Exploring the diagnostic markers of early sepsis in cirrhotic patients with CAID had emphasized the significance of cell immune markers in timely detection in the ICU setting.
The current study had demarcated significant elevations in ordinary sepsis markers like CRP, PMN counts, CRP, lactate and sepsis index (P=0.001) in ICU patients with sepsis. This is the usual picture of cirrhotic septic patient in ICU (13).
CRP, being an acute-phase reactant produced by the liver during inflammation, is recognized as a valuable marker, known for its characteristic surge during infection, often rising significantly (14). Additionally, D'Abrantes. et al, emphasized the predictive value of plasma lactate levels in assessing the prognosis of sepsis (15). Hyperlactatemia and lactic acidosis, as observed in our study, may result from increased lactate production due to impaired tissue oxygenation, stemming from reduced oxygen delivery or disorders in oxygen utilization, ultimately leading to heightened anaerobic metabolism (16).
However, the need of early predictors of occurrence of sepsis and mortality in patients with liver cirrhosis was only conducted through investigating various immune cell markers, including PMN CD64%, PMN CD64 MFI, PMN HLA-DR%, Mono CD64%, Mono CD64 MFI, Mono HLA-DR MFI, and Sepsis Index (SI). Statistically significant elevations in Mono CD64%, Mono CD64 MFI, and SI were observed in cirrhotic patients, particularly those with sepsis, indicating altered immune responses and signifying their prognostic value.
The study proposed several markers for early sepsis prediction in cirrhotic patients, including Total Leukocyte Count (TLC) in ascitic fluid, PMN count, Lymphocytes count, CRP, S. Lactate, and immune cell markers such as Mono CD64%. The diagnostic accuracy of these markers was assessed with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy.
One notable finding was the potential of CD64 as a diagnostic marker for sepsis when used in combination with other markers. This implies that the accuracy and reliability of sepsis diagnosis could be enhanced by considering multiple markers simultaneously. This aligns with the idea that sepsis is a complex syndrome with diverse manifestations, and a combination of markers may provide a more nuanced and accurate representation of the patient's condition.
The sensitivity for sepsis and non-sepsis was 100%, with specificities of 90.00% and 87.24%, respectively, making nCD64 a highly sensitive and specific marker for sepsis diagnosis. Prior studies by Davis et al. (2006), Hsu et al. (2011), and Dal Ponte et al. (2018) have underscored the superior diagnostic performance of nCD64 over traditional markers like white blood cell count, erythrocyte sedimentation rate, and CRP (17-19). Icardi et al. (2009) further highlighted the predictive value of nCD64 with a sensitivity of 94.6% and a specificity of 88.7% (20). Lewis et al. (2009) and Zhou et al. (2019) emphasized the discriminatory power of CD64, particularly in distinguishing septic shock patients (21-22). Additionally, the combination of nCD64 and CRP has been shown to enhance sepsis diagnosis (23). Chauhan et al. (2017) advocated for flow cytometry analysis of nCD64, asserting its superiority in sepsis detection (24). Neutrophils' role in liver regeneration, as elucidated by Tang et al. (2021), further adds a layer of understanding to the complex interplay between neutrophils and liver function post-hepatic resection (25).
In a recent study by Verma et al. (2022), the mean fluorescence intensity (MFI) of neutrophil CD64 (nCD64) was markedly elevated in both sepsis and non-sepsis groups compared to controls, demonstrating the diagnostic potential of nCD64 (14).
In this study, a significantly elevated total bilirubin (TB) in septic patients compared to the non-septic cirrhotic group, pointing to the role of sepsis in this elevation. Cholestasis induced sepsis (CIS) differs from hepatic cellular dysfunction associating cirrhosis in its gradual onset post-ICU admission, marked by rising bilirubin, alkaline phosphatase, and gamma-glutamyl transferase levels. Diagnostic criteria for CIS lack universality, but in clinical practice, a bilirubin level exceeding 2 to 3 mg/dL and elevated alkaline phosphatase and gamma-glutamyl transferase are often considered (26). CIS encompasses the following factors: (i) diminished transport of bile acids and organic anions, accompanied by a decline in ATP-stimulated transport; (ii) a decrease in bile acids excretion or reduced basal bile flow and basal bile salt excretion induced by TNF-α; and (iii) a reduction in the uptake of bile salts by hepatocytes, coupled with impaired secretion of bile acids into bile (27).
Cirrhotic patients with sepsis demonstrated elevated ALBI scores, MELD (UNOS), and MELD-Na values in comparison to non-septic cases (28). This observation aligns with the understanding that sepsis is a significant milestone in the progression towards mortality, and all these scores serve as reliable indicators of short-term survival (29). Elevated bilirubin due to CIS contributes greatly to these elevations. Also, albumin, which is significantly reduced in cirrhosis-sepsis cases might be an important incriminator. Hypoalbuminemia is more common in sepsis patients, particularly those with septic shock, due to the leakage of protein-rich fluid caused by capillary dysfunction. Previous research indicates that low serum albumin levels are associated with higher mortality risk in sepsis (30-32).
Mono CD64 MFI (94.29%) stands out as having the highest sensitivity, which is crucial for identifying true positive cases. The combined use of CRP, S. Lactate, Mono CD64%, and Mono CD64 MFI revealed the highest AUC (0.929). yielding a better overall diagnostic performance. Additionally, this combination had the highest specificity needed for minimizing false positives.
In summary, the combined use of CRP, S. Lactate, Mono CD64%, and Mono CD64 MFI has a higher AUC and shows promising sensitivity, specificity, PPV, and NPV, making it a potentially effective diagnostic tool for sepsis.
Furthermore, predictive models based on univariate and multivariate analyses highlighted key predictors for early sepsis detection in cirrhotic patients, emphasizing the significance of factors such as creatinine, urea, sodium, total bilirubin, polymorphonuclear leukocytes (PMN), lymphocytes, Mono CD64%, Mono CD64 MFI, C-reactive protein (CRP), S. Lactate,
This study's emphasis on the diagnostic potential of CD64, especially in combination with other markers, suggests a step towards developing more effective and comprehensive diagnostic strategies for sepsis. By leveraging multiple indicators, healthcare professionals may improve their ability to identify sepsis at an early stage, facilitating prompt and targeted interventions for improved patient outcomes. This nuanced approach aligns with the evolving understanding of sepsis as a syndrome with diverse immunological and clinical features, requiring a multifaceted diagnostic approach for optimal management.
In addressing the limitations of this study, such as the sample size and potential confounding factors, we delve into recommendations for future research. It is suggested that future investigations should focus on a more in-depth exploration of specific immune markers and their dynamics in larger size studies on patients with cirrhosis.
This study pioneers in presenting comprehensive findings on the correlation of immune-related markers with sepsis in a cirrhotic cohort, showcasing the potential of these markers as early indicators of early sepsis management in cirrhotic patients, emphasizing the broader relevance of the findings in critical care settings.
Conclusively, compared to traditional markers like CRP and S. Lactate, CD64 has comparable diagnostic value for distinguishing sepsis in cirrhotic patients with the advantageous timely character allowing prompt management for this high risky critical cohort.