South America, and 33.24% in North America. The rapid spread of CRKP, in conjunction with a drastic reduction in effective treatment options and increased treatment failure rates, creates a formidable challenge for at-risk patients, placing immense strain on global healthcare systems. Thus, it has become a focal point of international concern. As the prevalence and associated lethality of CRKP infections surge, the urgent need for early identification of prognostic factors for in-hospital 30-day mortality cannot be overstated, alongside the implementation of effective interventions to reduce mortality in these vulnerable individuals.
According to data from 2016, the World Health Organization estimated that more than 1.9 billion adults, representing 39% of the adult population, were classified as overweight, with 650 million deemed obese—accounting for 13% of all adults. Numerous studies have illuminated a strong link between overweight and obesity with various complications, severity, and mortality rates associated with infectious diseases, notably influenza A and COVID-19. The conventional measure for assessing overweight and obesity in adults, the Body Mass Index (BMI), is widely utilized; however, it fails to differentiate between skeletal muscle tissue (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Such distributions of muscle and fat tissue tend to vary considerably according to age and gender, with women typically exhibiting a higher fat percentage at the same BMI compared to men, and older individuals often experiencing a reduction in SM when compared to younger populations. Abdominopelvic computed tomography (CT) imaging, when paired with modern noninvasive postprocessing technologies, offers a more precise and reliable means of distinguishing between and quantifying SM, VAT, and SAT. Notably, there are significant differences in cellular composition, morphology, receptor profiles, endocrine functions, and metabolic characteristics between visceral and subcutaneous adipocytes. VAT refers to the adipose tissue surrounding crucial human organs (including the omentum, mesentery, retroperitoneum, and perirenal areas) and serves essential protective, stabilizing, and supportive roles for internal organs. Contrastingly, SAT is found just beneath the skin and over the fascia, primarily functioning in insulation and energy storage.
This study primarily sought to explore the relationship between CT-derived body composition metrics (including VAT, SAT, total adipose tissue (TAT), and SM) and 30-day mortality rates among patients suffering from CRKP pulmonary infections. The research involved constructing Cox regression models and personalized nomogram frameworks aimed at predicting 30-day mortality risk in these patients, with the ultimate goal of aiding healthcare providers in assessing patient conditions and implementing effective interventions to avert adverse clinical outcomes.
Materials and Methods
Study Design and Patients
This retrospective cohort study was conducted at the First Affiliated Hospital of Wenzhou Medical University, a reputable tertiary and teaching institute situated in the southern province of Zhejiang, China. The focus of this investigation was on patients with confirmed CRKP pulmonary infections, substantiated by etiological evidence and clinical symptoms, who also had abdominal computed tomography (CT) scans performed. The study’s data collection period spanned from January 1, 2016, through December 31, 2020.
Patients included in the study were those whose initial culture of CRKP was obtained from sputum or bronchoalveolar lavage fluid during their hospitalization. The diagnostic criteria for CRKP infection were established through a combination of clinical symptoms, signs, laboratory indicators, and imaging reports. Abdominopelvic CT images were examined from a 15-day window surrounding the first positive culture of CRKP. Exclusion criteria noted were applied to individuals under 18 years of age, patients with incomplete clinical data or whose families refused further treatment, and cases where abdominal CT evaluations were compromised by severe motion artifacts or technical difficulties (including limited visual fields or contrast media application).
CRKP was identified as K. pneumoniae strains with a minimum inhibitory concentration (MIC) of ≥ 4 mg/L to meropenem, imipenem, and ertapenem, adhering to guidelines established by the Clinical and Laboratory Standards Institute (CLSI).
Variables and Definitions
Comprehensive demographic data (including age and sex), pre-existing conditions, illness severity indicators (Charlson comorbidity index and Sequential Organ Failure Assessment (SOFA) scores), treatment interventions (such as invasive surgeries, mechanical ventilation, vasopressor administration, and renal replacement therapy), laboratory results, other infection sites, concurrent viral or fungal infections, body composition metrics (including SM, VAT, SAT, and TAT), antibiotic regimens, and patient outcomes were meticulously extracted from electronic medical records for detailed analysis.
The study commenced observationally with the date of the first positive culture of CRKP isolated from either sputum or bronchoalveolar lavage fluid. Laboratory indicators and SOFA scores were recorded within 48 hours of the CRKP culture detection. For patients whose weight data were missing due to severe illness, interpolation methods were employed to estimate their weight. Vasopressor treatment, mechanical ventilation, renal replacement therapy, and antibiotic therapies were considered pertinent only if administered for more than 48 hours in the preceding 30 days.
Appropriate initial antibiotic therapy was defined as the provision of at least one active drug for a minimum of 48 hours based on the in vitro susceptibility testing of K. pneumoniae. Invasive procedures performed within one month prior to or following the onset of infection were included under the surgical category for analysis.
In the context of prevailing conditions in China, where familial consent may be less forthcoming, cases in which patients interrupted treatment due to deteriorating health and were subsequently discharged voluntarily during hospitalization were classified as cases of mortality.
Assessment of Body Composition
A thorough examination was dedicated to a singular cross-sectional CT image focusing on the complex anatomy at the third and fourth lumbar (L3/4) intervertebral disk level. This assessment aimed to identify and quantify muscle tissue, subcutaneous fat, and visceral fat using a specifically designed multi-platform semiautomatic software tool (Syngo Volume tool, Siemens Healthcare, Munich, Berlin, Germany). Notably, the body composition analyses derived from the L3-L5 levels were found to correlate most strongly with overall body fat and muscle mass. The segmentation and quantification processes for specific regions of interest (ROI) relied on standardized Hounsfield unit (HU) thresholds: 40 to 100 HU for skeletal muscle and −190 to −30 HU for fat tissues.
Trainings were provided to two experienced physicians who delineated proper CT planes independently. They manually mapped the regions of interest in CT images and performed evaluations utilizing the semi-automated software. For accuracy, two measurements were taken for each patient, and the average values were recorded accordingly.
Statistical Analyses
Data statistical analyses were executed utilizing R version 4.1.2 and IBM SPSS Statistics 25.0. Continuous variables were presented as means ± standard deviations (for normally distributed data) or as medians and interquartile ranges (for non-normally distributed data), with comparisons facilitated using Student’s t-test or Mann–Whitney U-test, respectively. Categorical variables were assessed using chi-square tests or Fisher’s exact test, with findings presented as frequencies and percentages.
All statistical tests were two-tailed, aiming for a significance threshold of P < 0.05. Receiver Operating Characteristic (ROC) curve analysis was performed to ascertain optimal cut-off points for TAT and VAT. Additionally, a nomogram designed to predict 30-day mortality was constructed based on univariate analysis results and pivotal clinical prognostic factors, intended to calculate survival probabilities in patients battling CRKP pulmonary infection.
Results
Patient Characteristics
A total of 89 eligible participants were recruited based on predefined inclusion and exclusion criteria from the First Affiliated Hospital of Wenzhou Medical University during the designated study period. Among this cohort, there were 71 men and 18 women, with detailed demographics, clinical characteristics, laboratory indicators, body composition parameters, and treatment regimens summarized in Table 1.
Notable distinctions were evidenced in SOFA scores, vasopressor and mechanical ventilation utilization, along with variances in total adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue amidst survival and non-survival groups of patients with CRKP pulmonary infection. In terms of antibiotic treatment, 13 individuals received polymyxin B-based regimens, whereas 52 were subjected to tigecycline-based combination therapy; however, comparisons concerning survival and mortality groups revealed no substantial differences.
Impact of Body Composition on Survival
Statistical evaluations involving 89 patients assessed through abdominal CT at the L3/4 intervertebral disk indicated significant variances in Total Adipose Tissue (TAT) (P = 0.002), and Visceral Adipose Tissue (VAT) (P = 0.022) levels between survival and mortality subgroups (Table 1). The multivariate regression model analyzing the relationship between body composition parameters and 30-day mortality showed that lower levels of TAT and VAT correlated positively with more favorable clinical outcomes, after adjusting for factors like cardiovascular health, vasopressor use, and SOFA scores. Notably, skeletal muscle area measurements did not reveal statistically significant differences within the regression models.
Moreover, analyses examining the link between adipose tissue metrics and clinical prognoses via the Log rank test indicated that high levels of VAT correlated with an elevated death risk when contrasted with lower VAT levels concerning both 30-day all-cause mortality, alongside CRKP infection-specific mortality. The optimal cut-off thresholds identified for high-VAT and high-TAT were 11.59 and 22.1, respectively, when considering 30-day all-cause mortality. Likewise, the cut-off values for high-VAT and high-TAT were registered at 11.57 and 22.62 respectively regarding mortality attributed to CRKP infection.
Risk Factors for 30-Day Mortality
Following adjustments for significant comorbidities and clinical characteristics, Cox regression evaluation indicated that male gender (adjusted HR = 4.37; 95% CI = 0.96–19.92, P = 0.06), vasopressor application (adjusted HR = 3.65; 95% CI = 1.04–12.85, P = 0.04), and VAT levels (adjusted HR = 1.16; 95% CI = 1.01–1.34, P = 0.03) independently emerged as risk factors for 30-day all-cause mortality among the studied populace (Table 3). Leveraging outcomes from comprehensive multivariate Cox regression analysis in conjunction with variables closely linked to clinical prognoses, nomogram models were devised to visually estimate the likelihood of survival over 30 days for patients battling infections due to CRKP. By enumerating various risk factors, this nomogram translates intricate regression findings into accessible visual graphs, ultimately easing the assessment of patient prognoses. Importantly, SOFA scores and VAT were recognized as critical components in forecasting both 30-day all-cause mortality and specific mortality attributable to CRKP infections in patients with CRKP pulmonary infections (Figures 3 and 4). The calculated C-index for the nomogram was determined to be 0.771 and 0.756, respectively.
Discussion
This study addresses the links among CT-quantified abdominal visceral fat, subcutaneous fat, total fat area, and muscle mass concerning 30-day clinical outcomes in patients with CRKP pulmonary infections. Initial assessments revealing clinical feature comparisons alongside univariate Cox regression analyses highlighted that increased VAT correlates with heightened 30-day all-cause mortality risk. Following adjustments for vital comorbidities and baseline characteristic disparities, both multivariate Cox regression analysis and the creation of a 30-day mortality nomogram revealed that VAT retains vital predictive significance for prognosis. Furthermore, our findings underscore that VAT emerged as a more pivotal predictor of 30-day all-cause mortality, contrasted with TAT specifically in patients attached to CRKP infections, overturning previous studies’ notes of significance associated with TAT. Coupled with this, the augmented VAT was definitively implicated as a mortality risk factor within this cohort of infected patients. This added risk can be traced back to factors including persistent inflammation, an attenuated immune response, and adipose tissue possibly serving as a reservoir for pathogens.
Research regarding COVID-19 has drawn close connections between excessive VAT and delays in the immune response and chronic inflammation along specific pathophysiological pathways. Furthermore, distinctions exist in the protein expression rates between visceral and subcutaneous fat cells, leading to diverse cytokine synthesis and secretion. Visceral fat is observed to hold greater arterial supply and nerve distribution, contributing to a higher density of immune cells accompanied by augmented pro-inflammatory factor secretion, including interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), along with other critical inflammatory mediators. These responses could significantly influence biological processes like host immune responses and inflammatory responses in infections. Consequently, this accumulation of VAT seems to perpetuate a state of chronic inflammation, fostering exaggerated immune responses, particularly in the context of pulmonary infections, significantly affecting prognosis. Additionally, VAT is implicated in the exacerbation of the complement system activation while contributing to ongoing chronic inflammatory processes. Numerous studies have indicated that obesity hampers the action of CD8+ memory T cells responding to infections, thereby enhancing the severity and mortality from respiratory diseases like influenza and COVID-19. In conclusion, increased VAT levels correlate with elevated pro-inflammatory responses and reduced immune efficacy, leading to adverse outcomes among patients grappling with CRKP lung infections.
This research carries with it acknowledged constraints. Primarily, it remains a single-center retrospective study limited by a relatively small cohort sample size. Moreover, the exclusion of individuals with CRKP pulmonary infections who did not undergo CT scans or suffered CT image artifacts may pose a risk for sampling bias and restrict broader applicability of the results. Finally, patients suffering from CRKP infections typically present with comorbidities and advanced conditions, indicating that older age combined with serious health issues may contribute to enhanced risks for all-cause mortality.
Despite these limitations, this study stands as the inaugural investigation into the relationship between CT-quantified body composition metrics and prognosis among patients with CRKP infections. The creation of the nomogram provides a pragmatic tool for clinicians aiming to evaluate the prognosis of severely infected individuals, assisting in effective interventions geared toward improving patient survival. The hope is that future inquiries in this field will encompass broader, high-quality studies to further enrich and substantiate these findings.
Conclusion
The study’s outcomes emphasize the crucial role of CT-estimated visceral adipose tissue levels in prognostic evaluations of patients suffering from CRKP pulmonary infections. Those presenting with elevated VAT levels demonstrate a notably increased risk of mortality within a 30-day timeframe compared to patients with lower VAT levels, while SAT and SM did not emerge as significant predictive factors. Additionally, the research isolated male gender, vasopressor treatment, and increased VAT levels as independent risk factors for 30-day all-cause mortality in this patient group.
Data Sharing Statement
Ethics Approval and Consent to Participate
This study received ethical approval from the Ethics Committee in Clinical Research at the First Affiliated Hospital of Wenzhou Medical University (Acceptance Number: KY2021-R096). Informed consent was waived by the Ethics Committee, recognizing the observational nature of the study focused on microorganisms without patient interventions, and all data collected was anonymized and de-identified. All experimental methodologies adhered to applicable laws, institutional guidelines, and the ethical precepts outlined in the Helsinki Declaration.
Acknowledgments
Our sincere thanks to the First Affiliated Hospital of Wenzhou Medical University for their invaluable support.
Funding
This investigation received financial backing from the National Natural Science Foundation of China (grant number 82102457), the Zhejiang Provincial Natural Science Foundation (grant number LQ22H200004), the Zhejiang Provincial Science and Technology Plan Project (grant number 2023RC046), and the Planned Science and Technology Project of Wenzhou (grant number Y20210110) alongside the Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province (grant number 2022E10022).
Disclosure
The authors declare no competing interests related to this research endeavor.
References
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Introduction
Welcome to the thrilling world of microbiology where we’ve got a real heavyweight on our hands: the rising star of the infection scene, carbapenem-resistant Klebsiella pneumoniae (CRKP). Yes, folks, while you were Netflix binging, this little troublemaker has been busy multiplying. In China alone, CRKP has gone from a mere blip on the radar to a staggering detection rate of 27.1% in 2021. I’d say that’s like going from a minor sitcom to winning an Emmy!
What’s got us seriously biting our nails is the mortality rate these pesky infections are racking up. Asia reports a harrowing 44.82% mortality, while Europe is close on its tail with 50.06%. That’s some heavy-duty statistics that could be mistaken for a horror movie plot! It’s clear, our public health systems are grappling with a beast that not only comes with limited antibiotics but also brings the grim reaper along for the ride. So naturally, early identification of prognostic factors for mortality is as critical as my morning coffee—essential!
And in the name of science, let’s not overlook the body statistics: a whopping 39% of adults are classified as overweight. You see, body mass index (BMI) might sound like the new hipster café down the street, but it can’t differentiate the athletic from the…erm…slightly overindulgent. Hence, this study aims to tackle the correlation between CT-derived body composition (focused on visceral and subcutaneous fat) and the fate of those battling CRKP pulmonary infections. Spoiler alert: it’s going to be messy!
Materials and Methods
Study Design and Patients
We set up shop in the First Affiliated Hospital of Wenzhou Medical University—the influenza of hospitals, if you will—where we focused on those brave souls who frequented our wards with CRKP pulmonary infections between January 2016 and December 2020. Now, many factors may seem insignificant, but if you want to level up your health game, you need to think about what you bring to the table…or in this case, what you bring into the hospital: the sputum or bronchoalveolar lavage fluid—yes, that’s your exclusion criteria right there! If you walked in underage or without a CT scan, you wouldn’t make the cut. Tough crowd, eh?
Variables and Definitions
Our keen eye has scrutinized data about demographics, existing disease, and even the surgical procedures undertaken – it’s like the busy writing-room of a sitcom; a lot’s happening behind the scenes! And for those fascinated by definitions, we’ve defined CRKP as that devilish K. pneumoniae with a Minimum Inhibitory Concentration (MIC) ≥ 4 mg/L. Who needs coffee when you have riveting microbiological definitions?
Assessment of Body Composition
Next, we performed some serious imaging wizardry on cross-sectional CT images taken around the lumbar spine regions. This allowed us to capture the inner landscape where we’ll measure our protagonist: the adipose tissue, henceforth known as fat—those “fluffy” friends that everyone secretly despises!
For the technophiles, we utilized the fancy Syngo Volume tool to classify our contestants: subcutaneous fat (the cushiony stuff), visceral fat (you know…the creepy fat around the organs), and skeletal muscle (aka what we pretend to work on at the gym). Ah yes, the metrics of health.
Statistical Analyses
With tools sharper than my last pun, we crunched the numbers using R and IBM SPSS—don’t worry, not actual IBM robots, just very smart algorithms (unlike my last relationship where I lost the plot). We dove into continuous variables and categorical variables like mathematics’ version of ‘Survivor’. What we ended up with was enough data to keep a statistician up at night, debating significance levels and cut-off points.
Results
Patient Characteristics
Of our grand 89 subjects, most were of the masculine stripe—71 men versus 18 women. It’s safe to say this could be titled ‘A Study of the Boys.’ And let us just say, significant differences were noted in various parameters—like the SOFA scores—which sound like a fancy couch but actually stands for Sequential Organ Failure Assessment. Honestly, could we be any more dramatic?
Impact of Body Composition on Survival
As the ink dried on our results, we saw glaring indications that lower Total Adipose Tissue (TAT) and Visceral Adipose Tissue (VAT) associate with better survival rates. Yes, you heard that right! And if you were wondering, the same could not be said for our skeletal muscle areas. So if anyone tells you muscles equate survival, you can now confidently say, ‘Not in this context!’
Risk Factors for 30-Day Mortality
A close examination of our data revealed that risk factors included being of the male variety, consumption of vasopressors—a bit like those energy drinks that promise you’ll conquer the day—and of course, having a hefty amount of VAT. Our analysis speaks clearly: keep those visceral fat levels low if you’re wanting to bypass the 30-day mortality menu.
Discussion
Diving deeper, our findings emphasize visceral adipose tissue being the real villain here. If only those sneaky fat cells would stop playing coy with inflammatory responses… The crux of the matter is that high VAT levels link to poorer outcomes among CRKP patients, likely due to various cybernetic issues like chronic inflammation. You just can’t make this stuff up!
Let’s just say obesity isn’t just the extra slices of pizza on a Friday night; it seems to significantly impact our immune responses and overall health. So the takeaway? Keep VAT at bay because your waistline isn’t just a number; it’s a life saver! And with every byte, we risk a lot more than just our dinner plans!
Conclusion
In summary, our study, while filled with complex scientific dialogue, comes down to this—if you want to help save lives from CRKP infections, pay attention to that visceral adipose tissue. Yes, it turns out fat is more than just a physical characteristic; it’s a potential death sentence in the context of these infections. Also, male gender, vasopressor use, and high VAT? Watch out—those are your risk factors knocking at your door!
Data Sharing Statement
We’ve got the information you need but don’t ask us to share it willy-nilly! Seriously, data sharing has its protocols, and we’ll only share in accordance with guidelines.
Ethics Approval and Consent to Participate
No ethical faux pas here! obtained proper approvals from the Ethics Committee of First Affiliated Hospital of Wenzhou Medical University. Informed consent might have been waived, but that’s because we made sure all personal information was locked down tighter than a famous celebrity’s secrets.
Acknowledgments
We tip our hats to the First Affiliated Hospital of Wenzhou Medical University for their unwavering support.
Funding
Financial backing was provided by a slew of foundations, making sure our research didn’t go hungry.
Disclosure
Rest assured, our authors are free of competing interests—no funny business here!
References
There’s a treasure trove of research backing this study, and trust me, you wouldn’t want to miss the academic rabbit hole we’ve published.
